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1. CA2653811 - FILMS AND PARTICLES

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]
FILM.~.' AND PARTICLE ~ ~ S CROSS-REFERENCE "1'O RELATED APPLIC:.ATIONS 60. 8,)9,334, f'D.lett i::il NSC3S' 3 ~ 21006, ie7d, U.S. 11ri7visit?#.es . pphi:at.Ãi)Ti :3C:i'i%i. No. 601,'844,, E" filcd on Sz.~,~3.i::)1ba 33 2,006 ?'S1h#:+::li are botl3 Ã#ic43T'',~:?~.?rw1tc4;: s3eiC:Ã#e by al.,oem;kÃ;i i:1c.il"
entà rL~ty.
s.,TATL>ME;.Y.8\ A$3 TO FEDERALLY SPOt vSOR3`:-DRE.3Y:fARe.,I3 i + This :a?v..Ãl-tioa3 03'Ã.#;i made with Gi?v('mnS;)t support u?:.t:t,...
US. Al'?:.ay,'CE`t}pm`Ã:rho 2-'iJ`r06. 3 iic `3~iYenmiva~Ãf. ~:t t ~~ has ,:~ ~ ~Z,i t tit i~ r~,h2 ~
Ct 3 the ? ~3#~S1.,~ jt-tif:~~. ~`.
ag#i.emG#:x No. 1. No. a~~ ~~D'^F '^\r+...
f'IEL~ OF TIIE .INVEN'1'.ION ~s,?rr .:: .i C+ cut::,.i>7'C.i'E'!:. +"i fiTC 4.::: , sYI)kh.` C r Eant~~S r i11Id p3'ss4s to ptpsir[: pol }m?i:#' bc.S \li i':.FF'~.i:,.t:s fG>.~, and f, ~ 3x~::t; ~.;~t~;.~l~)S)~i3'~Ã~>Jan, t2:t"FC~,t7it~F~.GS~~;~ #~,?#' delivery :S'~.;~3t;.':'.s.
BACKGROU"Ni3 ormEINVENT10N
N,.c.:I`:cine t,%#~`.~Ãt!#3<3:i3.1+` Ã.Et1li,_.#y.~ or "+i:q,sa,4?.l i>1.uven¾1Z}:.)s, ft?r the treat3)?eT.ir of disease. Specific ; s[,;``;tÃ.i2g or localization of 3,:`,:#3 #1.21i.:.()l~:g.k.~?:: ~)13ii.i<..tgÃO~t#; agents to d..5;.?cd oi,~:`afs.? and fissile is a complex &'allu'1?,~,W.,e, I
W ::hawn?p.i, Q-uwoà .", a lec..ef?.i7.4 cause of Ci::=<:ith fim, bot,] mt':i and WE?men lii thÃ. United
States (Jem<?.z et c ..,
i.Lli.t :i = :>~ j StÃi~e:Ã?t#Ã1 ~.7"tit3.f,)~.:ia6, c1.I~'5~~.l.~.l.ii,~'?'wi1l at.54'L:tlt?23. : ~ o"lieicii i\S FS I ;.~1# #<.i'
\eat>ce)..~cc\rF.#,enoc $.~Ãndl\)m; sL{E il. va . t.L.e(Vtn{ei.tf.i:o7. 4'ont.tA..,az}.`~,'f `s.i;..ZA1.,rF 4aww4-CtAE-4n mn?<:i?.j rc.la:#v4l' ,neffL o6ve,
Ot2::t-or diseases and. madit1oÃ`3s whi4-}e utilize dÃÃ. q, Lactam :y
w1?#.1Ãic' hct:là n`a..', 3nf+:cdt3:.iJ d??rv).ac., vnmsp:aots,
and 1~iI<'~ f.w of vaccines. ~~4Fg~:.t7.t1`r.iii ~~~ LFg iriai?i3.iLFti?.e8
L)ft.:=:"? ,p? i,.sC'.ill 4t??il:brlÃ.t+%,: ` ~#i.~ s) oriE, a.
C>? ~ `,.% <:rt)i~ ~~~t.Ai)'tii3~.,Nkx:`~ `.`i. 't)~?#.?sFi~.`#'i~tÃ(?:~.4,.
Thus, a,i2t.:f= is a Y s e ', c :'~,#a F '3~i:ÃÃtz*ik:tit.`=d ,nt..els:ista.n.`d del.T4L.`. y of therapeutic iiÃõC:Ã1t.j.
eit`i]_i.:?olt'4ti:LÃ`s, poly:.aÃ"bÃ.?maL4, m1d polyarnides are `.+fod::grctf,<61G pi?lp7'af;.;.'s w,ith lowif?x:eft G#.Txd dL.Mmdi:ifi'C`>I1 properties. Such pt?l472^f..i"'~'+= Wdi:de p\>iv
`aÃ+:3l}`(#e3'd.Io:{ill:oriL ), ~~`J S ~~Ã'.371\~I ?.t FaE 'M=<? '??CZnalO t?L:?y(mnl#.o e:Ei:'.#ds), i33Ea );`t~ ¾ 34 . #C. :~#:d '7~3l;t(l:i~:=tIt;~ t~Ã:l{~~}#=\Ã~~.,, C?.~s 5 ~ts~=[l.4?`r~[l i:'r i ~J\. \7¾ \. 44 \: Agrawal . . ,
Vss.fÃ~;clk'~::'3c _.4, S: ~?. 111?., TY2, 1Eii3M; f~i:i.~c3:x[',s: et .ai.,
J. ~~i~>.F3Ãf;t.i. ~k''a.its',i'. util.'i, ~f~. .2-3? t ~ 40.=
cr~~~es :3~.~~,~ . ~. ~:~_il.<:~. 1995, ~x" !::l.~:r ,~ '+ to: a ~;. I~, `xi.~~. ~~.~~:i~., ~ '~~= - .. ~~~15--
8: 12 9-1 .~ 198 i, at3:#., ALtIan<3tiiC)U. ef a?r., Ai`t. xi"t:i-s4 oj?Z'';
JI'l0es ~F+'_?t~.?7t t,~ aI\--:.Twt3 >.''z a viinÃ:.y of appil#.:atÃC3i7s ÃI?ClL:d1ng the dt,hE +::: y l;-N'_i%i 3.pctafi#:. phys.{.,.11 p.."'C>;?'l'rfii:.s, of the ill ill'llrL~:ÃE3#l :C~ pi1l}'rnE..?s i:l.ri: : ftc. l.` .laF>ed 1~.,~ IIv à at?iltzÃ>.#ca S'.",..eG:i(:}n, p+?lymorÃzatioI1 ted3`Ãiqut.J, iFtta pt3s:^poly7n+ ÃÃ.c..s?rÃ"r%3 miAi,ficc?t1i7::'t < P. ! Z?pef d:>.`' of 11~terS'.=1à ÃnUlÃ.ade thet f'zF.'t'1:l ~:.~.d`.õià t1.t.2n Wmpt:Ã'ixtili' `x, bulk aÃ' nz fr: :Ii:YR3Ã~t~irl, Ã'ixi`~~~;`. ~~'igr: dt1t.io'#1, cri'~~affif1aty`, i:1d h!'dT'oph+.'.+Ni:.1 Y When,
`Ji#l.~i~i.t<is are iÃt5~~..'~~..:~i it~r ~.YFS~'~~'i~' 2~~~1l>~,of.i~'~Ã'~~.~~.tar i:f.t'~. pi3t''`2~c~:iii '~~~~~~~~~~i~:.#.~/Z
J! L'~~e ~~ii:1.4~r..;~`.%:
affect host I':,spJ.l:s?. Heni+ww, ai1eL''=d. c:4.ÃstS for pol5'{i"ItiI`s and d\,.Ã t'ei't scstcn.G wÃffi, 1 v &stÃ"i'.d :w3..= si`.'t. 4f1-i'.i_"fivi for trs:;i3:tiifk11t. <?f dIs 2]Re:i Ã3::3d ~ ):;iLiltlt?Ei4.
SUINIINIARN' OF THE UNVENTION
I.w based, c3~. Icclst in ,~,Dai .. on the dly<.o's'or, t:?iit ?:.umln a t. dZ='fale~Ã :f~;;`~?s fide:: c-;#.i b#.: ut~Iifc.t,~i t1,o?i.#pt'.`=utÃcyill}` <?nd/0:` cos;rIVt>i.0i:1-y. For c`::c3_n1p.c, many o ihw 20 ~`..~23nn`a and particles ti`~\.sLi anl:=dherdn can be #.i..Si::dfo.t."
Ai1o3=i.>ntToii 4s:, li:psf..r'2l.i.edt, and si3.\:_iÃ:I%::i3 i~efiv exy of vii3 Ãou: agents tC3:: tT'C:i:tx'~~'iuÃ3t of d#,svt:1Sc'~' nd
L,o#:1dr~'iiot:5. InGÃ.Tien are ~e pa:ic pol~'nlcl' based Ai.:3.iis, paS.II#,."s.L=s,guts,'.in.Ã rGli.#toi.i t ) ?3;as,.#~.Ã':s, ,~iil~.at processes fbÃ" i~:4iiYt'.n' of i~~eT~t;~. ri;';
E:to'`4~.4..`.1.Fz are p.3C?l\ t;7L.77i: f:1'3iC and p#3a`.1~.~:~i 0≤i<f~ :~i à ~`~ LgÃl~ i:"I]`si~f~ ~~Ã3.~~, ~Li~F3 to t)Ã7i'`.= (St #e:Ã3:'`..' `~~1~'a'z~~~Lt~t~: :{Ã~'zaf~s. ~~~t3 a Ei)S 2:3 shL'., w:ii':re il,,~ rd<'.'...~~ of fl.10 o1yL'= o" more iÃ.yY:'f.`ai:, from the fiihI:3 or particle is .LenAi.lti:d by a TAi u~ _~' ' ~,codls~pradal-A#:, pc~lyn1et's. +,::at[zt.~, ~ x. Also provided .. ~
l.t;: w7e:" <3s3i..~.:.. the Ea3'#1Ã~I~ .at..Attics t?~.i.~.:Ã3#.~#a~s tar
P<3li.am,', s `~t.#\ #:i'~.*~ i.. ..~~'?~:~:EÃ tl'#1f."
nted by Formula XX;
"1 .a3M OrP0l~M`.1.;PSs Q i~ :?dCdei3 ,fr'L.3~ m-no?~~0., Sg Sc, NIsa G .~s,i1-
u ft:3#n w: on .~~e i?zlo`'i zg > E`u~,:~3.#'L4=
R= Spli jA ~-~~ j` ~=,~,i a r r,~~ Δti
R^ .s sc:ea`A fr.s92a;r#md}ng h`edz'f.IgG'1: et-t sitI't33wTh[ (?I' br3ncheid
A1', cyWAti i . e:iii EIT,;=fz'#.?., 1RFl. ,.1~,'a~ r4.lZ'izr~r c <~?k~''~i.~.~~j'E {r ~tw~~1a;~.Gy zig , . .. ^,3~~ L..i~a~r~iEa> r ~'~ =c.; . .. :;~~ ti .ih.~e~, or ~~~, df2.r.~Z4~a~~:sa'}L~.~: ~.~:,..... ,
vx'hcxeis: f af_ii.3lkSA, cyZ.doa.[kyis ~~~yl, L.'rS`.+fm si#yk alk)'MyE.aaytd.4i, a{kft yl1 a.2wylaFkZ `.
o: fl#`at?aoi..'s?Si?on +,.l-icii#i, i:-, optionally sLi`i-)st#tut(:,d li"~ternal3y or $e#'Iillnall ::3'v:" iy.:e Oi' mute my' carbo':vl, ctEFboxyC.stZ'.i, t:'cLt=.C;f}'i4'2tmidi., .tl:--zino, #.nono-
hyd#o s.li3s:#.ru~ik~ i #,f3~i'li.~, r~~1.iC?4s~~L:~";, 7 .#~fiiF~:', 3~'1~3sA~,#~3-lw. or halogen is tiele;.Wct. froiia aamng hvdrogL~#i, mo-d 3oxyf ot[zoxz' amino, a Stt
>_.~W.i Lbc]tFr..=~A~Z-'~:~ `ka!x'~ ~ . r~:l~;talk~~`. S,ay1, ~~l~..~a.a.<
Sil~r1. i~l~.ylsilyl;,, t2#~~~~sil~~l, :fly yJ;zy;. or ~:~~~vri~lk~'l
` {}: 1 ~5 L;.Rtb433:2:!. R,,v Rz.. mnE? R{, are independently w....iiGfa &k;n. ..a.3om- a
I l z C?r i~rz::~a_ ~`<.:is~i3`, iy(.lL}<}.l~i~'S5 dli~r1 islL?~~3i viili c3~~!':J ~.~ 3, i~Lf~sÃ:)''3 aY~~ ~''>~i 3, ~;r ~c.,Ik:~l s..,hm:i1; 5>f 10 L:&i'bi7ns, .lI?id R=; i33:?i`i R,~ ai:;e cc3Q `a i#"tdo?iC.ÃEdei;tl) sc.3:s=L`+cG ftC`d};
MMOD[~.iy~.tr\~,S'~.'=~2sf.3a +t.it'o::3i o.i s~?~~Siil'~.~~.~=~s Ci1t~.Elf: i:yC=dl.Sci.i.~Cyk, Gi~i~4~~. rilEi'~rSC,.,'.i; ~.~;. a,"'.1.ilktil ..,.ail;.ox 1-50 U;=:tbons, whereiti cach &lkyl ::ycl<?.Ãlkt], a:i-y;. t,1cfd.., .lx, v;.~~ ryl, oi_?
e:l'z'`r iii2lki l Lh._zl.: internally or tei'`zI`s$Ilt$fly l;1y ome or F,3o.
Q ~~c,iv diomF'l, bvdÃC'Sk>+i..tliir, Caibt`xf'3, cc3rbi.ZE:s:.-Lr., tiatb3x4`?;Sm1dC.=, iiimii1o, iF.io:"io- or aI?"11tli;, ttiio;, thioc;+t:'=r, 'wiafiiEtv. (?htJ`phait; ph~~s'plIo"1at4, or hilo, g4"Il sÃ1b-stztuents<
z~yõ#:..yE`wiil,,~ ;k:iG Foi'fl:?#.lli:#
In s~?.3 ~i?.' i:Tiib3dii,:~,:..t the C, rl,.z},C?#~"'z~:I';~ or ~?L~s <
tfi.Tis.uÃ:aJ, n is a,l !Ã,, tt4:= [~Lifr31I~ 2 "?i~, i3i1<~ %3r A> i~1i~7':~1~~ _iF~:= or pts.~#:~
F:~ mls:'~1 ~:}~.~ ~Ã,C A:~ia?
xtLn31`n<1: gmlio, the ii:.Ã'la,iÃ`al gS,Lp being, 'aeie..=ted itlTiong el1oasi has aF maidis, ~, ~~ z t3:~~ s. s c`. ~tYiki~`?~rÃ~~e,~s,, alkenes, and +.~i3~~'S,
w"};ni;eh _.s~.Sect, iliU iiivei~~ion f"c;Itures oligo?.ir.er4 (.rr ~~~~~~IA,Ã.rs, OT x>c)rt,o,l.~ `lorcof; ttizii {i,: .epr,:,svnted by Forniu1t1 XXI, XXII, ~..XIIIY XXIV,
XXV, XXVI, XXVI x xxviii, xxi.'k = xxx xxxi.;'2.xvSi y XXXF F 9., r}.xxiv, xxt1 vp:1.1R -1, V3
?,'V. \ 't'`,~\ i ~S~-~ ~~ i=?~ .=~ t r y .
\ v..~ to,-V i ~+4 Y ft=. ~ at.; :. `= _\` i { }L.4i ^.` i u..~ .\.~ =, ~.~Y.i ::, . ~l .~ \r f,
xvtN'M
X'KxZ= r..
In Gt.cl3 oh~i{Ã;3t-rs or pH,YI--vI"EIcI's, or pt"s2:loy34s, the3'eot Qr is ?tl:keperidlGtl1 'y St.aei;t+.~'~C.: rI'C5nn f., C~:F i~~,4' ~. :3''~~,.~~=i:. ~ .=o, aaImF'l4F 0, S :s.,, 't?:I' M l S;k' (3;f, and ,, :~7`G. ~.~f~.7 ~ #ils: ~, ~i=i3~. ~ ~ Ie1 ~ ~.~ "t3 ~i <.~731s3f1 ~': t ~ {-following ;~tmd"Ures:
ai:i{I cia ili'G: not the s.:e.i7}i3: 3~F is sC hai:-lI 31:E}FEx iFT:Y~3Fi#~? a s:i 'Ã4.ti or bÃ'a3 c,.#ed. :`+lkyEk cyclcaalk;< aryl, tz1cfin sily`, alk4fls avl, aÃ'y Alk::I, o: fl:.E.f carlbztrl
V'haÃ#aoi`3 5(_)bar1,7o#2s >ho).c.w5ci-Fcti a`ki~l, cy\.1o(alkyltin = yl..o e(}n.:Silylr,. Ltikl4l.sÃSL~lq ES saÃ'yi3Hyl, c? kvdi.s,.1,rE.. aux.ci.kyl or fli;.off3[;.ii'lbt3i7 chain is 3ptioi':IN i3tern.,lly Ese-
ten;i,..F'Ã.iffly by omo C.?:. 11-mri' hyrArf.#i1.yl. layd'F'ox}`'\'.g...f~er, cm-boxZ}'."a Cf~ailboxvZ.steS"
tii#"bt?xt~.i~ax~t1:, :i.#?.I~..? Ã1i~?Ã~ii; or <~:ixStl~?T~ttu.~.i~ i3~Ila~ii~.i3, ti~Ã(.` ~~2is3~,.;i~:~.F = si.:lf"a , ..; E.~:`,E. ~.~?..~t~:=. 3'^,,'}s,}5> .~~1t:F~lczie, or ,~,Ã?(?<YeÃ.ii~3. tÃiI3['I~rt~; or ~~ zt is 4s.l4l:i.i Z. ~ y3Ã?:: ~}C}>4 (~..}~,Zzci"EZ'
HlycE}l). poly3o:hylSne t3tSf e; piy;,`'ffiydrfsxi.'i#.c_1d)) a: a, pIC?Ãi`.Fi'1; a ptF(yp:pddc, a#l ta,.lair'li:? acid, a I7tade?i acid, a #?uel~.'t'?tÃdo,, a pol.,v:i7ut:la.,4}aÃdl:=, any DNA C}i
RNA :psf:jmm<`nl', a lipid, :Ã..?3i<3ly4..icU..>itii"1d`~..'y an 1T:1tÃbd}dnr'. a phtin?le.=.s.'(::].tF.ccii iaz,zF.3iY or any 13t1?:}'t' 3~~E a :Y`tt~ tZH;;#C%tf. Ã#,?Ã::i;?Ã~.~'!"; or ~'~l; .1s ~iw~~lS~.k;~_L~i ~..'tip:3~F~. among i3 33~'}~3~.f;9S.'i~~1';~~f;.~~$1~+'s.~3I%'. t3
A43..11c1l':y crt3sti?1#}ktible gi'i3tap: R,};z iS :se.~ctL-d f;'f"sm l`i17.~3iIL, I'1, a siI<3ag .t i?i'
bn.in`i la:df.1kS.yr'l., Lyf;low -kyE. aryl, o3.4fim, silyl, tilky35$ly4, }ryAsiAyi, alkZ'}:#F==y a.4+ii3ky3:, o.#. ihwaoatof~ chi.:n ol. 3 :?:F , atboÃis. L.ach tixkyl cyc.loalk .~ ar, Y. akfin, sfly:, a1k sfly=;
lti ~lcll\~ _ ~' > ~. ~ ~.. ~`~, or ~~it.?ii:z:~:{.'~.'{?:a t'. aÃI~' wh Ãia';
t~Ã.I'~ i~1`~ <#.~ti~:~'s.i ,~'~`~; ~aÃ'õ ~,i or t<`,nmfnal.) bi` i?>3(.= i:Ã' ;n'lriÃ: h-.drL'r\ v h\d>o4yetbCr, t:?. b431yl<
a`?1.:1A Ã27E?i~:~ or ~i Sif~`~~~t:.~u~.tied i.$3.'}~.il-lle:s. l.~aii~?.iv. to..`53S s1i.I [2 ~4i~.E Y ~,)a~Ãi4~+p..e.l`~.E`.; phi3`,'~.pa`età ~ ate, or hi3.li?g,.-i'.Ãkl zsub4filue31t.`i: x and y a1a ez3eli ?,,3dc-pe#?d:.=~~~y -scles..'.,.wa frfzÃ'1-Ã. an i=',.1toLL?'L`rZ3f 2 '.5is, a is 5e3`i_:tiled fr:'DÃl:l an i3}ti.gfeI of ~ 25v b is *e ,eL=t[:d &o#}'. :,#. :atcg ~.i (fi4 I 14 c ?.a an integer of > -14: wEad i;i:let:b pZ?l1 rIC.riE:. tl.#.na#:ial c.;`: #l Fp isset'+`C:t:;t3 fi-Orn an^o:~g aÃ^~~nc.w, thiols, amides, -~~~~~sphates, ,t:iphatz4, liydso_~ide4, nn.mis, alkumc:<,.
a.lkvÃie.`> and 3.iA alif.?~~~~3c'.I' iaspi::v, ttat:~ dF,L'i=latityÃ:e :~~i'`~~:.t.lines f?l1gC?'I.:as.f>i Z?z ''~3t`lymnw k:a, or jpg:tf Ãions'
br:a"<.itle, T'C.-pla.s,~nitisd b4 Y ol"#311dia .=`R~t~XVITT:
XXX VIR
Ii3 Siac3; t"slagox'..1i:3':i or paltn3c >õ Or pC3ilIitt1s flt(:.=r4d, Q is 3I.e1f3ng 0, S. Sc. or NH;
F_'r is s::lC:L=t~.or: t ~~# a i5 1~.~..~::~w.:~ ? `u`- f~'~?d.Z ~ ~ :e~~iC~~i
from ~:i~~#5i.iti% F.\~:,=
1..y~-AVA:~b:i.V~Yl.t~d~~iy olefin, st1 iy tiilk~') i[~~~~~~. aJ~~lst~Yy
<1:'A.3lkyl, or fluorC`Lat'b%.Viti tflit33ll of 3-50 cil. lbona3 3v'In#:.3tflZ
R:ziL31 3tkyA. xy{'lt`;a3i.yl, w `;i,
31~.=fi'T1. anisyl, acid',: sl,vi, xords:~#yls ;:l~,` ttl.~I~'a, ail `33.:hj l, C3:.` ~~Li:y,}4..c#~`,~,:1 E~~tci`~t :s C3?3~a(+17~:z~, subgiWtol iÃcWII l3.y or ldVanki:$lly by one or i:I3:CSTc hydlIoxyl, h (s.,<;xw ethos ..=i:ii`buxi`i,
cait?Crx'So"te ., i'ti3i'bt?xy.aTliidc, m11no, a.iliant,aw #1' d1 si.ibsiTtutod ,i.i~ifl".i3; thdÃ3l , .h;t?eSie: , he.3~$d?E , ~3 1?3~'; 334+ ;~~'a'33ti~~.~{F3T incl, or halogen substiliu+::.riE5: or R is ;i%luewd l'I;oITl anlJ.Fig p<ii E #.`t.~s~:Z lent, `;bynCil po.y(tthyle:il& oxide), pof 4 (bj%dIo?i.yr#c:d);, a c.'aTbo;1' d..;.te, a
Fi7`+at6:ti, a ~~t , a.. a,`:'e t~?? ~J~. ~:=, .-, #.i amino acid, a pKA. C: `dI iii{~ pts-, a :i~..f; l eij.l.~Ã:~. <l ~i~,, ~ ~~ ~?; i..lw=`(? , ~I;
D%A t3rR;ZvA,s:.>~'.t]^:~:C:itl, a lipid, a pt)ly4accha3ridC', .ki, antibody, c1p}i:i?'I',?acÃ:`uÃ1cii:l tfrfi=1.l`c, ar k ~ selected ir' any ~.j):~,,;q:?.. .i3.t` a .3ii..x{)} iii::~l l~.=tii~~[~3f or ~ ~ of is 5t:law.~..tC~il fr(3ili Ll;.~~t>l~i`~ s i_ ~t1 E i: A..PSG.~.~w=. or ionically L:ios,fiinkab3:i:' got.Ã.p; x and y i3Re cxi(t 1nCipoTiZ`i4FaLlti sC;i+:cte5:1 fimm an idatt;gz:i i:d 2 '"i: iistilb.c=:i:d 11:'i?I7` an integer of 1 8> and i sakli r2t;li.3li z`7i ianI'xik:l ;ro 1i:p :s tiolec`i+.d ft:7m t:Fia Z?:i;ts zir#,:it;"~~`~'. tl.~ii?iS, 't1~3~a.El+.::i. ~
Ya~af)s~~~':atL.s, l1`4 dTi.?.tilt.t: =~J,. metals,
1tka..tcs. iikcnt:s and s; nmcs.
a.iloffieI aspect, Ãi,e, invention feaÃu3'0s r;]lIgi3nnea's or pobri'az'Fs having a ;`eπ':<1t unit by F'C3Pi i`.'Lzi#. XX.
111 `laCl] 'o1#wor pi3.,~;=rT.Fi'=~s G i.?.clud('.s a first group Ãb''sat is
Q~(}3 n.'z' rt.ill:' to a si.`=::.s.'sild 6 t f`Cxafk3 <3s.tftfLfueià Ef'0f73 thL >iaSà ~;I`lyi3:~.;5 at a ~.}~. at or bf'lLS,,% about 6.0, such <3J :3 0l4fw` abE?ta 1551 or 45' R is '; LieC:Ã:;d Sra a,nfa7ag hyd:`i:_}4?e:i, asà cafghi or branched .2a H?,'`l, ycloMiky= a=yl, AQW, sdiAw alkylsh)l, ar,lstr)l, a.l.kyl.alyl, arylaikya ori:ut? :?i<skm 4hi1in 4>:' 1 }ei E.`:aT=.3C3a4. A.2ai::h cEl`,`L\!'# (.yC:Soialkyi, arV`fi., ol;,fi#. 4elyl, cE MgyI`'il?`a iy_.i-dyi. alky3a:,-Z.:l, drjlaiky~ or fl:#C,inf;i,tlrbt?r, chain is os?iit.)13c1al',v siEbst:.Ã4_aEad.Fnte_'F'Iliclly or ti:.3EI.`a,.l1's.~flZ' by ceo :3r mCiri;~~~krrf,.f'}'x3 ~}~ carU"(1xyB, L:arb(rxyt:"'.:\tF.r, amifao~
rnwvlE}^ or i.s 6ti. tal ;mÃI,i(> 1:1i:ol, ,j41[)C ii rq 1tlfi:stU. phi}sphalC, ph<3sp'"i~i n z3ti:. E?.i. a#:? itiEliL;lr.,-~; and Q f:= se.e`,ti.teLi fir+i1i`a"i :1Tr3i:111g 0. S, S4, 31 ,Nlt .
1.11 z.a$?,a"`>he 'saspf.4L, !.h5 fcawrt:5 pix ÃiC:lCs having a, fi1:Ã.
MCafnt: and. fnc.liid1;;"", an L`,:.I`oniet' o.having {?a'pLyatiaif.it tL.p1 e5ef`.4ed.?y
tÃ#'? such pw l#.i;:1c4, (,"i ill"Aldes a ldr:it t-~.,,ioup ii1'c.: is c(?.BlywL'>`Ãa~."?l2:' frit ., second group diffoa e1ià f'(? n Ãlle fiA ia n:f i`.up at 3 IA'A ia.f frl` bel?:9L3' about 6M, S.a.E,:: <`s bito';'i c:bi3i3t 5.5Y 5Ø o.,~ 4.5} R?? is solt.cticl .zi:E=:3 among h,ydz;t)g+,::3;, a tiogy, or b1m1ched alkyl, t,yci.tstaFk~'Yl, siI}`, a;ky; _ yl., arylsilyl, Ldk;hwv). <~z~vtaIkyl. u:Ã- flworoLarb.>n chair; of 1-5.; LFaabon:~-
iliEyS t V:%3oa.i\y~`a Y.'4'l, Z.ids.'.=fin;s tijiyi'., al2' yF4:lyl, aI'yll'iiÃyi, L3i.kyacarr ciry#a3La_z3_,or h<<to<<yl hydror. J .<=ffi.. `, ca:boxyI, c,i rbox; csÃer, c.Cz: boxy:Ã.fido amino, i;'i{371o- or Ci.3bs,itwe;d wnum, :~iiol, Ã1hicrosÃei=, sulfate, pAio,~p1:at.e~ ~~~~~sphfn.itc,
iubst.ft',ic;.nf =+, aÃnd Q is 4elect`o~i frL3st7. ,ai"i7t1iig 0, S, Se, or
NE';.. Welm, the paz #.ict.; is pl<3f'.:,'f, ir, an aMv.irOMInen: 11.:ving <i pat :.tt .}r below about 6-0$ the pi=..~~~~le tt,cr..a.-,.;~ In vx.zlurne iv-m the fitsl vE`ll3#:14; to :.- s4=oii12d v~.~lita"1e tb:it is Ti-l(33"e tlaan tv'o ti.Tm2 theifÃ"st equiil.>..tut:? s :;~tabl}s`hed,
p(3hn?'1eric, .<.ihn, oa .z3il.z ,.iL1.G~ Lill fTi{~ilC~~' ci11S` (}211>?F3`li:'.=:' or t i'.z' i~o~~`~>'~.~~C~i.~
h0vn'mil. In .toiiE`e+ L.~~\f2A~v4+=.T~.tx3e pLTly.tRi4;5ic particles lllzlude Ifia>r 3=\*.'l1.i%!l~l.ET at i, fii=.t i}id, <zm? a se.,ont; Bourne at a s;.:ct~~id pH, d;:k?it ftt?m the fh3::n tliw first PI1, For C'marnp1c. tli:.
Vecz fit 4 `: vs,:3luiõii:;= i,* IX or mt?;C.' tlii#.n tilC: first r'oewhti.i3 ft%C,' SC,cs3nd pH' ,s i<)w-eE10 ~:'=i~.~ the fin'A a, :iiaL:h cls 4X or n %3i`c greater t1tal=3 Oh+.' ~:? S. ,=iti3uITa4Wi1:.a: th1 sec.s;bkd p3 a lS lt~vvQi ,~` ;~~::`i the first ~~f:[. or 3 ~X i~:', " ~:r~~r~: w7rt:.~itw.z~ than tIi~: ~:Stitt v~~li.,:no ~ ,~s~~.ra. :~ s... ; I I is lowt;;ri;le, }r,sT PH.
A13,~,' .i:n or pi3:I.1c.10 L=iii: lncl.tde a L]i.era:pC.Y.4tlc ci:joi1t,
For ex<3=3..?.e, fl1L. i#..wt.,.lt cii:o bti= a b:zi;lo M;.c;.ily ...d,.tive agent oC?b3;1pmS;.3'1g one or I1St3i'e of <I.n x,, i.Ãz.t, il:i~.,unt3'tr i.lÃ'~,'i~~t r~<. .',`i~ Za.:l##:~ <?i a ial agent _. ~E15., 15 :.~.C `~ l &; an. Lin.,;^'` .~~. A ~~Zi~.;i'~w; ~ = ei3r ~ YcrL=sIC%, an
3't?ua3d hu<l,ng.
For cm:aipxe: ta#e pi.#.il,cles `..il,.a b:: used ft:i` applying to one <S.I'
C? r a si~~+s%~:tall r,=se~.iii;i t,ial'g"~1~, (#l) S=i'Et~ilil.1 f.~ i or i:tilt.~.~=c3~~'Ã~ ,t:ai:if3f:
i;iS r y i`a.la3 a tc3.t'~,'L. ~~Ã.tt.. .i~. Ci'.lse.iist: :ls~~~' ~~'t3iTe a si.#.i;Ff..ncil ilicil"g+:1, :litd (is), a t.a node. 20 ~i ~~1. ~ ~:aS,:F~'.= fs or any i~iiZ:<`~:Ia ~ ,~ Y have one or i,iorC
tax 45: azi.~ ~~:u.~~~.. a ~.~`~~.ttc:t1<r or 1Ã;ti:~ t~3.iri wE.}0 Ã1~~;Vc>it~c;to:' sa ,t.~c ~~ as less '.:i:in i?: 1.j'+;~ ti.~.~a ~.0Ã.1 i~;.'..i{Y;~i~#_t:to.i'S. For C;:1"ti1] slt. tii~' if~E3~.=,,iOS ~,iiE` :i 2'> i ~~zi~`i<32] ~~..t.~.~ . ~ ,=
clIziI1i4t.Li 3fiF:.E'vve4xn abt?%a I num aa".i{2 2 'Tnicit+i3s.
Any of the particles [:L.: onb3.:d herein can be applied at a iF:it site,
25 surgical 3 nui1"Ãõ~ii .i:.ix ~i~'i`~'.i~z are 5;.<~i.Ti'~7'.(a by the to tl. ;*4.%.t3~'nf~ 43,4= Ã~ t_st"^.'i >?x]i of .~,L, first si tL, stac:.7 _'t", a Nip.~1 I1ir(ac. hi zE,3dii it is deS$mbl i.`. thcit t:he v,.1;t:4ks iha = Ga d1e.0110ze:' f3f lsk `ta"1kn about 250 r#il.i7:`..il'a4=ti,:rs.; such as less than 100 nummGEe?".A2i or e!=t ri less +t.ham 5:;
In mof_lto., <t;ipec.i., di:, iitkiontic.}ia ti:attrcy app1vim" any Jelhnn or pmk.iu:c duJc2 Tbeta w~õ~ 1-w,ei''3 to a 43~; i1sxT4?gST:tllreS 4tap~~.c;+, aI1d./C#i' adIlesiveS,
s:ii ,.:iio'h+ tI1C, 1i'AVet7.t:Cv" features applying any fist2'i or qy:iF'tit k f1[;"w,il;Ud
Ili:=r`4'#.;. to t>t.`.iipa1n, rim to .iltu hecllÃng m.=.g , to avo1dSSwca2 fs)"`i1.i.tt.i2Il.
Uni ss, ~:pLc?fic defiÃ.Ãfion`i are pit)', tdL,d, E. g, s?s, aÃ'ii.FÃ.c.3Ee:..~~ below, th4. izme?;chi1..'c used in r:{3n.loC:to;.3 with, and tl]'l lkbC?r:itl:: Y
Pd't?'4..t..=itWC', and Io-,.i.l.a::qtl,~S of, s.nG=e; ti?;,.,=ii a,h(.;3F:ti.ry, i.?i13L,'~`'1t::Ã;7zsti'y> synthetic i?:Ã'fwi3k!Ã~'v obCmÃ.:?f:#"4 u?'zd ,edii<.naE <1nd.
>~~: art, In Ã~~~:?i ;i=`4:Iii that i..~l~."i~~'_ ~.i~:'~L,r~i~::~a E1~'?'e.I3 are those known i?a flac3.. Vss a LIrafA,~ L3f d + fi..1.:::L3.2s I#:3i tr,rms ltci'e.5r thosc In th15 ti.'.t.t:i? n pre va`I. >~_Lt.`t~~ 'I'of;?~. <l.i`#.ei'Ili? a3ct.s, and
As .:si ?d heiemq the:. ? abs..~rf`+;`icltil)ITS for any }. r p.i<4 _õt~ ~
ot` t:.=ennpound~s .;funless inÃ...~ilci1iW o:-hÃ..?z.1'1:use, in accord w_1tl ;}:Ãcià v<?mmnwFl ti:i go: ii::t.ed t.ibi}i"1,.viati.~;c.sn or sh>'. OEt,!PA1r"IUIBOxanni.ison. oi2
BeE.YL,honica.
1I'942-944 (197;~?).
r''3.:, ~.;~L~:C ileE:.iF:, Ã:4t; C)f the siea?g3E`tc':' hl4'.$2.d#:.~ tho
Pli:ic3l ..lezC sp`v'clfiu,_ll~'
A4 Fd`?.:d herein, "or" tilt ~f3~ 'i#Ã1C~: Cx~tr? Unlt?4s stWtcd t`..h%=rwsc. ;'urtht.".F~~.li3z"e; u,c;c of the ti%'run "including" `lr't fl as 4>ti3t:~Ã' fo.?38} such as "1mliie.ies," i::i;.c lirdfir:g:
A s used h.i;i?=i, the. terms "treating" or "[roxtiT34nf' w'I1L`;Ã.?n'3'?,#s': cit.:per t+T b?ll-i 3 est.~3?3?itii~'a= m1l P#'.3pr1y9c$xiti .-i7ca4Ã;;.i"es,g., dev']gi16l tt'31`ililbit, :0knv or E'.c oÃAs~er ofN zI2piu:"f3.i#3 u.?.niScs:sv<?r iIist?#`dvÃ, z:t:hÃL. .vc a .ta:1 or p,.itO:;..icEl;;i fiS'`:"i of i:by;;',pZ;:2n1 C>:~
d'": ' s'~:~, ili~vt . i. to ~; $ie, ,a a:~i~.ÃL ~ TH+ "`fV. ~~ ~ ;Si:3, i: Ã" L.~tÃS'i: a z~.4 .:~4a= or a~; ort~cA :?? ;~-~Ã`
its syn`#pEo?its.
I?~ of'z`Ct't~T..i~:ti?., of t~SL~ sõ~xl'i~;3[C#3i'i:s i:pfi- particular d.sE`+z:t." i?
As used .i`,3oa~-.: :,,a b: <7.d3....I2a`tnat:oÃzi. ol i3 particular t:.(?inapiZl.ind or phaan1i1CousTL;.?l 4:rlyipi``r`atton refers to a3iv
Y Gi:., ~ie$w~.~:i., ~+ #? w7s~'f, SSi}4~'iIÃg %~ f l3 ( 5:~3 ~ tMÃL~;1, of
3~hS~;~f~~iw; of r'.~:i~`y delay . . . .
s~iI1g ajr iI<3n`ii:air. t:dt>at c<:i:'3 be 'c.'`sÃ_,but.ÃtC'zd ito or 3~'3:+..~\ s3L~I~ ~3i.`i.#s Ã}.~ tt:l:i~i~~Ll~.i`4, li]
z:s..o6:ete-.t s,.dint.}.ial..ti:ctii#n rii.-IdIS: oC3m}*.]o:1xi.d or c`1.,9mpos.ibou.
`~'~6 As used E'1cÃ'e:n, :a1i' `;~i`t7..., ` s1:b`eCÃ" is a }ltii":1i.tn or an aÃ"1.Ãmdl, f:) 3i.:li.ly c, n]anb31al, <EaLi3 .a,~ i: cow, h'..~.Fn, dC t;~, Li.t,p1-, 4hE'~ep. monk-C:ys or i:)tl1i:.i' lixb)iaEto.y or t.t?.I-nt:=st.S..iLiS:i.l sZ:~:i%~~1i1l. As k.~e`.',i~ ~.?E'a'vil~, ~.i. term "patient" ~ includes '`s' bÃAXn':.i 'c-1..`. ::i3.~.21zi~. sub)4?s:its,,
As i.\od hi`,,''ciF3, .:tL' :eÃ`Ã?I i$:=firl's t] a compound thi!.t fa:.Ili~~te:i :,11.0 riC:uÃ`p+:?rat?f3:'#: of mitt`itf"' tf3]?:ipt3-i3i1d Irlti? cells or tissL7C:=s, For oxidic, d?:nr.; h. i.
f~_~.is'~~~~~ is it:,{?T:i.3i i3?~l; used to.?'3"~~=I' tbr li',3pi'CSZ?];f "t4izÃÃ?)itl.3: if of t,~.; t~sà f.?'5.'.~l1?:: ci}?'3)po.il ds Lt,.i``s or fi:?s":#e5.
As ~],:st =C~ '.,`.Z: tE'I1 ~`3~`'`><?:L'4L#t.i<;e`.il iL{7`s~1~:3t~~;~a~Ff3:Fr:f refers t<7 a a{#f."f>3#?:.i'3.; f:C?l]Tv<?i73]d or 5::Ã`1I1p3.?sit::<Jn i:F3p6bic of inducing a desired hc#"+:peut:c L..c:i:tsi{ tF:->:F.t~~mt. wnt3.hi i.:#7Ihi?f:xJ114i1t'~-r`, a p-hiFm7af'cf3t#L;:3l cC`?:3"1pC3FsÃtioÃr, ci?nta]t::`, i3;to aC,i#vE: qgcx'ai, "O?fC:h #S ffiFw i-ge;:ts flilf3t 3:{:i:ix'=.`ti t:w dE:sarr:,.f.: :hvfc{pdf-it2C: e.f{C_ct. P}e .?harmL1w~&.al 0 can co1:tetFil ~a prodrug of the herf'i.{l, Ix3: ct.im3:1: emb?da1c3+:'.F'tT's, a uhi3nmaf'.i:i3###;YFx iff 3'~?~C`>~1`t~f lr LC3I?.~i11:I ^.I)T3L.+.F1tf'.= tI1s.I'f"',dxC:fnr.t:;z s;;#s..b as, .:L3F L.xu{a?pley {.mhÃf:fs and *~.xc.lpiunt:y.
As :,Fwd he:i:i`r.'#, tht;li;m`t "thE~#".~.pC?ut?l%%'tl~~ ~f"Te<:;..vÃ; i#.Fallot.#nt" l6as to .ka art"sE{t.23`Fi. of a ph>z:533a ,~ ..~~ ~ ~~ ~~.I~:s,z cti~r#;"iI.t \ Z ~ ~*~.? {lE:.}ik3:.if.: a f, '~s7if:i: S f~'i..~ r+; ?i.#{'#.:G: e'~.i:= r i~` 41~2{,, ~~ ;~fF~~.s~F<sY.~ f...
As f#`sedl, s eF"C'3'i# t13i`= tem, "~.~I':t3.?'#2'tai.vutct{.fly ai.'.cepfablf .efe*;:s f;;) a ~5oiÃ'z~ul<ItiF:Dii of f;i~t7~~i5:.i]t.~i i~3:F3. does not s1#rt1#~~4~>:1TFt~'~.~` c`'~~~af)S.?c.#ti:= t"~?G ~~l#4>lf.~`si:`e{l .Δti.:t#S'#.i\', a
Fk.i 17.z%f C 3~3}?~i:l ziC:ilv 'v wad,=?# other properties of 0'lc `~.'t:3Ti'#:pt3ii71d whi'.=Ã'i "hL so3'1-y:i?.Fl<1tzi'.Cx cf3n1pi3::nd is tf` a 4:Il~jmt In t:ettdii.T oa"ibf?dii?1at;, a phs.3m Alx{-
c.ica.tptablL fbmwlad4.'s3 F doc;3 >}ot cause s#~,~;ifican'e iFTit<li..-on to a uFb eC;:
ray used ;?f~'+33.i?F~3~A::f;;2~tlt%CLItt.ult'1' acceptable derivatives f'~~`i3 ~,:t5?:F?.~~;t.?F'1!~ 1#?c1#.1~:?v _,:; axii not l#ll t < f~ `~ .. õ ~: t.# 5, cεC:.f; t.stC:F`s., t j;~ salts, asx~~.x~, f:~?#1. '3 eCh'.~.~:i, f:*~ZZ?3 "s. a $<aa.~s, k~:::'i.. ' 2ls, 3t ~~~~?'~.F~~
ai:'.ids, bases, solvi:te8, hy&,3ke`t, a'E~~YlaÃif'f#`:, or pr;,3dEftjgs,
S-Twh cif.fiwitve:: can be readily prwpatsd by tissue of skill in tx?is arl fishing x,?; min n?ut9.Fo;.~s fft:- such d,..xiv.btif.aa.-.+m~. The f:cainpoond.s pj(,,slucoP..d ca:i be <~~~n-fim;;ferud to .F>.,:.nats or h# `.?i.tl:k 5>thikin Si1:l;ad,d:i1.:#x=il toxic i'~~f'c4t:i and either are p}?#ir#:x<l.:=eutIcall~~~' a4tWG or . :;irf? ?~?t3..~1~~. ~~~1 $1.15af 4F`3L`l:.?ti t.it',a:Qpt<1.?lf' salts 3t1t:lf1de; but ily"i; not :li':]Ãt4d to, t:nti.i'.aL S.?l>:<11 sv,,f .? aM bL.f n:v,HFf]'11ti;i e.o, 5:~-d:;ri.?pi;?;..a?nv, f:hPl3.tit., ` S~#~?411! S ; i i~FY ~:{At t+F:3 ?':?i~ .
i~l~`+~1 ?R >F~~f~ ~23i71x~t fi. Ls~~1 t`=tAi>t3{kl?.i#:i1~ rye \i.#2'imm"ES t, i3.4~htaFxo1:3#?3#Fac "iIFc.3 other
`i?~.~~~=.S:tl?it.~?#Fz1F f., get';tc1i#?~. ~-'~~;:i3:1,~=z }~}1f?Y~i',~~'2'~It1~?,#~Fa'. ~-F~3~1F<? ::~~~{3#`-,~"#L~Fif~. f}1ok4Ylami?ls= and i;+fher altiyl#:mi w-`F, pip.F<--iZiFtf: and illkah metal ':iS but :.3t?t ll#:i2EtEsi'- to lAtb""I:E.m,
poka-s"'#trii and 1t?d:ui]-iK %Fl[!w[b.in Z-wtii mwta( wl1w,1t], lf.tc7.t as bNCnQ-it S{Eniil.f_, to bt].(`.{1:.#?i 44>.if-'#YFnn and {71:Fa;T.i.;4.if{MFa, .. 1.d-1:~#t#f?i`~ a31~.;::~~: .<1lfS. :aLi4.1'I. as but #1(?t~. l..i?1.i.5:`,<> to :t;#.', .. ~~F.3~:i3 c?th `=s FT3oE.a;
sFv,+s,~.'# ~ z$x but ` ^ to ~.i;=~t ~'= to sodium ttiT~~i~'C?#~~.# ~ Tr Z ~
Y..{,ti,? r t'~li$.<: and ? o .#.~ ~ i~ ~.~ FS..~ ~~ ~3:~Z~.~:r'~. also
F;at ..~.:~f~ eY, 'x~#`.-.ttt. `1 c3.i~~ #.i..t. if?LWi.;:;1#;. bf;t not i{m#lfsfa t:?. S-.lt;, of 1'-rdi'1c.{t3.a c3:'l:ida, *`.s13Qh LIs b5.1ti3ot 1l1?'1#.trd to hy~LÃ"a~~:'z`F~f1F7t~.:k and .xili.3 s<1~t5 to.~.f?i``~a:i7.tc acids, iu+i7 as but .,#ot l1mtsa:r. ::) 11 l:3cl:ates. Inals3 w6, tartrates, citrates, c14ivE5i'i3c3ti3ti, '`.'aucctTls. tes. ~i e`, I c1::~S t'ale, a;v's ci:1C:~ fu_T+:m:i1tC:S, Ps3wirna:.Ei;:C'Eifii,:al9`v acceptable 4ators include, but c`~..#'t: :1~.at aÃT.".(2itiKdw, i:gktl, eifln.c,Tyl. alk`v:1yy 3, c `v:xyli '`i4tfi::oz3r' bly aTc1lk`v'l. 4~ t, "+~'. i.~k "*' fi;3Eil,"E i ~'l t f.;;or:iv.+ Csw.;~~,: ` `~:~if~: 7C.~~i~f.v~'i?~#ii~+`3 i:~.at,: ~?i:`~t{. ,. esters ~ <ai.x groups, it ciudiiihj.; bu3.:niSt J:a.m,:t5.`d ti9, carbo,Xwyl1:c :lt.:id`?, phosphoric acids, p }t,14c, 31PtiS 4:.dfCkni+:. acids, s&. fimai: acids and bs.?r;'}`.lIc acids. Pharmaceutically ci4ceptai3,.L . '`~.'~i:.s3l QiI"i.::.'s, 1#.LlÃ.tek~ b1Ft i:Ãm rt3o": l117?3teci to, derivatives of foE'n.i'::#l'rl C
CZOR.r where R is ~3? ~='~ifog~.`Ii, L]lk;Y;, >c.:r rwt ~\ >~ t ~ ~~{:....~SC?~.
dcbtst.I,~`; i~;~`I?' aryl, }to.::>r~?>~~';i''l, cztf3lk'v, h`v~i:3't>aTs:l~~ s*~~,> i'~~.l~ .or ak1r .# <,i' ye: NE>>~~.
co..e4t~tii::#le enol esters IIiL.iI#: , ;,?i#.Ã il.let: 3?~)t2.#1..3.1~.5:=i~. tC?, tilt.L~a~<iii.v4~,`.~?a=..
P~?.O,.I#.~'1'e.at..4ii t?4;.': :fly i.1 r-mWa C -C(OC(O)R) wbx-e R ig hydrogen, alkyl, a1kenyl Ital-)I, heÃz:.r~>A1t7~11,
1i ~ > = `4';-' l~; ,~:,,.~, ~.tac. ,.`~`. ~ j i }~i:~~G~.~~:~`i; or 1c~~~~~.s~:~~;1~~;. :~'or,~.~~~~[3 <~w~.:,.~~~~:to.to. ,>~~ wÃ'es il;3d }1vd#.,..xeA are c,f3T:~~"' >3lt~:4:erof a i:=4,m?,pouT?d Wlth E?iri:, or f.':'2S)-to4f?kv;le or w,.it:;=T mt..tl'':`.<;iFC,a, ;iS i.o about 100, or I to about 10, or one to about 2:t or -`, fiv^,li eÃ?
tt Alkk::;r :a? "<'3x#. >t31.?hafic hydiC?Cw1etxm FF.E>u"#;f wh,.:h. can bi
a.z.#!'# ag, I i.i? about y`.3'+~a' ~~`~:t'bi?li atonas 1n the i:=hc, i11., w]d w1h.2E.h pI"i'.:#L. abli+ .`l, t%e about 6 to about 50 'L'a1'~.'#t?Ã':ti iTT tt7e chain. ` Lt3wif.? alIfyl"
I'6er_7 to ;Ln atll:.' ` w,:'[3tlp having 1. 4i? Ilm"LIt 8 ci?R'bZ?.t# :1tiF11et, t" ftij?ca iilii\lee refe1' tC? :#t1, at#kF ~# ti?up having about 10 to al;:>ut carbon atoms. The .1kyl group mtl be optionally au`t'astimte,,J w=ith, m.% or more alkyl group s1,;m5fituunts W#.?;.dpi can be thÃ. S'L?nlk' or s#ffI,AgeI.:, k}w,lcaf. "s.,3k4"l group ir3c~`a.1G.es x?nF.a7i?.'zI`a'l. } yt ^>o:S'La, i.liki`x,`r', 'i'3:['ilE??a;.`, a.ki?l+3Li :lk~ltliai?.rZ.~thfi;t,
20 malkylo35.y. GErt-~.tky:i.F.ti[}> carboxy, nikoxyc#.3abt?nvl 'C3xv %',1ttE t Lyi1tSalky-l i.bw=.if.; can b5: t?p _io11:?.tly F;3sm;,'d along t:`e <3.lk;)''a chm3:i1 oI?.t:= %iI" more 3x4ra'e.., silicon, 3*:.~i1te`, i?-r l~`,"+,.tiu# Z.,~ t #...~l5yes~..tWTR.~23 # ' ? t'~.i~~x~:by wherein to'#4?ii:tI~~~'~=d~ .naa 4 Ã-~".s~::L`tti~~i. { i.. ~ lf~t=5~~,. ti\=F-iZi :-~~E ~5n~2~.~,',~~~ L~~s. 'Y L ala:yl, taBr3i3'ahL`dtt rLAC1` to an ilk4'3A gTi?1Ep in vwh]tih~ lowct akyl `;r+.3L3~~~ s`alv..f:i as uactA`y l. include ithyl, or putt nyl. attached o a linear alkyl chain: :x4'1'npli]ri vmmps m3..ffiyl, A`.'.ix?y.i.; i-prL?~~~.?'yL, n:'.bufyt ~~kftyl: n"'per#tyly heptyl, i;c yl. decyl, dode4yy.F.r vr#.i..SoJy.Fy l~.~t~ .?~a..3~ ~.ibi3. or straight 3.,tri:~iC~b o a` x s~ , ~rir, t~~'Zt~~ . ~ r~.. ~~~.# <~lkV'.[ groups
~a=~v 3.af..'C~3..S,.'i,~~i, ~-~ts~. v õ ca~~~in.alky; gx.?La), ~ `a L.f 6 to ~ 50 ~:'{:~~?c?~~. and v:~~3 include the
f~+~?%~~ ~~=F~ 3)~#y t.#lr z~?1~7 t %EE~ L'~ ib~"4`1~3~T:'s of if~~1CsL1~'. 1..' to 4r~.3(.1t 16 v:i~l`i:~,'.?`a.
1s.3l3iw'?ayl" re:var,I'4 to ,".l,Fa alkyl gr(x3'a3 ci7ntc'xli1in4.:.a~ least i?T.?e R.ai'bt,I? E....`.'bo=3 di,fe,t?:e c?nd: `l.':c a;:~,.amyl. grt+.~~~p can be opti.c:}iiully ;,mbsiituFt:.d 3.i1ai oine or :-nore ;ak_4ri ,~;Aoup si:constituent-,~." a ,,,.cmp1,jy xitkenyI groups incitidc: vinyl, t1fly1, i.penten,,l, ~~cc,my3, docleÃ.vriyl, ld-radec:t.d:tnyl, her.loadc.c-8-en=-l-yl. and hep.advc- 8.:
Aak4'n'S rac -,elk:e13 to ama ixlky`1 gt3up C;onai3:it1#.l"lg a i;.ubon 4.=zex`b<?n i:iple bf3...tS `he yC3up i.<ln be (;ptio#:?ti;lly sFas'.?vt3.t1tted with oriu or ;t7od-e aLa.iiS`;. g`::ft31? ~=~S~1Lxi~:E~~h. < zlkZils.; g
Erxemp1<3r: a:lkynyl g:hours include efhy'nyl, pt'op<zr_gyl, a-pmit; tix:1, dN<3nyx5 and
?E~C4..L~%~'ii +..~Sw~:E`a;, i$~.~k~`C!3''l groups ai1Glt~( if.,~ ~}`= lf}~4G1` i~i3k~raettl groups.
T;'+,:.lo";Ilkylr> 3'e rtõi'4 to a 31on-,`s?it,milli.de mi?ni?, or i23I1lficyw:1c i lt 3;i f':stC'r: of aE3o3:1E 4 to ~~boul 10 ,..:rbc3n aEoms. The cycloalky1 grckup, o4~~i bc :~~~~iont;lle pakba:;by mmwair,xtcd>
Thi', t !'t:l2`c&.kyl group cm>. n s:i:?3:? optionally 4t.kbstit'.1teE.i with an ilry: group stabstiti.iC:,i1L, omfs .i'Ttd;ft3r 1,.k1'l'iic.. Representative mZ?i'!<?cyGl3c cy#':lt)eilkyl ning4 l;i_,cl:adw Lvyi:.zi:2p..`'1ty;, -L' t.~14x4 =_ to,t -`:~a cys , .~`~.,l x~.~~ty'; '~,.si :11.l?~li~:fl:?~.Lett zJc c.'cl4s.akyl rings i3'.iS..i.ide adzlrl3ilntv45 octi2hyd,(Ei=?.a1li3131ZJI:~d.Vca""'ii]y cLx:,[}p"nÃii, S,lampha12e., and iAotsaVC2.f'. -nmaly2.
``i.2yl?' ?C.f:+,'=d=s tt,? .xni1mn;t.it: cF.ibocy+.==ilc, radical containing tibC?i#.t Sj to a:-xwr 10
Eur:nT.b#.}n aWan: I;3't'. Entry) group L.=aii Lil+ ~~~~~ionaxly 4~ bstiLuLt:C3. wiil2 lint i.1:y& g;roi>p
Y~,f L=ti7~{r'~'~.i i ~?~~~ si.Ito::'~bi` i..#w..~i.~L~:vS 1~. ~ } , ~ t ~ ~.~ c FixL. , sC3.nY2.: or ~.~~~3 SSi.~:i~`L_.at-. of.tz1.3:=f:~ tLt3~~.i", ~ ~i~i~.~ can ky.E 3l8en` 2 :1lk'i2yl4 31'{>rl} arc~~kV, hyd:I=(:xy. AoxV, ai Glo:'4:yx aralkoxy, carboxy, .:fr(3y3 halo Va>Lr\}+. tl'a.haiomeihyl< c5fbii(oy d.".~kox't'earbC:ny1, ai~~loNyeafbomyla.
i`Li:y, m4`K aicy?iu?l:11c). an3$`ai.#.rn;ni?; ci.3'~..?ui`[]:C]Yi= 3:.ik'5lc:'FbamoyL C &;r1C.c: `i?ai ioyF, fS'fth1o. it.sky..ttist.` azo yli;ne; and ..^ NRR`. wl1eT'C' R and WaF"c Z?C:b c#:C} l, .3:l.~d ai adky: E?S.empt.:ry aryl gg"{_1ups include substituted or u.:to.:>l1bSthut...d phonyl .F:iii sWbs,aitiÃ:Ãed or un~~~ ~~~~~~~~od n.~~~~~thy1.
"<Yi.cZ.'::, õi.fLi4 :o aii T.'7upy b?b'l'1ciC;in alkyl is as pf;=Lvious.y dw::iC:r#.i')ed= ai:yl ;;ramps cf?n1j.,yr.se alkyl of I to about 30 carbon atoniv. Exemp1a_q s
4 t),#p e i?s.Jo i1"#:clI#.d.L- cfiL`,Z TCO'], pr43p+.1noy , 2^mfi:dhylpfo})aIaZ?yl, bi.Etano'y5, a"iia. pah'n_it#,35,'"=
f~.~ ` ~~~2a,~;; v) }` ) ry~~ ~ } x~= 9)~2S ~y~a to tc [\~ q ~ Y(`' ~}<
Z%.=i lii~L~.~~l11.t,'r t2ntYw"t4~`.-dry.'k.~'- 4.~.rt)li Y
Y'4~.iS.6=L4+12:f1.~ Y~ 3~Lis ~.wji. t,it.~ )'.'`tdY ~24s~'..1.a~:i.7.a 4i:mp~`ri. y aroyl ?4 ~i~ic=i~<~e ~3~'?~.IÃ~~'la and 1- and ..
! ;},!~23SZr ,~~1 C. ~~',..~.s .l 4~2}k~~l.. '" . ~_ p,~3'~~~.~i 1~.~:r~:z", alkyl is ~'~~r~;z'ic3:~s.y ~.~s~.aib4~.
i :`c.ori3plarZ ,a.?,kovy' grE?i.lps- ÃI].cIL3iic nwIlhu-3.Z;~ ot'd7oxS`. F,,pFopi?xyq i-pÃ`opZ??;:.s, i"? bi7:i.?A1%, a#.~[3 10~:t<3x s<.
Arz toxi F` ~c;t-Qrs to an, aryl-0- t:r.3iip, whet-e::n tlic aryl ;~;~~LZu s is ws ;slvv3fft~~ly dcs;:nbed. E:.~~in:tar; aryloxy gro-La7.)5 -includo pher:czxy x-id naphthoxy.
At.ky1Ã'bk't3'z F.'6c:'s ti, an alkyl-S")- group, whs:;I'..'Itd al.`h'.y3 is as previously described.
Exemplary al.?~ylthxo, gÃo-u-p4 iriclzÃdc iiiot1iyltliiu ea~lyi~~~io, ~ drop';=t.Bio; and hivy:ul?ic3. at''M tis_a?f` 1'cf:.'i's to an a:4:=l--`*-- group, w1lerc1:: the a:1 e'. gt'i3tap is as PreYit?:.#44y dL;sc::bed. Exemplary <li'y?th S3 c._%i'oqt3s ?.i1c;.use t~~ic-iiyx NC>,;:n#.: z3a-j?li hy.thÃiE,
AIsllk`u t':#`oNs to awaibiilk>p'! `?=ls`_?~t,"?_W ~.xf%h:dL:i~: i~;~~`3 and lf i. aF4,: as prC v-toi3ti3y s_i:esc:ribs,d. Exctnplary, t?nal.%.~~l .-~.~:~~?~ zit:,~u~I~:1~~,Ã~.zt']t ?liG-t~y~.~.~.~k'l. zip'i~.~ . int-~~~tr~.yIt`~i~Ã}x~:'l.
AAalky,omy` rcf.wrs to an :ri,.1ky: 0-=-= group, wher~~~ii t1he w-a`ky; g:oyÃp
prL.vli::u,s..y (Imsa:..~ib1^`.d, An i':Y.E}Ia:plzt.YS' aTillkyl<7Yt\% group is bef7:'y1oxv4'.
ie:{ors W tit: arid1kyl==S.,.- f?'f~)q)y vhc..ewn the Leuro4i}RAsLSri p:t;t'ÃZaus.y de?sLi`Tbed. An 4u:YC.113plc."y aralkylthio gd:}Lip is y?eà ?:yllmft3.
r Di.3lk4lC1.rn:no" !.er':i'.Ã`s to F.2i ' N3\1\' group, w_?ier:tà of R t3.nit. R i"s independently aÃi alkyl group as prei=iousI ; dea~ilibed. Exen =3la~~y al,. v lw.uint:< gr.>ujps inclade ;~:~d d'iet?:lzÃmino:
alkoxycarbony." reItrs tU a.n aklyl-O__Ct:;Ã.... group. aI .oxycarbz?n;=l 15 (g{r4tp4 itiUhudl'~. a'rwfh[3xycai'bi?nA 4ffioxYCaÃ'ba1nyl, bF t?'lÃ?xycarbow f and t-
A>I3+~"tiyi~i~"bi~Ã;,`~~;ts refers to.) `t#.Ii ~.I. ~'l-~~ ~~~:~- group. ..
goups is z.ludle p}:enox:.r wad naphth<:.z:tyre:zÃrboÃ=lyl.
AF`il~kox,f.:=aibC3nYl' refers to a31 :era iYc:y~-O '~'l-~ ggrouk~p. An. f:ktim}YFaiy wralko;kye,arb,snyi gomup is 'her'~azy1tAxyi:.azboT1yl. "ti'[I~lmnloy1 " r;.1eri to an I[ .NWrCO-e gye>~~p=
" 'Jik}q'l{va~'fF1L=~~tl7Zs== '-etc'+r:`i'~i) ~.t F"r=:'~~!V^'^~~~~~
T:'Cia~.~'4, `'a~.Crtia.:i~. t.i~.t+ ~3~. .~ and :Sci is à and 3.~~-:_>~c~~ and Ã~~c.~, :>ÃAa..~= f~'Ã'R a:~c: R' is filk~ l a4
Pte}='iousl,= de;;crÃbetl Ãeiers. to R-PRN--CO-- g~~wp, whemAt~ ~~~ch of R w`td Wis ind.~~~emi.~~~~ ly alkyl as ;z~reviz3iÃ;,d3 descifibezl.
>s A4ylt;:~y` res43t`:i to atc acyl 0 grmlp, .xI1eE'ciÃ"P acyl isas "3. e~'2~`E~},,~3' Lai'.=SUIfb~.~E,
Sf Aic)'l(Wmfi,.oõ r4.lfVY~,~ boill..2 ck.t;yl NI`3.=.=` group, whe3.4'S.~~w a4yl is 4~~p.1.`=e wi1.`y'+ty ta~so-ribed,
A>.o:}'..e.#.~~nÃnf? I6essi.o an aIoy:-N-J'1.. g(,) tFp, vvherC n aroyl is as, pf.c-v&+:?uslZ' d:;sc-rÃ~~fed.
A:kf`le:`3ao c x+~fQ~.s to zl s¾i'a1-:ill or branched s¾3h'alGnt aliphatic ll3 i~;:' ~.~~~?Z?:i g~'f?i.-Ip tsZ?.31 : if, about ;.s~? carbon MCims. tIxhe aaa.'ylo33e g:'f)up can bt. 5u"t:7`i.}.,hr, br:...3L=hi;=+.i, or f..yi:lii;;, '1135.'. .3 Hk~Jene ~""ioLlp '~,`i3I? http: also C?pt7:t3nwflly 1.11.>c3wir<.[tod w:ai(3 or substituted w7.m 01W OIr liltir4 ~~a:#k?y'l iIlx~~~e cill. be opg:t%?I3ally 1_nS~.:B'WEi : kmti :i1e 3Ikys.:,ii~= group f;:die or :n. : ~? i=~1 s?.tlphu:-, or su}DsÃ-Ailkef: or ansub ÃAt#.?wd nitr t~~in atoms. w~~~rc:i,: rhc. substiÃ-,writ is tx[kvt as prev:v~~~~y dG.sc-tibei:.
Ez>.:.J:11plary alk , k aw ghi.':sps .#1L-ilEi2c $21f;thi'`Ln' flh;.`l`s,:i,iu (-..Cl+ CH{i ), p: t 2ylen:```.
WI E..:r:? " ~ GHZ c:is ~~+.'.X'S':~i.=.+#'`~ ~." ~~r,~`F4fi ,_~~~ ~~~. ~3.'- _~ ~ -~::; ~ ~;.F i." t.*:.Eye ~u~k'3, ~.{Se:F.?..~, _...
f0 `+`t~(Ctft wbwi,f=m n is m'I lnI1..wfF:r ftom iibi?ut. I to about 50 ianfi n .>w an iz'.v .~ IRX~I 0 to <3b(? 1t'SOwl":eÃ`l..iIl each :sf '33': wn'=.~. Ii `. 2#+fe4~.'. a3C~~=Ã
i~~cgi: from , to b:uk. 50 and R is l~.`~r'd~~?geÃz or alloys, trif ~1:~
1lat f:fllyaehnCi>iC}xt ~? 0..... ). AF3 ilikylE'.ne ;.T,.rt~"e.ip haL`f. about 2 tC? ~M:33?m 3 ciA 'Don12Comsai14S oYiii fC{.nhor have 6-50 +ruboSdS.' 13z3i.^.' or : hrlai&i' T# ci: to I311:3r1de, chlor1Lz[;', b?';3n1adc, or li)t.lck,
The t+,'3-ni t a; fe#.?trr .#1:'f.,ll`a~acS w3thC3Ãlf. lim#~ afiC};t1, 1~`a~=i~:eC ilE~]i fl:~= ~ , .z~a311 a~, mi'mi't3l `upplC'ment +..Sub'..=iancC.4 ti4ed 'fc?':' the trf:.satin'~G'" a..'at, )rLa-v'o' .tion, iiiaMno'?if',,crtra or nail.~~a~i s.~~a.~ effect. [tte 4tr11cE0.rs: or A`LIIiL`tiÃ:iTT of the body, or p?'(t.. of f.lwilw or ffi"~LsS, substances .
t>ium. ~;s.wa11t,:i i sQco.i7:tL, b1{?:C`,gic:~~ly active T3r:t13f?re ai,'ÃivC. Af[et t keyhole bef.r p4af,t/d i::3 a p}3'LP.Iite:ii'#?n,p=d phy\:iS,rlo-.~.Ca.[ CII.G'Erf?m-l?.L=nt.20 A tNo:be,.t v"', :lt,~,Ie't3t" rt..fi:.hrs to <li1 agent ti'ii.~.t is c~sl~.?abic f?f c:?::cI daxo a biolo:.?IL;:.Il
GffG+:e.Tit vitro andior in l=`tS'o, -11'xc 'x3#i3i.of.?iS:=al eflCrci can be
herein, rf=fLrs it?so tf? a StAb;~ta1#:4~ that is lv~wd in cC?i3-r#cfi=t.t7Ã~ ~vith `um i~:~l~Ã.~'.8'~.f#, ti.:ii:}~+ l~'s$ ~a~. `~'~.4Ãõ3;.:4 f}.i appl.lcilt z>L3>"# t. `.3fif~,to:3`s't,~. ~~i in g nature, 4IE~:li e~ tz in
iEbm4=1wa' of a d.ESLa-so i#.i a ;.?'Lii;nt. Iõt7c bit};?.E`~ive zlgs?ncs, can bE:tie1:t?'i4z or pos# ,lvf~ y or a.~ S= w3:s~~'~~~:i. ..:Z tlc ~~. ~.~ ' Fig;~I1~ y~13~.'.:'i i3 c ~+ ~~v~ ~i~~l'~=~ t4k.Cuiti3ble '?1L.?%1Ct1-v+`.'. age ~v~ 1. i(=~~.#:e<:
dlu;zs, cells, g:zscs and h`a :=Z?us prec~3isoi s { e;~., ~~ or ~#1t~~~~'1 4
Z?: ÃV?.3.~?3:= i~2: .i' . t~E t, 3`lloia;sT.F 4...n<'..'v':iT L'.s, growth fi1.E:toT'S, vitamins, 5tfro1ds:; pf?lyanio`".y, mtidc? dC:S, Ã3..#clS:otdt,ti, poka]uGlE.#)l-lfaes, 3nG Z`i,:ig:rtf.}4.1.c awe37.t;t, `Ea.ci] as contrast agents tf`>r use ?!'> ct,`>~n.t::tAlf3.i1. 4'w?ill magI?Ud<. = ri:ii?3a3'.it:c ;.mag1'ng', uitTa4t`i.S.i1Cl, poS1t~.rL3r? Ctl]i5:^'.:f9.i 30 tf; aphI , :.:Ã.Jf:i7putid ial nf`>gpph~', or other imaging :-noC .il3ty of a ptf
"G[:31ctit i1:>3ii 3'If3ls i.3w`x~E f ~ ~;at:I2~:ri~llÃ% it? #':C3C.~l~.tit.Lett,.;~ 'c3x7~.~ ~~C?~.~'~,f2f.~.L.~~;,t?v,.=t ~Y tie53x'1'#.;.bi3nuo3czc acid (DNAi :!?`tdi'ibt?i3.Lft:lo1L~ c`-'~.ciCi (RNA
Ti3G lryf :E? <...tfi i.l'lc#~t i'~c#2 cCIIi be z;ii7ta'~.a by f`i?iotTc :heA`tF.c:3? ,{Ii.t`thf_ 3d'L~logy known to tia?.e of ordinary skill in the art, or b4 niL I t of recombinant te+,..l1txoloÃzyj or by a tt?iTl~')f.Tlat.lof.i of the w4,s. Thw :I,NA <1:3d RNA i:;'asi opt3Ã3.of<31lc+ ::07171prfS..= :.#?,111attirxil I]i!4=leofideS f1.11d. can bC >"It:gIc ordaLFble4t3x3TiÃled. <Genctic nulti> ia.l" zhi:.fers a1,o to sense ax?d anÃi..Se~~~e D1\1A. and
IP'NA; t:Va> :~,, a nu.:l-e;~?Ãi&
sequef..4=e fft{.dS: vumplement~e~ryio Gf `peci-fifa sequent':e of aucFeoiidesin.DN; A wici.ll?i'
RNA.
The -vohme.`s pI'ci'r'f.d`a'(I hf_'#'e'C,ii. C:an bi:Atti:f3ii 4G'di.h''u'aape .t.Le.fly and:E./L`.}.
For C-xam~~le; thc, poiy?'tien- in any:form described horn:;iii can bca .a,e,t #o pro#:aoie healing and/or tFel.. #3-.fh#I73t disCi.je by t'co.t'~.~x,,o:7i'Eg ttri.fg dt.'slit s.ry t*.:1 tt?LWE] e.fF..d fe<';,tC?Ilt:l caA4;.FRs. 17ht: polymers hprt)vI3a`ei`3 hi.s4'h..i.:~a1'.2 also T3e used R)ra wifietV t3Aai`,lpifL.`t;::ff)f'?s .i;fiQ i.f.3la'f..''`. bLZtnot li3'Ih4t'.d tt}. :izi?di.,c:1t}n of []:iicY'i)- '3:#1d 1?ai1CiPPuatcle.s, fihmv, i:.Ã?aiiug`, sf.1t.:e7, and f:Fathi;pcL1aL :liai.k.r.t;is. S :Ic}i materials kat'f, be used to i`i~~pa;f` <lt? f. ~jui't.d ;},gga.i,, b(3:w.
i35 tl,i> ?~is4S +..t.~~:~Ã,3.'.= ~'~i3i~=~i??,f<=~'S pitiZ~y~~'~:.f.~?~s;Ãc:.itl .:1w.z Lido ti:`c.t.'iicai: of 4i.t"l y.
lf... or i1? .'.Z`;kmgly;.>eGe":;d Tn<llxgi'3aÃ..a.Ãi`s; p:eÃiz:awni:,nt of mcllignatif'-t~s, or ot:"i:.Ã' :=t)aldildiia as . Se:]sit..>.'.e:` ti? <1:i1.g3a]e#?: thE:napy of fiItxl`t''m'Eli.t` x$4;Lnt atlcl-i as wit.I,#"u~+1..211>:1 rt 11,.11FC i'> avoidance of lt,?Ltf3 :w. Ãt71ii3l t1l`?d:'.= :F:fid.tastis`4=s. Ã$ug?,2w:1li3t1o3'T ?f local ,w.EFaE.: .3. c.~.l',:3g and dd".(.are<-f3e.ki. Piif~.-`c1.?;;n. ?1#ii.il#pulc;titrn E?f5tru4"t1.f3~..' aTlct :'6b.7.E}i'1'Iial. ser foi'.,`.:=at;t#ii. ;1F:43 fCiI=
2,~.,~`r NV tmifvElicait of pC?st"(Yp1.zil.ta re Pai2'f. 111 {,5,.:tc ii`.1 s`:mbotiiiiZ+::,i1.ts., .ti ' 3;?vE#eLx: i7ef..it? :]t't, tawz to treat t;tizi'3cet'. .`ift` t':ifii3:'Iple, ti1G Pt?v27i,ov4 provided ht:t'eii`_ Qcifi bt. i.f;,,c:': to orf,at i';:i'.s,l`i.iy s'3~,o`~,~'of.gnbiT...`fe_dy i'..g, lung, colon, prf3sifite; pe]n,ca<'..5, or bteastU..Iii,S.:t'= Fo:." +'.:Y.iai=Fi4`h'. :'.a3el2 #.i filf'i3. carrying i^rIiU o1".i2?f?Ii flief'api=usic a"CiIta is i.7t1liZeC' E+.t.'f:.'at ,, L>iYiee::`.
it oan bV iltiaplt`.\T.C ~9'`r[tLir'k_=dS:[2.kl.Of. glued in j.+laLe. e.g_ with 4Stvy.1fou1.+[yl att r4s2[Y..
F_:e po`3,Twi'S provided 'h#:`fi;ill t;ail also be used to {e.i e o:" w.;.''4' age:I... Tho agL=11``: 4 3#` be in any p1ha#.me:liõouti1:i1liy i;,e4.:cpt's.:C)lQ. J~,=4 lf=elf.fd`:i1g, w'rC ep:.<3ble st3l J. A la e(; .t.f..-bf., of Ph,..;".'f'i1acLu:1.c.3a agonts are k`?Z3w{:i in tbe ait e.tid <iy:.' ilil:lena~."+ak; i<?r 3;.fsc:= &I1 tlis,_ Pl,:.za-t?.<7.c::i:9l.U;:l c4?#'`.1P+.`~?id3at` t`3fq,,e pol4'1"i3'Y;=i.c li1ata..Ail.i described hC'rC'.3m
Acceptable agents include, but ari Eif1t 11iii:Ybi'.d to, 4hemt?{he'apow,r:(..t`ef.t_, .:Ãrch a:+
f'>ldIiJsS'.=ns.tiif;`r4, ie''.f:~~~tor Mh1b.'iO1s and a,t~01.:3i~ .lt: t;
Iz#lt7:ian<.
~i~?tjsul'si'f~zi i and ~i:t~izict i'~ iiM:l?~iS, as C4fE~Ihlili ,, {3~*~'~a ~~1.t)i'>5 or ?:<'Ã~~>CIi ~,ViL~f <,i'
without the co-inC3;3Ipt3, aIok~ of tumor or pathogen t1t1t-i-gG'nFi to zF'#.i,',recFsL ttaa tlf1.t,-;1vi7ph3st.10 response o..1 a Ãnewi:i of vacE:F.?<= devC.lt3.llmC'F3.t., IC;+L;a.1.l c.#.Ili,.8tbC;di: aE?#::nt,a, an~ib.,t>Ii`v:'s, tÃ"' a3,.EaleFi.= <iL3ds as c? niG4F?S of lc.3;,a~ ge1:ie 131eF`i1py,
thllt.~~s od.eni iSe dS.'.fFÃieds o L?. . as abova:, all tC.'~~,thn:O%il "Fnd ` .t.Ãf#i.':L. terFa:s used 1-wF'i :FF `ilat e. `^-ii s.3mi: Ã?ci$ii i11g as Ct3IT1.iF.7otlly understood by f3iw of S3T"dfF':i~li `r skill in .i"Fi:: a1~'T.
Ii"? i~'hicb z,:là n 3:nZ eT:=1wn b0o 3g3. Although methi)ds wad `:1ax,.=rAi:Fl`:+ NÃ.mffl.:P_d' or k.qi.:ivc..YIEa=.t, tf's
Y=~ a be ~='~z., C alt. the a > r' .fi to ~ the a' ;fia. .?~: i::ÃA ~ aÃÃ< those z~~:~t~F`Ã~i#E~Z~ :`3~F`::1, can ~?~ E1ST;~ ~i~:',~I~~. *,~~FI2~; i3.
# . zi})`e methods w1d materials are described below, AU pa:?F1{vat#Ã?Ã S. patent tappl.FC;:itlÃ'+Ã,~, pat>.3=it:^s and t7th[ Ã' references m',Eli:tloI7cti.
Fi'FZ:i`a:Fn ..Fm= #rii..of,~.~i}'.cltL.d by ..L :(.'=a"~C>.nc*w= ?1-3 their L.ÃFi ai`.Atty -undess noted ot3 C'.F :vlsv, tFT case of i:3:Ifl7G>t? the i:fusing s`t~~tiSõ'.lfficalio`a`f, fflc.udF3t,`, i i%fimF#.5ons, will Lo$3tÃ's.)3. Fn addition, the I7.latcÃi<.F y.."Ãt.hoL%s. and .;}isa""ip4es on1h' and m~~ intended Ii) bi: IiF T11n:;.
Ie:S;` la io=F1Z.e is i:i.c3E~.~t`:= to a URL or other suLll ldenfiÃ.ier or iFddrcss. it #Tld#. .F'Sw(?d f-a3:3~ suf h #deF:ti':1t Fc`,. can change iln.d paFTt.cE3:aF' #:nxt? Int:.tFoIi on tl}o #.-'}.ti:Ãn;t.t. c:aF:3 i),, btiE i;qui= t:lcÃ_t:. F: FfS3nF7F3.tir3n can be R) iFÃ3d b-', s4a.itrblrt"3r: tl3c of?3c and
~efe1'"a Ã~~#:cc. thordez u~~='~#.T3e.F1i.:etl the availability and pLibl3t 4'.el.ssi'=Ã11Ãlti'::Fof
Fi R?rn.la`Ft?;:;.
tiL'E1nknui:Ci can be t7s`.=.~~ doi L~3iaFFIÃE:F~: "'zp:Fd-ww.,, c:Fzi.:F2i:C>%Fl ctÃt'k:'i`i.':>, phvF?'Iat3.+'..i..Ft.t_,.a, 2TI'vpi.#.Fi.1t#.o1, formulation &n.d delivery, #.Ãed, x1i.c3i'.1`#ei3t :o-I= s-.tbj+.cts.
Standard :.o?:.:?~"#:F;.ÃqL#i.:s L.ctÃ: :: .FsotF -fi3r ii;=coTY1b3.F"#.<:=`o i. ''s~NA, t1~~Ãr.3Ã.EFI:i<3~ 1+ 4' .?fl3.i.'9 a, and (Issu :` C1.#l.u3"e ;iI2d OL=ct3C:tpCk3"c``: ..Ff?" R4:i i a.i}.Fls and
Elu3`IficeA:Fon fci:=hnÃq`i.Fes cwi be pC3itbr%]'t`~.'l, t ,., using kits a{,',cv;di;EaÃY to :E:i3sF..#fat':'F.R.Ff.F'~.' " s ~C.'+,.:F~;~cf~,a~1:`s or c3:i i',=(~.I~'1I133:TiN' FIC:n,'.of~i~.~9] ÃS~'~i'=C% 7]1 i`Ã~5,5 :a or as described herein. ~~Yhe foregoing techniques :1.id prCr.edlll t..`i ;"f.-'.='I2'LL .'alt\' are pe'fi3:7':r.ed zI.".:QC} d1;.a;:. to ct;IYvi.`.Ã"#hoÃFk.:3 melt,ods well unknown. in the ut aiid as described in various >,õerieF`a: axd moÃ.. specific 1'cfGIvÃzi i^thw are cited and dF4i=Ee3'wd ThT()u ~?i4~iC=7:t ~3E i let 4
Swmbrook F.t F: , Molecular Clonangt A Laboratory M;wual (2~.i e,]. Cold
Sp.ÃFig Ha.F~boÃ'
Laboratory Pross, Cold Spr;iig Harbor, N.Y. (1989).
Other :uatt:#res and advantar;4s. of the ~n.vc;n#i:r,<: will bc: appa:c..~: from Ohe following da;:,led wid ftom the clai:iris.
BRIEF FIGU RE DESCRU"11O'~
FIG. 1. is.: :xa.' ~;~=~~~~~:~ ::~~<.~~~~i~~Yw t1~:~. ntÃiiib~.r of lIs..at;:cr 4r~:~Ã~tyi?~:1?: vv#t~~ Ã)-iyd#Z??%' c3"Ã#pti;tht i-Ãi3 loaded fi%:i71s, control fili?tS Svit'It3it ~ i.i i7`ri~Ã`i:3:S yC it:I?~~ J. ?4.ii1. ~~i:
IG. ~,' is a bzir graph shmving the nur:bei o1"cclis Ã;eat.-~icritw:fli 1Ã3-
cfaded aihns, i;c3n.tz'f?1 ffiltnti witffiowt 10-hyd::oxvamp#othec~r,.
a~l#?~~s, wick. ,~~--h,~~~oxyc<3:uptotla FIG. 3 is a >3ar sÃz1px# Sz?cm-ing ehe cyl+_](E=:gxi.C.ity of a?E`?ly(`'a.~i:cÃ,~l f:=(? L.p:";31..sclo;iel 111G 4 ik .i :)cir gÃ`a.q~)}1 haiii.]~A."1#3g ti?.c cyt'~toxÃ4ity of nulnE>iluti+.-.C,` vv?ffi 10% paclitaxel.
FIG. 5 i:... bar ~,'~rap}i :=hi>wÃ~~~ the c~~tot:oxii:ity of poa~Q.l~sw> iui?'Ã4]pi.:F"t2LlL's, W11,11 P~`ES ri.:fylati3Xt3l.
5 is a ~~i',3q?x? 4x]Etfi #1 g the release of 10~}p5'ET;t?hyi~c?#2;~3:i?~?#~.1Ã:
Iv 'p3J3yilau1 u. myÃ'Ã>itÃo, p$lmitac, or stearic ms,LcZ.=wl 1~1(_3. .77 .,a a ~i't1~3}l S}lOlWÃrlg _0hyiitCt:tiLYf:'mTttAollacc:nti,Tw<Isi:= flt?n] poi.S{tite;1.rii= gftlc>ol "A~`i.?:iT:es on pS.YiE.ari:muÃi.i "itrIps.
IGS, 8at. and `~3'B, t1i:. '3+,:u1di.37g clectI'liÃ"~a m.t;ri}g.iph5 of I glided poly{st4a:ii, glx cea'.?l TF1G. 8A u1,ow-. Ãil~~
sug ~~~c:.~~ of the fi.m {su~le bL}r 3 -rniw:rc?vs), and 1`1G, SB shows ffic fiAl:~~ in (sccile :.3<`*i^ - I Oi3iAi. t'i3mS):
Ã'iijs:i ;drit3wt?g IvarbiE+le .`iwr^llÃFig psi;.L wlai<,:3'uS pl-P:e.
1 5G:10 is a gmphs}?l?wSng Si.ie do].TAC'L]'~~.'i~tY~.~l~.[ \}bsi.3..4~+.~..~ l)\t .v~7.4\~a [.fC>51.'~+ C.~7i~.Thy *t _ Ct ET. i~ . v .s 1..~E:ckÃ~". :"viõ]~'`jy -at a ~Z t~~ 4a.S..'i~iss4'tA] S`.]a
` }' IG, l I is , "'zarm:,ng 41ectÃ;?n mac.raasc;?p<' (SA" M) of FIG. 12 3.<? g?"ap of the d3.i.li2wtu of st,#:9i`~I' derived TnEÃ"o4phci'i==4 at viu'Ã.#:3uJ r:3ll:?; Ã"aG . L? is it bc3Ã' g3'~pla 4i-if1wiJlg ti.#AI?or rtt]lÃ,121iC: in 2'^t'=.4'pon;iO ti? th#:;':I.oÃh41`F#.py-. ?otWkA 11z1110piia ].clf':5.
FIG, 14 is c3 beÃr z>'si`'~3,:1 Sl3t?w]I:g i'i1LC'i:#r Li"tlE1m- in response
Ii3 .si:ia]4Ã.a cs#`aci]us 2zoryri,c: ~~lm Ãn]p`,;yirttalion.
FIG. 15 t` iz R,3tiir gmph showing tlt<. percentage of hum1 s,.sps;3T.isG=
i? ad::f:i R04-1(CPT aand uffle.?aded fil:~~?s.
k?:3~' '~il~>rh s~'a)~1'CTl'~ G aa7:L'caIICC1` activity of riiEa.l ~`s~: l I ra<$<>`~
pa.;tc:os wzffi UrC (lun F ieinwGÃ') GC7al,? 'L'3.I'T'i).
J'a~~. ~~; i3 i^a: i~ÃA. g3i~~~l': }}of)s al~fS ~~aC t9 tip'Ftb of inc.~G~.lti~.,.ysvt loaded 2]l'~~'2i?~)c?Iw~t ~'.~ : s?:3cti.?thehomi# ciol;.5 in vitro,
FIG. 18 is z; bar gmpl: sh.~wnn;; tliic wita-caz~cet activity usf pac1:>axe:
s><mopamiclt:~ ~~ ~ ~-., A459 Minn= hang cancer col1s in vitro.
DETAILED DESCRIPTION
Pl"tt4'1dQt> .1e1'i.'ii? %'.Teci7mp:3uS1dJ at.22d pd't?cG>scS to prepar-' b~mt;d fl3Yli:i. paIEi.:la;',3, f;ld:;r ,A.xd :Alw teCi co;.11p(?s`fit331`'a, c3.I1d `.riZ3C.E..S4ct fiof." d`l.l iv`r.'.i`n3 Inki:.'= following de;>c3.i~.~c~" 1i'3~ sy'nfhcsi;' of M3'f'fotnter units aiid the pOcynmc?1:'si6i.l`: of Lhtsst'
i~lÃf nffi~~:G:~ z.1~13~.ti. Also ~;4tis~,'I'Luc'..La is ~~lL : ~ a1.~.t'~YS of Pt`1:vi31Z:3"#:G S.`{'uL%3..E1L..y <hs.i a.Ici.''qvx:tto t } .hef~. -} < 1a5z3`lS~? diIr1~Z~35.1~.#~Fl~#.s to '4L~':~:at ~'i~'~'i?3~'I`<
Z3isi`~`~.tsC'.S a.::xL"; a }f1~a<)¾vt:xt{.]Z. i~~ ,s,>r 2s :A at to:fG. y~`~ 5.A. V"t~1r>d4 :.?f C:.~
dis(?'k'd4 rs.
WL will first describe i 1t.1ya n1?no271Lr:S that a'an be i3sed. in .ia ak#.ng ':~~E:= .wi:~w z~.~olti`t]'.ers, as well as ?i1etlious of synthesizing the s.3'?+:?t:?c?..7iens. Wev: i1l then (#t;,,i-c,'ibz' x?e~a`~~3;~s ~} ,~~~ 3 a.r ~~g and ~~:;rex,F the pc?i>~~~ers. ~i:~?,~~ ~: will describe Ã:?~: ~~: ~:<~~if:tÃ~. of fiflms and q<3C:f3 il's, as wi til. vs fliv i11T o3~P~:ET':.~~tli?Ta`~ of agents 1:i1L(~ r]t}lfK:3~= :C: NH,`#..+`'a7xGs.
Finally, .~~ will di,;cell the applic:~fic?ns c?.~~the po1yrn::~s and ps:?lymer-ager:F 4.=oiv2ib}A. Viia~ I Monomcr Unitg
$: As shown below, va?'lC?us vii?vl .ni)1?o1i1Gr units are disclosed
t?JaZ?:3~`~'r %#.i7.Fts i#.Y'." l;1tiE:d to pop:iTe pi3l~7T1i,'.Ts5 a's >Ct. . .~. 11 fiuther dc`a"r,:l. buji3"t, V;~ik'i t?nz>tnor ,,inits include cÃsrnpow:,dy of Fs?m-1111;1 1, lib ~1r~Q III.:
iv'h@.Acadl Q wS >tdk.'-'A~cn{.cn.tlv sS,iFi~,cted fTt3m wwonYti0, S. S{. or
NHr
C7 or 0 In{: $~ t g;:'=thS..:, ~.~.{'o st:lt,~`cted.ft't?fii among:
is, sc,e:.fed frona amÃ.attg a Sarti.~,Eii or bt=us .hod alkyl, evotoalk`
tizlrl, ,<l. yl, ]Y?, at slszlyl, alkyl~ry1 ary:Ialk} l, or'fhotocax-bc?> chart of - 5:_ car.~)c?ns, wx`{eri:.$n L4E4 zi ;1~~Y `{<< L3c:E!.. We 1~v ~, i33T.v1s3T4r~.,
or fl;.Io?:E3aYtli'bi.`.ia cha'erf is 3,?pt1on`2'.liy substituted iI1tC:mi::li j' or ti.nninal ;.5' by o-tlw' {3r;I1C?I't; hydroxyl i`y{ i{3 Sy''v'tfief , {=aeb<)a y'. l:a{'b55'S. "Un.I di.j .::k3hao; m(.>uio 5;F (az^
libGtdb3ted .liu..T3t,, thiC;l, th?tt{.4toI; sWfi?.+. phi.1sphat{'=, pa'1i34pha{1 1t:{d, T3r f1{ o, u?"#.
I1awit's; or
R~, i; S..tC,dcd fi-t3a;I wn"zi?ny p3ly(S,. htt C:at', ~r?.ly;t3l)
l.aibE1hydratt:, a protein, polypC,pt1f1C.:, an 's.:T:l1Alo acid, a t:ll:ck:1+:
c+;oli:, i:i>al].La%'.of'.fdi4'., a ,"t3olyi2u`t'ieC3ti+;..~ie~ an't%. .'s.a,f'.1]eÃ:Ii::: material, such as a DNA +_i .PIN'A 5i= '71w:nÃ:, a .:p3:d, a :?[?lysacch<1Fide, ziFi :?t.tfit?ody, a ph.intAcl:'.cutFc-ai agent, or any cp.itl)x3i;
1{)# a ``F#i3: to,~-,Ff:i.ii receptor; or
R. `.~ vQ-k...Ã',~:d flam. a.tmo.-aÃ? i.: P~IC5Ã:t?E;I7)s5ltl7kciblt? or ii:;n1E,a I.I ;y= c}c;~~N I : ?kah, I % gZ3up;
Fi.\, comprises a first ~.,f,.Fi:i..t) that i.s f;=o.F3,-vi:Ftlbl`s:., Ãfi a second >i,[ap 3.1affF...i Fit ffor;:~i the a..Ãrià ~?~"(31t~? ,1; :a pfI a-à oTi3e`ow about (),0;
R.; i'~ ~&`vtÃ;d ITI)iF'i .{niE3ng hydrogen, a straight or :7.F":md:+:<d alkyl., {:y4.;loÃ1l-kyl . :3i'ghi, {alC,fm,,, s>ly.Er aY ~~'il~S`t a13k~`~ls$iZ+l, e33~~:'.~ca~.SiY'.~ l')I~. 3s~*i-~t3Ãi?~,.:FI~~.`~E?4~ i.:tÃ:~ C~. 1-50 by c"~. .v~~FL.>.~:;n ~~yc Cd`kZi ,Alq cys., ~)i~b~Cy., ~~ryl., ~. 1l~:~~F~.,
Flk~lh,i ~' ~~~l, for>15i1 t ~tn~,yit~~~~f2,
<a"+-l`lkyl 3f flÃat?ioz:ari10I, is optionally :ia.li7st#Ãtaod
Fnti`.F`'.,ali;}' or :on:l.ldwi.:y by +)ne f?`: nao,FE: `;'}~'~F+3,{Z`~. ~?ii~Itia =Z't'':tCF ~.i1:i~?i 4"v x i ill":`!s`~?~}`~'"itC':', Ed'FaF"btiyZ'i3~F'la~~`~, i3iTFi]SFi)K ~:aFi.F#:f?
iiF :~,,1>)s.#. F.tÃed amino, thiol, Th2oiaie.:', SiFlfaÃe.pj:){)sp,03<"F:Ã<', ph,.powp:"Fof'1:,;Ã~.', or hka o:.Fi=I3
#;", efi..?i,A.ÃGiFt }Fol-r1 ayTai'}l.lg :.?.'.IFi'.31; l`a,, or branched alky, s :'Z.`.lo.lkyi <lrS'l, C3lZ:fin sÃ:[~I, <~I~ ~r~~ia} l> ~.~ l~ilzr, i~lrtr~~~~~ l, ~r~,~I~3Ik~~l, or Ã~.i?~~t~~.are)~.~~~ ~:l~.~..iii of ~.~-:?,j i,~~Ã~-~r~)~~~, 3~,rhc.o-:<in alkyl, c4'`ioi$lkyl, a.I=Z%l.; olefin, 4alyf. alkyl;?S yl- z).r\ l>.ilyi, .~ask'i'lary,, :1:Iy~llk;",J.
E3F r×E'xi?;.t?f ~F~'3<.3ai cha#r, is apt1oI1allJ' slabsÃ1t4.Fti;i~3 #IIter4iu"Hy or tf.vtlin.:3clyby- o#.ati= m' l.'FC3i'C'.= ar:ydrC3i':'l 1{'f.~roxv'dhC'r, c<~Ã'bi5xyi, G.FTboxye5iea ', {.t3.1'boxyF.#m:id(:, a.1F-n;i1:?.. ;'#1C,n{?- or di\ubst#t1:1:sta a#:r:ali.;. ffiFo..~ thioesÃa, s1FifaÃ4, pH'sf~:9sphate, phti3splaf4nt`3.Ã<', or l.4iliL>,'=;kn~
I1, F,ciÃ.: 3? a i:=LA#^t-3poi321d t}fFonnF=;Fla 11 is sE..zet :ezi fti)F*.'~ e:lfEat3"!g a cC)Imi,i?imi.. 4EatiwÃi i7el(?i`r:
i` ix s x eiE3 ~:3 k ~`'H a`hoai R's and 6 1'#:'f? :itad'L'pGadl'.Ã`itly Sf:3,i'={.ieCa. :i4 deflllfi.d
lu i.C;naal? :":mbc`d.l3-i'=~?.~lts, ~~-ie compound of Fti#.Ãlzi?ila Ia is z, of FCZrf:nu.lc.i
IVt wzlf i'L Q ls oxygen. 11.1 4:>a#'lfÃ.tl3 C;ilibC>dIII.1t;Ã?t:i, the i;mnp(~,E..`eI`.t`e o:..FCZII1'2alz. 11 is a i'O;:~ pC`.ul.:. l:? FE7a7m; a V i?.''hC:t'~~ Q ii 81:i:fiiÃ'. I.['~., t,.eTL:'a'.8i cmboa.rr,l'.nti., ti:Fe mn'{:oE.F.d i,'A'
Fommla 11 3: a 'S ::fl7iP:>u1le`: of F"L?rmL3l'il Fat''!, where Q is St,`_ In 1..<;F"ti:ÃlI. C,FI`.b<.xt.~..,a~:v.'+i ve tht:
_io~~-ipm:nd wa l?ftn-nula If is a compound of Ftx;-~~~~~, VII. where Q is
Nil;I:.
In ,rà h.er ca-ii;?oslim4nt>, a cz?mpf~undcz lffz3rmu1a I1 I is s, leg ~~;d rrcz:;. xnomg a
C<]mp3oun.i ;k.l'mul's? VIII,, tx X., o1' X.1, as show2i ill)oLC:. 13i_ c5,rt.3liri :..inbt3d.m+,:nt'+, to'.e 30 ct;zrtpC~u41.3: t`+?: Fi`+i'in ula e11 &s 'c1::Ã)inpi3uI.d of `'3mufla
L'11.1 txdht.'IÃ:` Q Ioxj'.SS'I^, b t;t:i:ili.Ã1. 4;m,boc~iimeÃ,Us, the conapc>~~~d ot'Fomuala II.( is a co.Ãllpound of 1"Onnula
IX, wljc;re Q ~~ sL~lftir. In ceat.ain ::Mlib:yd;:Ãni..nt4. the ct~~~ipound of FormuIa 1.1-1. is a 4ompo,>nd of Formula 15. '4~.3i:'~'U ~ ~ 14 :~o. lÃc :~"~7.~~ttiMlil~L,tts. Ã~Ili i,t3mpÃ?u.F7d of Forimifict I3T ts a L.mr;.pou#1d iss Xa w;:`>4;ro Q 3s N11 1'1.
[z# C3#ti'r eI1~boteln',ti;3]ts, a C:=t.'?mpi.,~'u11d of Ff.'sr'i-mi:a It 1s 4t,.;ec .c;=.d firom a{:';o71g a compound Ft?nmta~a Xi1, XilI, or XIV, as shown belc:sw:
XVT 1. NH where R' > ;tnid Zf wre :i?de:?enc.~ent`~ sclc>E:.Te41;~~ defined l.z.:rdn.
c?1?b>d.1i1"?Gnt5, ti-?.c ia`~mpfx?.IÃ"d of Formula I I isa wYin:'.+tiund of
XII,
Xil 3. it? ci.A:,$i:ti ..I'? biy(,smU'#?ts. 1l3ccon'~pÃti3.,,?dofi ,,)I"Ã?iLIl.Ollis ~i 4.~?A:"tlTL?f?a?ci~.)..'' l`(srt??U.l:} xiv.
A cf,rnpound o: Forms.Ala III cm also ~.~~.: indepcm-donÃly wle;tw, `f: s3rin, among a conipf?und c?f;-omnalf~ XVY XVT;,. or XVlI, ,~~ shown above.
`j? >,:C..rwin t.`.l?~'"~7Cdl;'~3Y'i tC, each G F:rC?up is..clecieL% fr+.2m.amoi?,~~_, :.i ;;ilZti:p slwfivn whE.=p; Ã:::ath `tQ is i:1depenÃ;i<:i3dy selected #.ont a:'~luilg 0, S, Si., or Nii;
[1 s~:=?c~,::,: ~..E?k"1:~ i~.i"~~(?~i9 ~]'s'Ito;F~::O. m~tht3x4'', ethC's:`s.y, `IEAI-4 (), c3. sti-a ~",ht or btwicbM .~~kyl cytic3 lky=I., aryl, ~~lcfin; s<ly1, aMyhi~~~L aqAty:, a'~~l4aiy , < raryta,katE chWu of 4 `C: Qarbo-ns:;
R4 Llild R a.,i'C' cctt.:i ~.I'$~~~~ :I'L~i I:~~?v st~~=~~C~~ i:"~'=t1naI1It$ng a s;3" mt E}r br:3:zica1F'd aI~~l~ c3:.lod:ko aryl, ~~iefhi, i;yl, alkzrlkl,z, aFyiSi:~14, Ay-,<uyl, t?t ~ryla,ky t? c=;arbÃ?ns; t:old
R, i i :idf.4ted f1";3sn among hs'de'3;yf.-n, a 4(rat4.~l;Ti or branched al
&i.:3 i:yL=zC?aailyrl, aryl, Al<:f#rl, i3lkfl`s3?'y3, i.'s~uyA<3.Fkyl m:iaaI-n of 1-50 c..sidbÃ1ns, wherein kl;S::
<;,k~), ~:}~c~+_Ltlkyyiryk, olc.ttn, aI.k-,`1aAyl, or ,~it~yfialkcQl uh<Iii is op:'t\?nal^y subk:tt-0iec? n...rna:EA4 o:ermbnl:ly by afzc o-rmore:(lydr;zxyi, hyd-myeffier, caibz}tiyl,
agar'#3CZxyLstC':i,, iwrbFxy':i:lid.^', amino, mono- or di-substituted all:#o Ã.#Fol. tl~loGst:er, suI1aw, phosphaai.<., ~~~izosphonats;, or halogen .~.5 h3 cutaln i'.:`>lb(ri:lnwnts, Ã'=<,lS. F3 G f.;IRE1p is sCõleeiLld ..1'~^~m i?.llJi*il~? a gi(ii.ip shown bi.1t,w:
tir where ~~.>Cx1.'~~ ~. R~ ; ;ml ~ ,, ;3:~~ ~.<~~ ~ ~dL=` - ~:tlcit:~1t,; ; ~i ]l~, .~Ã.c,t~~i:5 <. .~s.'~,E'~~'e~. ~
IIl sso~~'tiliti. <?"I7.~.~+t1dim(.'? is, ea4dil G g;r#?EFp j:a sG;lEs.'~ctC'.d fTs.`3m x3i2-3.i3Ã 1 $ sgn,)up shC>vJI`~
p-=. (.Y.r l~ ~~ ==~.v. -_-" \\
R` R:, R. w ). 't337.C~ ~'i %#id ~~?s f rf <~ i ~ inf i1[iF ~~ ~a~ ?t::`='t>
I rtti g~~'<2. i t '~;Luc .3 ^`~ ri t M siÃI., {{y ~, :~;~....~.,:..~. ~.s.3~?~::17t~f3.~.+'~'3 ~~:f`ik:. ~ 3`~;.is.'d Z 's ~~iJ .. ~'~~4.~'~4 co:.'~~, Cl ~. si}; , t~lkyNi z'~ ~rylz Iy .Jaakkola:yl zxa`aÃyl alkyl Ch{ziya of I N10 waf;roms: zand 4 :.1cUta'Ã~ S k .~ zai all t~al~ ?~? {g x~i4~r~ ,.t`~~~C:n, :k#, : fE1: t , riÃl.czlt`t:. L:i. R~5 cvs-lehr:lk1`l, '_~t?':'
ohA#?'d, i3lkL'li .F"yL it' ar4`IalkL cha:#.n t?f 1..50 d,:wbi>w, ry:ht=IvIn t.heillk4l, incloslz?ivt alZ'ly olZ.i'li3, tilkyli.t`yl i,i' anli#lk",': chain is optionally substituted Il1 eY#:?:.dllR% c,a Ãt.F>?d::Gtlly.: R~
mw or Tnis,c IiVdi\,j'./,li hJ"dto^f,\f..:hi.)1 UGlrifo?}Y=i.
Z.^{YrV`\xyosCGD, ctArboTya:itzd\>> amino,
mt?`lo- :;i darsubsi::uwd alz`]llnw, i:L 3.C3T, :h1+L.titmq 5ulfa[S, p f's5pt`.3W, pla4;3spy3t3l1ca:4, s.)r ext Ont S czg
I.~ ce.i.thin s:,m}?C?dim-tenÃ4, c.3::h G {3I'a`}1.i~3 i5 s( l?~t;.to.~~
I~fTl ~:t:`~iÃ?l~,it a FE>~I,~~ :lzlL~~z
<'i'I7l.*To cm.dl1. Qj R^, R4, RZ 5 as dot#.n'd hUree.11.
In ccm:i$t R, of F<3m1#.Zlil I gN sC:lwed fiC?F13. al:nt1.sg b'tdio',';f i7. alk,vi, cZ=dl43<I=.kt 3, alkvic, dc`c2lk1; f:Ã yl, md hLt`'.IL?ar:4''l. h1. e:ftc3.;1.: e?nbod::mth nts, R of
Fonurfla I :s s;:Icetid fr.?M rIMOV-9 Ct C2r3 alkyl, vv,=cloaikyl'., :_~ryl, and In ~rtum, embodied.. .s, tts: ~~, ofForana3a, I is selcewd.faom am..a <w w;tiy gso,,up :~1Aowr`
methyl ethyl
Ãsso p r<?py f v =\\.r~ . "v ==\_=r' .
"=. =,.. y . 4`l r ~` \~i =\
_" :~.\ :=\= .~'~ /~." -~-'~, e.'"+..=_ ` =\:"\+,! ="\r_~~ ="`:': \.....:'or . . If1 ~,~'. =.~~,. .-\,. `\.~;, '~\.~;.. "\.~:-r \-..: =\,...r"l -!"\...::.r ==\:f . =`\:or'. =,
In curÃxair, 4m:sodirm-mts. R, of I{+}miila I is sclected fruÃYx aal<xn9,
i:aloaiky , 3.:eÃc.Brantl.(;:s 1c<<z>loalkil, zAlkylc.4'ckmtky=., tura=` and acÃoroaà yi, w:l::Ã`ein li: aliay, ha:[e,~ Jzks ;alkva, tvc1c?{iiky1. .~lky1c, cause ~lkyt, ~ y"k, and h,.wawiryl axL. ty,~~iona1h.,~u:nsfi'Wied, In oxqa:i-n miabodimmts, R, of Fo>~~iu1a -1 is sclic~~d frÃ3a.n ~unEs:x
C# L ,alkyl., wz.zn:in fl:ev;lk>>1 is <rpÃi4}nA}substittued with ~~ Glo,
s37 (=001'1. ...7 csw`.Fetal.n iat"ibod1:r.t3eJTt;i, the Ru ; . : m..1d<Z. I
Fs Seemtee.l ffiri~m at~"loI1A,
my' W i:up Slii? w" bi ;low:
OOH hte
B. MeÃhod* of Syn#.hesdAng Nlavl monomer Uitto shoml i?eaf3w, ihZ. vinyl Y3:C?hTi?iT1eT tJ:niv descT`#bed }l..Fs3.FI' can, 4b'tlvhe;iz~~L by TC .=i3ctiIli.3. a cof31p-ox`:nCi of.FtJi1'1a[! 1Ftf? pIf?v.dv a ct?'.'2pLrlsa'#E3 of i'oIalidli# I:
R.----------- -,_.._....~.__~._ .i =
`A,FL.: Gts
`11w. S,'. ~. " . ~ r~ li>x jl.,eLe =~'~L''=~` and IZ? i~I~:=1'fs,C~ , ~~ tilt s'`.=:s`~f: i IC:<_ "~ as i c~~` ~, ~~j., f #, or ~'} :3Eiix of v4~{.=e~.~ C:l t:fi;"ied.
and 1.6 is i:l lC av, gyo'i as --e n a cc?mpound of F~.3rn-mla EQ0, wI~crj`` Qand 6 .;rQ as deffi-;ed h.feiTl, is d:,;:,L3lv+`.<i:. in a s?lvs:ill: tiucl? 41.s h.~.Z-aIlc, bc..t~zt-?ea tE.3lllt.nc> diet'la~l ctK~er. k_f:iayl ,.cetatc: ~~iddcf.i'ott,Ã:thanc. 1;4-d.ioxome, tolÃ4tffy~,.~rofar;m (x`HF% acGtonc, acotoaÃt-ndc (MoCN), (DNIF), z~irnet.hyl. sulto?ti'ideti oc:..fic acid, nLDL:3~f1f'~l. .SC)a;i~;:f>~`~i.~.InÃ}l. I~.~~".x'[:>-~~3c.i.l~.l.'+3, `=~hi.EtE:1l= I138.-:ll#t.#.17.ol oT.6=atL:'.r. tE3'~~E:Itti:?.1#.:
S:i7,,bodl,.'}onx:~, a
Qompourid of Forn?ub.i l-TQG is ;:Ti<:~~~lvi:.d in THF. To tffiis solution is Cadd<. si t: l a. A yltjyl haltda, suda k h:orde. En 4c.stain crnbtizdynaen[s .: lsasc as a ti,x:kyi. amine (e.g. lt: te`hy:al-tx,t1: ), is added to the Ile:i0tof: 1:F1:i?...tir4.
The rLyu . wih; product his, a cCE-y3pi?;3i3d of Fof'3:3't3la i.
I'`., atnotheE' i'.m-bC5dimint, a ci"31pt.'su? id of Formula I is ~~ ies3:ored b4`n ac}i.ing %>
z:omn?:sb}~Ind o~.':Ffst::-lu[a s~~~QGJ. wi:czc Q and C3 are i.lefined: zt-i ttbove;; with at ac.ry1 aI.h't'dn"dL;, `utfh as m4#h::t4;I'yl1k3 anhydride, en tiae pr4=>i=.Tii:at: of i3'3%;SLY s;.td'.= as tI'?ictiI'v[
C. Me-th{sds of Poiym~.xrazing, V ~~~l monomer Units
As sbi;~.sn :)cI}.w, a t ..mpd1und c?i"Fc?a-niuls~ I can be pol,metizwd' to v
comp.~~~nd{ & Fonnl~~ a XK
X X 1>Y s1'op} 6~=
XXI pitti#ac : hs+rt?phH:zÃs
?~FL, - ------------r~'. 0~'
lvhÃlv eaca, (2, (3, or (3 and tugz?lher; and ~~~ Mmo indi:~.~Ã;ndentl N selected as defined and r is ati ix~tc >e: from 2-750:an(I 5.,:3ch p3 eL''113Lr1c tt.: il b143A i,fi~C?up is 4C'1cb'rwd #i'T'o:'f1 a:nJn`f wnmni:4. `,:b.iobõ i%:n1dZ`\.so ph l.spa3atei hyd:toxic,, a:kof1eSv and zflkya3.G:5.
A. iy .:TYE..thodi o. Z ;nyl p13%yrni...-ri: 1a-iion Ssnmvn i>.a. diC' arL Can be,..:\'~,'d i or Lhis
#'L c c:7.i3Ã1, Fo> ,:~mwitpl a cun-ip{ ''14.`~ t?f Fon3-i4.1lt1 I i ari bL`>
F`cai:=tf-A wÃtt2 a fti. .. '.".>lisc'sil mit~<l~i~.a~. ;nC:lude ha3cF4en mo#ixutGL., Nucha4 C1.2, alCi eompownCfs~, st,c.t .a4 2 , 2 ar:cxbini3 Ã:aetb:~lpaoyiioDibilc) {)VlBIN)> and org<Tn,c puc?aidcs, ;;wh di 4-= buty,pw:roxiz2o, Th;c> polyitkettzation canaIso be Liu.:uced by !:ghi an\~ a ph.}.,zin:ifi: =oÃ';
-i one cn.t?i7Ã~imer:t, -a compound of Formula I is di;:4c}:vcd i.~ a solvcnt:, so...l-; as 13_`x'.iT,o~ i>Ci'1cfiL. to1Cze.,a.:: ta3efl'-Tyl Lti#.i:z, C:hlCiTC3fl)C=m, tfiyl c;c;ft:3tF;;, dachlo>l>Ii C.thc]Ido, 4r.
dho<3Nw>4 tt.v&hydr(~furf.Y.tA S=iiSBIZLicW.w1L2e, aAreto)fitl=L.t4' (MeCN) \~+3~I~~~lPJ.'.~\1(~x~i~Y:fJ.6{i.='
(f)'~4F'), or dÃk~iofli,:1 s=.art:3xicie, and re:actcd wiÃli A [BN to tri..'.. -a u-sms.Vc>.und of Formula
In ccaaa.l3.Yn `~:'3:nbi1di.i`$ 'L':nts. the z?(abl:1`mf:3' of Formula XX is hyCsai'ph~'~~.?a.c and i;=C)rmul:t:`s
P.H n3il:ve group. Cl groups that mz> pFB sunsitrve can besc1e::.iefl.frc?.in aai:z?n~ ~.lrp:>
xYt'irraps dcsi:ribed he.rcxn. As ah.ow,~~ above, ~.,t?l.rnc.v~ of
Ft~rnn..ala:XMI 4.nm bw= Omaip6d lt: a ~ ir~ ,~ ~~l:l , .r;=.~:zsc group. A".3y- ?n;C'fla+3d aff acid ca4,,fly,,t:d hydrolysis kais?wIn in 1hf' art can be uSed, f6r this Ãõt`I.ns~i?rÃnataE?i2.. For ctx<mapae, the 2irpdrf33Zs#s can E7e r1.c1.a.zi.:d bv :a3:lia.irst:ng ehe p;?l~'ant,.`:I~ of
Formula XX ~rac? a htitfi-c?w:h..aric aczd solution. The pti of the scAuÃion be between ~tifsr:, is ~:~~~~..c.a~ I ~ z~5. 3- >i.~c`
1 ~)c and ` f 0 to.l and `3.5. ~ .~, ;.t=i~:to G~~ ;~Ã.s~ii~~~~.nts, :1-~~. pl-1 of ~.~n~. s<~1 (
Q~t:7npic. Ã'~c rsi-z can be b;::;<3vv about 6.0, A .5; 5 0, 4.5 oi: 4Ø In c:ortmii Ãhe,
PIJ 4. >.? :5t.3L=.k' ~.:.11'.a,bod.II1-l<;nt5,~ thevIll sensitive group viln bC: rac.;aTlf?vZ.i:.i 1:::;.dS...r bust:: conditions Flnd'Err L=iin b:: cleta-vod +,a ry-m 3fical`i,%.
As shft;.vn kt3ve, the hyz~~~~~Iffiffic poiymcr of Formula XXI czir, :ncroa>~ 1113 SÃ21':e f11S i'oT?lparod, it> the Il~vdtoph$3i1#t. pi.)l~mncr of Ft:.1n13Li.G<a X-X. JRb:G 1.7:;fit'i:sL,d z*,i t'. (S;;) S,:.n1ib+:'. 7etw,ei:'n. L 5 :mtb `:'..0 or 2:T3a':: tll1'lc=`~^' [T3t'. C}i1,I3Lil
Slz`4.. (S 1). [n certain L.t..bs:`d amesite, One
Z.~ .. C aig' 1n ;1ity` L ? to S2 is L 'j~. ; '~: ~rvlirw'~~ ~ ~~" ~^....a{ ~+ ~iL~, ~.a.'g.,z., ~ ~., t i` =1 '' f';e and 3~~ t+ a. i'.~.~ 3~! . ~~ . ~. ~~. _..:;y :a~n~.. , t'~ ~a~~4 ~~:- ~=1~ 5 ~.~\:
2 ,ind4., or 8 s.:n6.F 10 times, ffic origaana} size.
E Additional Y9='~uv~ ~~ioncsmiers,F Polyma:rizations,and Hydrolys.as,
CÃang~idorts
As ~hin~m below, a .:.on~po md_. ~.r., cotnpom.,d J., 21, 3. 4, 5, 6, 7, 8e 9,
13, 14~ 15, i;r 16, 1spt> y7r.A.eii.' :4~i;~~: alone or in
C:.oml:sÃa'ltat.o1'l w,`.:h ians`_idaB,I Fa:{3#`to#:Baer, to fC7rm, a po1"vnier, e:A, . cz.impound Ia. 2a, 3a, 4daa -5a, 6a, 7a, U, 9a, 10a, I I a, 12a, 13a, 14ag 1>.."+a, or 1~3 ra. Aa> KVtY i~3~>i#a~{`4rv~ti of ~?YF rlc'~.~i,iiJ:' 7 S { t i ,{ l~,a:xE;' .n s`,,. f>coin bf:. > iÃNw,) e `e = r1.t~43'~~ described l~ ~tJa~ ~.KfK tr_.nsft:rmatitan. For exaryiple, compf3fi~id 1, 2, 3, 4. 5, 6, 7, 8, 9, 10r
? be r~.:~:0-'~.u(~s t='~~a~.A a 3:reo-~izdkal. 3lni.~F3its~~ 4ilt h as (AMN ). I Bio rw.ardfi~g c;.}nnpound Ia, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a, 10a,
14¾a. I 5-a, (:~ 16a is sts ric-rally a hyc;roj~h;:3bic joiner wl Ãh a p:+ szr:Ãmi,ive t a;?up. 1kily
AnofE-iod of acid c<a:wd'tr~c~f hydrolysis lot-[42wn i_rn t}3cm: cw xb% t3sLd. to cleave Ã:3o pl-.
3C. ;>ta:isa[: vk g.r[3up, as d<.,st,ri:7ed ht?.i'k'tIl. Ea1zpm<3t1C Ivyd3 alLs:r:4 ulo.ill;., or i"n
For r~?:4:multiple, compound 2a, 3a, 4a, 5a, 61a, t a., 8aa, 9a, 10xi, 1 Lt. 12a, l3a, 1.4a. 15a, or 16a
Qwt ,3:. ir:n,nc.=.;;ed in to h-,"._{rodh1oric. a:;ice so~~~tiorr. 11c resulting ccwmpowid lb. 2b. 3b,
11b, 12b, ~ 3b, 14b, 15b, ai 16b is a hzrdmp~~lfic po1~lncr want can increase
Ari si:r:
bt.:weei .i 1 .5 wA1d or mor(;~ li2?'1es fl3'l'% L7F'3r:iY3Ld size of w?npo`ttnG I il. 2a, 3a. 4,i, 5a, 6a, 7a, 8a, 9a, 10a, I I a,'12atY ~3a, 14a, -1 5a, or 16a, respectAve] y. For cxx~~-npt w., compound
I ~i, 1,i. 3a, 4a. 5a, 6a, 7u, 8a, 9a, I Wt, Ila, l2a, 13a, 14ii, 15a, ft:- 16a can bG ~~) mn _E..ldii'. ~,t~iuÃloÃ: f+3" wH,.Ãt?us pÃ'rI.od;4 of t1Ã&ie. Longer p;I'Ãcids t)f exposure ca:'i kad to itZ.#.'.`{t.well:fig A~te1'3'de`:bfiw methods of ziC:hTevivq; gi-f..el.of" g.+.;`i4't!'a.,T1L:.=31AQ aiiw,51ng :h oi 3:.1arc?.i..t'Z' ,ir'ec lCõk>e=.:-nG; thc ~T1-1 . `~.~~1L~ tl~9t'L'~. to 1'~i"ti'i.'.I'.1~1: ~.;."sil,to: sti~~:~l`;~ i.~:,Ã be ttc.~-.i'~'~~<i by =.Idd#.3'3f.; diff:3z3ctioni:~l czaf~~~ink~.?rs. Di1E3Flcl:aE1..3z cI'ossl1rkkt.'.?'s it3i:h3x.:i'. &11--<m:yliiW 4pe: =fLs<li"3d p`t?i td~~ et':?ash.Al x,` be-tweet-i =?iC3yinc;.t` chains fluil fuabi:; 7e5E.7dl thi ;~#n s.3f i.i;o p.:.EitzCli` t.`?t?-n Q." ::~an'sif?E:.
1, 2, 3, .i?ld 4 111d1vIdwily i2te p(3lv123cd.izGii to fot'Ãn :%po ly i 7ie#
e.o m p () u i ^d I a, 2 a , 3 a, :i n d- 4 11Y ws sho w n b c l(.) w:
~s'rt,~.~= w.''-.,i` ~~t _.{'~ 3a ,~E~
15hcre each Q ,n;, R? R;, I)t". '`'`I.~.d tennmal ht:Ip zIie k:}dC3p~~n{ji.a.' 4i Leif:>:. as t;:left
C.:1F3# out.i.` 5 and 6 are "B1ilivIdu3lly poliI3'wx`.i:r od tEs 1i`I,in :Ãpo~
co}its,a?5311'{.I~~ 5a~ c3nE~ ~811, itl s.~3\"Ys~1 ~.~~.SC`1S':
~l_-~Y~ / lw_:/~ ~^ri.
L?.'`leI k',. c.Adh Q<'{ R:?, R4. R. ~Etli{ t4=1ÃZdiIa.&I ;;,Ei':>l.p 3Ie i#,idC'pondGÃiil`T \(.lcf~:L4d as de.anS>i~.
CCa2a'?p<a:l.tad 7 and 8 m4= Ã.ild1vidui1lly pC3ly#'a1i .S'"s'c't'd to ft3am a po.yi23im t -g",
L+E,'s3`Ia.~`'J{)a.l`.ad 7a and 8a.~, as shown bo3.LJw.
~l = ' ~ /= ~ !~-... +f ~ ~"-, 4i herc. cac:;Ii Q n, ~'~ , R<:_R;. and :.:nninal ~~~~ip :u~ ~~~depcadc. t`y self.~;.ted as t1..fined t.'f?anpC`und;g 9 <:ilia 10 al''L'Y i1id;vldL1a(ly por'v:T3leTizt;c-I to fa l~`na a ~]C~.~!`S~~a't, c w:.;
com;?i3,3nd 9a and Ilia, as shown Mowc
NvhL.Ic eac:i ai, :.'>.?, KI> R5. ;.3ndi tiyr#3i1rlial gt}t.~.~.;~ %11`i;. 11~.~kS.::3`t~n~`' at,?.+.',f~f~'.f~ as ~..c,iÃ;.if.'~'~~
Corripoul~~~ ~ I -ii1 i 12 we .In~~iv'1d;.I<ill-vpt,fyZ14t,dir:ei; Effi ii?I'm s polSni:."r. O.g,;
co~~~pounL3.8..3 a and .1.2a, as sliow.~i beFms'.
Jti`\o --------~ ,
{ Fiv where each t' R:., R4, Rr, R,~.anta terminal gmup a.?c se;e :ed s~s d. fincol..
C._nipz?um1S 13 and 14 a,G: R-iÃ~ivzdua1ly pt31~raerizc:d to atmn a p:r~~~ rier. c.Ã_,.-
s)i?lpomnd 13dl tznd .1.41t, as shown belC3w:
wh,e1t!. each ~,,' z3 R-i, ;.~w4z ::~- med t1:17n-ii1:al gx't)tip aIle,
Fz`t~lepond4'.¾-led sLI.ci4d a.~ d0fined orzypounds 15 and 16 are Tn<lÃ3Fidua1ly poly~an~.1rt,xet1 to rann a pfr`
c#3mpi?faa?(i .~~a aa7Ca 4.6a, as shown tk;low;
t'; ,'~ ~, r \~ ,f,? ------`A- ;its wa]ew eac3i Q Ia R^w R3i IR+., R., R . R,.aF?ci td;:~~I'nAt":ii:#l gt'43up
E divinyl:~omÃ~~~~~y-mers and Copolymers a Todt..d I3n are p?,pareth bv p:;::v.T?C.? S!i'I?g a vi3`_?1pi_?E:nd c,,f
I~z}rzY~~~la I. In sonw c.rl-ib<.:?di ment=, compounds of Fonuu1a I car-L bc cc>,=~~lyn"w:t:lzcd ~,.J;h.
flÃ~~` vinyl ?~i3it~"#.i11.3i::f described ~"3<:Ã'Eli.Y7. or `t, ~'~':el in 1::,~, c`~'. For +`.=?S:i~IIi~.ClC;, C,ripolli:.i I ciu: be Umpi?l.t?2d 2, Compound 3 S.,<a.zi be L..{?'-p(>lp2:C.1'`.WiCell witÃi w?Zr
}via?i`.5known i'{?th ai"=t. ort'.:`ia?"npEZ.'.nn+alhyl.mC:dhav>vS'lat{ `.
Ir, t<thÃ,i +, .F=zlhi>diI7.?ents., any 5'E5mpoL.aid5 of Fo~`a`~~.L3l< I cwi be i:<?-pt?lyflz't;lizoie ;? :ch r, ~, tall i Z e= s ~~ w ci to tt ~ xI7?' ~`1Ã ~~ i3.Z.'xlt.Ã~ .?::'Ã~7E;to iit3e'11s ~3~ ~ 1#irlti%I3 in the c.~~. of. ~?T"...+.of'sff.` a .::s:fC~i?I~ E:i`~?Z~.l,i'7~ati;1'. %i block L1>~~f?:~ 4I.~.Z~.`, a_lltC:~I1zi~:F]c, ,.opi3lynlG:1, or 'i "1'<3.ft C.op..iy-nor wslng any mellt?dti kilownÃI=` ?lla< Llr'..
hi iidd?i.ioa]itl t'.I'fAi.'~4:'3dTlz3eI3I4, c1.icy' compound of I'i1i`'rII.El23 I L:;;Ã. ..tF :E3 ~?~?{.4".tFL ,~,;~=~: w1thi :t27y- V:?'lyl nC?Ili?a:iC:.t" described hS:.Y'cISl or Δti;,~Cywn in the arE'i+? Y"4.ld :`~ lidwc3'`
h#ur; or Ut3?,":3i~ ~.?i?ain~?t3 at;;Ii^~õ i~.Tly' methods ,~.ili:~ '#i Pin.t
Any2<,Z?i5 of a Sli ~~.,lo mo:flt>E"Y3er ?'c(atFv4~ to bclxs.3dw; 2]SiC)ni?.I7?eT= cw1 bc t3sed W -fi.ti?'1:i3. w. ffp.?lym...r< Difxue11t aatioS of Ã:-ic1iol3'?ei= fsntts i.?iipaT't d?ffert.nE. pz'7:Lait.az w1d Chenical 3"'~37~7i;3'"~.ie`?'L43 the i~xl3'i~lE:]', ~~::'L?~~i.~~'~#~;'.s of }zil:crossing include, aiut :3~o ?~L?t :`.l: I,`~'[' ES`.~ ~il~:~l~;,iii.k than.sitiot~ com ~~~..to:t~~Ãe, ~~a::lgE st>-~;~~Ã~~#Ia, s rt` t<~lIiji~:~,r, flexibility ~:r ast ~~ ~ ti ~~l hydf,'t?p.iio:,tcli'y, Y11us, by Ga.:'S:iiig Ã1101?0Td3.C:1:' ratios, it is
Pos+i:'Ile :Cr c.iff<}rd i copolyrner'
wiÃ~*i f1o4i.etfc'=>~racÃc:.-Hst.ics. For example, introcaui,tion. (?f a but:4y hyd.o;Yhob1G side t)T7p will. ako flIL ptYl'r.1n4i more hydq'tsphobÃC cEiii3 Ã4G.uivi the rat: hy-df`i7lys1s.
GF, Additional Polvnug=~ ~~~~~~ as Polyc;sters, 1Poly~lthcc`s, and:polvearbonaws i1~1Ã~ ~3i3llc~ilai if? acids can be prepared ~~:4cf11'e~ÃI~y; ii? the
C~4suIi~1ti+J~1 ~~13 ~iji~tS~. 1~'<t.4'. a' ,cSt. viAn be used to õ3'.iake ti153 filn3s, A:3i3I't7ik,,.sT r 'Lasõ and related dLticrl.bL.d 3.'tc3"5..ix3p aÃ:d can be usvd e.g., iCS Ci`4'l2v41`\'<1Cio..z: i{4õf ,>v4; g bitK3u li`i... cli;t:nt:i,
As tip:E~sZ I.'i bf.ltJw, ffis. %hcrnF<:iÃ:x :: i.?"l,ietutE.S of :.?Yi.3Es ÃleZv polyA.:iLg s ,m3.,Ã;:3g
F f;3-~nuhws XX r. XXH, SiX; If, and XX iV:
k'!~='~'+i~, r'``=~ r~,.uf,. ~.t~1'\. .r~> . { ,'\ r. \. = ~'`l` art ~'1.~~ ~ti~.:r'~ ~\'~ k~, a:1 rtr ?,, ?ixIt r"~ .. . ,Y`1.F`= = '~ ,,,i d.i~' `'.,\,. "r ~~.~ .i r ` 7~ or xxit5 !? ;
1 '~ ~M.+ 4 ~ ti.~~f '..:r=' ~-.~ ..i,. x: aiv ; i w;iG;Ii:: ci.ch Q fS iF3dZ''pC'.ndiilil;' s~dccti::d from sma.31?Ã:. (). Sõ
GY Z3i% and 62 arG l:~GIch indi.:p[`ndendy4iw,leS.:ti'.d fr<,`ii1 i:i:.no37&
or R.who'whi G:,' und Gi_, &-ro not ~~~c
Ri.' is :eclC:ott.'t. fi`{_}i~n among a sUil.lgalt or bI :I11d~ied M\%
0≤y<,.toaa`4l cli' % _ <?ie'ik.z,,
A yi, talk)ds;Ial_ mry,sft yl. alky'<ixyl, a:-y1alkzf) or flzxo>-txct~~bon dhain of 3v50,
tVhereÃi; t.is;.. alkyl, co ~:I~.~i~.lkyl, :x~?~ 1, c?lt;~ii~ :~~:'~, k~11~
I~i1~~I, . j l:silyl tl:>~.~~I a~,.~-1, ;or.'~~ilr~ :i hy(f-3.o,~~yl,, hyd oxyeth'4r,, ca.wbo~~yf ~,4i~~boxy1+::jE-cr, carESoxya~~~~1.~iitioa2 Xint!, n.ono_ or i~:,,
`r1i,-)StÃt17ted 3a:~~irlEST thiol, thii>t..5:~.; sulfate, pa:C?Gph3n.A`:v, oor ;1,'01o#r;o$] 3rfieili: i:S: cs:'
R,, ' is sZlZ'i:;ti;'.d fI'l?i?3 cxY3:3ng pC?ly(~thyii'.lle g.ity-col), p53ly1c~~.~:y1a;'I,;' ox1dc3; polar(hys?wotiykicizi)); a c,:rbohYdraw, a pri,?win, a polypoptli&~ an am;no nid, a Pudci:: ac.d; ..~~~~ eofide, a pc?~yi.,mclcr?iidi, t3iiy DNA or RNA si~t~~un~i:t$ a lipid,
p<~lys#?t.cha.i'i3'e, an fli:tibofsy, a phc3.i'rmaoci1tAC;i3.l c2vt:I3T, or any vtiittt?~.3t. r.fi` a Ti<;li)g14:.i7.l
R~ is :tit 3o::E i3vd frolyi .iFru?7ig p1ht3tC}cross11nk-c1blC' or 1o1iicall`0 4Ã oswIinkableg-r.3lp;
R, coIlipr,,:iZ:s a first group that is L`l)I1~;'~`(.ii`xlvic to, i`s set':l.t}nd ~i'i.'+%.ip the fin4 group at a pa.s os or below about 6,0;
`c a` lw W'.4;.tcd fiau1-n a`il.bL}n' hydroge.n; a straight o.i~~ branched alkyl Ut''Z'lIialkyl>
art1 oa fia., si,yl, adk aii.yi, arv'i:sily1õ adkj`xaryl, arylalkyl)-=l; o.,
Al..ion)c<iri.ois chain of carbons. 1,11Z a.kyl cycxoalky'1, a.23.>, alt. Tzv; silyl_ aikylsil}'1 aiy'ssilzl, a;ks atyx uy.ta3,tO"lt, t?.i' ::bcw3"i:1ccl::?ola chain is optionally 7ub.`a'+;i:n.itod n:ntomad_5Z' f)a WT-i-ti,10.~~aly by s:1:'3C.'.= cw mai`Z 3L'ilii;~~S53, h,`,rd13:;S:yChe-#'. ct.B.t'bt3xyl, c.?E'btl?:y~.aS1iT, :%<libi:;L'G'ai'..Iide, n'loA3C3- i~FÃ' di-;it3l,"Lfib,iPod ann`>nor }hatxl, thlt?L'.stc T, .: _e: <õtc, j3hl3~plh:3ES;, 131it3sphi?I1.3tZ, (;: .3.ih~3gc'ii
S and v are t.."at.e}: selected fro.ITi m fntegE .I of a >'`4~` and wL.~#.`. ~'~,~i~~~~~.L=~:~% tor#:~:ii-n[kl 4fT;you-p isse3.ecl~~ froiii aynovig an-fi:.e , i.#.nZ.ado;: ph<yspbat4v. v~:phate5 xv; il~~~~~Ide,,,, noaIs, a1knos, alkenes, wad :lk.Ms.
A:.so prowis:=ed are wmv.<?unds of Fo.rrÃaula XXV and XXVI. as belt?w,:
~j 'txvi
}:tr u<#c~` Q. :} , S; !'q itl~~ .e#'#.7111^~i_~ ~.?Ã"~3.~p are #is:pi`,1~L3~:T~~E~;~ ~~a:?4~;~.~.d ~~~ ...l,3e~~~` ,1~:2~.':it2.
A >io provided are oompowids, of Fz?rmuia XXV11, XXVT,i, XXIX, and X-X'X a,,
bozvii bek3~N-
%;2. ~~i ~ <S. : L~.=k~\ ~ f MAI KXX iixix
Ladh Q% il.id teÃ`m.iwii v #'~~LF~~ Fi[i indi pe1xd4Y)tlSs .t C:i ;C: ~l dÃ.:~fmwd 3 ik suhk{:'iQd &'tTm an ÃntÃ:f?.er E?f 1-25:
Aas{? piovi6M ai'c cc?mpi3und.S of Formu1.i =KL XXXI 1, XXX . XXXIt='; and
XXXV. as show.n. btlcn.':
XXX:t
Ft ~ ~\ r~ ~\ run #p: G> :\ f t\ {,,
R ~ `~i. ~ ;,! =,..-~` \~ ~"' ~`~, I ~,K .~{ ,,. ~ +~ ~ 'FFF y TV.. -~h, r{~~~~~-4 . .f~'~ ~~'~~ f'~~~'~. .,,..'`= ~.at~~'~ ~t~,.r
E I;:,'t` v; and Wunini~l group aCC', IÃ1depe~.gently scti,L.tQd as de:.7.u.ti; and b is Yo ccwts II'"oni ai-i Un:egel' of 1-14.
Also provided are compounds of Formula XXXVI and :C-*,,XZ'H, as s1::oNvai b;
XXXVÃ whoae cac : Q, (33`, R x, i', ytlici Ã'o nslinlal --yc};.tp aro as d;,'fim~~;
wid U is >oiQc:Ãed ali :ia:i~gcr of 1 -14: l?i c::na;:n embod:mf:.~rzts, [Eic. (:3' of ['(:xmud<: XXI.-XXXVat is sUlec>Ã.ci fit}orn any group sI7vvk''~i b5:low;
vz`~~~~4 oaci: and R :' ati ii:i~a'~~~3~c~e~z~~~' as aefi2:ei1 Iwrd:~~.
In i~'t:}~ ~~3".? X.;5.I.,
XXVIa .s, inciop4n -izmt1;' sÃ.~ec~od fflo:7i aa-nc,qga ,.~'fpt?p shÃaw b low:
methy l
Es>r.3; ;"opy?
= ~_rf'l ~. ~ . . =\~\!tr \ \1J . \\v ~\.~_ ~ \. r~=\~ \ j-~` .. . I'.-'-..\\\ \\ %r\:` `f ""\\ .-`~\.\ .
\f khe LLL \, tG;~ r ~J\
In i'3 i.<33Fi C::i7:lbt?d:?-lent::?, ti.'=aL'h:R;', Q', G-+`, and G' rsF<5?i,3 of c. tly of ~ ~ \1Cf. ~ C~ ) ,C `f.~.<~~`~i >~ i~:za~~;.~.Ã:to..~ ~,. ~,~.~~r~, ~'t~~z~ r~a~~~a~~N a ,r~a~p shown l~~;lz.<~:
`~.~%`~`~-,. -'``~,.= ,. <....-.' `` ,
NRC _ ``~...- :_=,~=- ~..f `~ ~:,?- ~. ~=:
=r''-~~`~. i,: ~~`.,%~~~~ti:.;-' -. r ..'=s` . . ~ = ~'~ = `-`l1 =`'. ~~
OOH i ;~1 '~=~~.~Y~~rr ~`Yt~J ~~r-~'L~{.
I ,`, t,int:a`n ti=irabaztsj?liE.a1t`. oach R;' Gs;`<G at:cA Gr' isFf3t.1p of x3.T ?S' i?: I'i?3'3-t71..I ,i xx ::.
XXXVII is i:=.idelmliai lfliv :aC.lt.cted fi'(y2`t7 a?-nt3n~g a group as
t'. r `=,.- r.\r= . ~`,,.. `~'=`r
Yi ~ -=.~\ ' . . . ,~ . ~~'~;:~,` -,>~: - ,
vwberc eadx ~~.~` is ~:~C~~~~~=.t#~~ ,~~.~}'' ss.=1ecied ftom aniong 0, S; SQ,
S L~ dll ~:133~7E7Ea1.:l;t i1~3y each R. (',', G~'y and G4:aTM'C3L1pi?fmy of Fi?:oil:mlc.. X.X3XX'XVU is Indà peridently :wlected.firom ttziioiig at ~~.Foup tts beIow.
tmch Q' is a:;idipenda ntAy wixlc~~ from amoiig 0, S. Sc, or Ni-l.
Iii cCrta1I-: S:,znbZ3dÃr::wrYt4, S;E{E:.h Rj`. G. and G' g>t?up t?fa,:ny c?. 1";?r;x~ZEEl._l XXIv
X?SY XVI. is ia dE?px'nb~~~ fly aLls S tCd ftEjal3 :I37 oIlys a group a.-s, slli.`w-n "!elE),,:i',
~a1 \ =\_ \ ~ .'t. .: \. .!\,.. .
f ~ _.r . - -4Y v \\. , -~:\!=
Sai
S i.a:= each Q 3s fiidwpor''C}.C.nO t .Süd'.i:ct~`.`.~.~d from among 0. S,
Se, f3T- ~'~iii:
fr or; 2 cJ t ` r :2r>l~$ } {r r ~ t ~ a> ~2= ~ ~= 1S( ( t CC Y>](t2i. i w ~V;_ayy.~ A 2 k.i~Yyt i~~fl}.nm:4.~~~~ r~ \.~4a~i..~.S ~~'r~ ~ *~hj,s.:~~~
Ci.ai\~ ~3 by iap-} l C.}.~, i[iiY~\~~ 5~2.2.i-.. XX>
XX_,'~ Y' II ?J :.i~.~E# .~ Trist I't~~Lr ~~ Δti.~: ..~ : '~Ti3~1: s~'Jl t3`lg a gel.~,`, as shown ~~G..<3tr,~=':
CvH,
tiv:+
wh1.~~~.~ > ~' 3~ :~~ ~~{~l1.~.>o3~Cf3 ; Zrl ~ ft2 ~`'3~; or ~, . each 2,~~ <...~'~ ~~.r ~.'f-~t~>:` L~ f~~i.'Fii~,~`~.~~1 among .. ;~;,
1lz i?.<`F,` ,,~ of A.? #~~i :'S.~'i..l
R ~:rR ~3 ry.~a~^r 4~~~\ C.~' F-,r", a + . i
Ir, 1f.ova x ~~ .~l bL.>~ and ~Ã.i.~~.:c~~5:~. 4:~
XXXVf. .5 :.I#dt pi=#.^>iently' ~t= tv~ ~ ~. from aT?-T11:4: a g;0R.ip 'a" shf3'4v3 bC S(t:t=`;
??ethv;
\'. A\ , +'\~==`+,\~`-. ~.
iL;,o pto\'idti, Iw C:s#;'.,#pf:wnd l)f Foii3el7h X~~XVH5, ills ;,f35'i
u XXXs II.I
`~ r~~ ~i~? ~ i' , , ;~ S and Ã~'.3"Iix7.~.~~, g~')E;:'3 s .< =~ ;aw e.z ,
`+,;wav ~ C ~ ~. ` ~: llrLai=~~?~Ã :41~.~~t ` i..,i. a.. ..~ = ~.:...~~.,.L..C. ta.~ w~~.~F~t..~ E,c ei: _ aad i> i4 t!l~i:t. ~~ ~i'i;~~: 'c11'# r31t ~,~;~1' 5f 8,
IF.: v~iiinfta;~ embodiments, to i::(7.i.71pi?wds i,& Fz3t'awla XDXA`#rI3a i:=a?, b(: a r~.Y;.k:m1;. a block >_.t5pf#Iymer, aliem;:tting cc)z,E~ly'mer.:sr, a rfratlctrpacyme:
ai.:fm ~=,bC?d?i?1i9.n1, the t;=f?f?ym"Fid [}fFT:EiT-nl;.a? XXXVIII is a c:?mp.?-ul#d of =o r3=3#e <a X:,~,-X2 X, es`
~i1 ..` .r=1 ;1'i r=. ...~.2~ r=~ ;<1
- ~ ~~..='~ `~-.;,-`='f i`.~. ` ~ +.`~~~. ..`ly}or ``~~r...:<...1 `'~:.
Vi3.w "i: wi#w'h Q, O. X. y< ~I.I#'.; lS:t=:don:nal g#'tafsp ai`i.: indC;pt;ndZ:nI.L tio_ReGtet ;::5 defined hi:nm1. i~ :n w.'erta:Ii-; umflb(sdltncÃ.`3~ flw cm=~.~ptnitli, of FE`õ$.Tl u,?~'t
XXXVIII :~: wiA:s.:tied nor":~ 'I f}
rii ~~ '~I_., ~:~1, X1:1I, i >~' +. ~'LIhl. ii L s s ,z,3~bG;,._3<.~~~_
> hc :t`L~ c,..ch C: x: v. <.,nd te-m.in.:;l t à oÃ;p:) an xndopi'Ã:di.'11t;y stewied as +::t.f.n4J.
a.i ce?':'.3:1.1 ;mb+`iiT.t-&t.3t4, a compound of Fwniw...:sX;`5X%`a11 s . 3cbvS:ted 3.if$i~~l w.n~`.3T]g a ct;'?1?:.FL i~?kE~3 of ~"~ 1T~;a:f~ X ~rz'liE Ir ~~~ is (oxy
In :<Ã~i~I~? i I1?:?~.C~.Isl1,' n`~.s, a ==.y, t rr..~`Il is ?C. -.7~xS;>;~i~~ <a a lS_rf.s~3 rs'?LFf. ~' Ã r i~~z._ Y
F`~ ~~z~s+~3~~:~~~z. i?~ ., vs?M' ~~.>wza ~1~.~~'Y3 ~i~ 'c#~T~`?3~~ ia ~ i3:w ~~Il t:h~~za :: wF , in c -r ~ 1 ic <> ~# < ,{ ,{ n e(:r;.:~~r.~.. a. ~ E ~ 4_'L.', ~ 4 tia~~~~~a:~ certain ``e';'3x~~ts+~h~,.""'...C`n .`~~i zx <._.~ ~tz?%F i.`~ 3. XXXV :~:; F is .o31..t{.',d =-~}.r -e s r c ciata~a= =rdn:~li~ Xa. ~1 r.:.~ i= ~ :' 1, ~; a L:~:iT~~??E.Ii~'to of Formula s~'~a4.:i'~.=" ~ is 4, ha
r mPoL>1Ti1 of a > : ?lt.ta 4 ~X'Vlll is ~O ,. d c'Cs1u. amEmÃ, a ci
I;':pi3.#.I`t of Forn.wha X1:.1a..
)Y of `'`. { or 4 .: `i .i :
ChA 4'VZ~vt-~A?t e~~~2C2\`$..fine.Skti,ti5v.., compound o~". FL,[Snuta:~
XXVI+I. j,~ Lihi.,lt.ctGV\,e )]ona
~l7g i CS.i. ~. ~%t !r :~~3~ 3 :~ ~ of ~ i. ,7 1~3,.~c i~ :S ~rLV~r, 7T
XLVI, L?I,~ ci5 J~'' at. v4sa1 s ,
fi ~'~`Rf,t ti.~=.r ` ~1r'' ~ ` i.~~,( ``ti=~ ~..~,: ' ~.
S> .4~..';:3:-<. Y X. s L:Ãf . it:to < !are z.ET{.~.iN~)v5Y'tll.i#~ >.iv ~
L[~.4..~.L 2 as Ei'ai~1~va..3.i6,I=.S :~'Ã. c..#Ãi3S)daauÃ`',~, a cf11 Ilp(1uTÃd i.+-rFd?n'iw~ aXXXV 1.1; is \e. E .L~. 3konrl
Ã~2,.E}e~lS a,.i i~,:;~t~?Il?.d of .~'i~;":E~~t.c; XX.:~3'. I.i C`~';:"~ti1#; i:a3.-iFi;~~.l>`..ti, a v<,3 -2-1~~);~..~3t' S?.. Dai,rÃ`Fnule3.
XXXVIII . si.,?.,t;l:E:d ft?b3Ã k3a~lof~g a i:oli1poÃ3n#:a E?f.Ff#3anÃ.23a
XLV. .i^ c.._E.,,?,:Ã'1 4mlbt?d:+ w.#t`:. .co1'Ã:poulld f;f.1,01."e nuaa:XXXV1.111. is ~:s=i" f.ikin
LEÃz3Ã}i:h:. t,5.:3~ ttS~
11. ~~~~th~~~s of:~~~~~~~~ers of Fo~~~~~~~las ~.,t'~.J - XI=NI
A-faSe #.,~a\:vh(id of pi?.t4`n icriza4a.ion. 4aii tFC:i,isx'd to pnmiLa..e tE ic poh'E`a4; ` ,, aM1Fi?~~~~ula.~~
XX1: . XI,.VI. ; or õxanap~e, polp-n;,r` of ! ox=mulus, XX1 ,XI_ Vl can bz, prcp,.wc1 ~ ~ .atm: -pl7# F;-k?t)i'Ãl#.n- pt.tlymt'rF1<3.Iion, or 3~E.1i5?i
As Sho':=k'n belC3%,-, a polymer of FZ?nitl.`ix_. XXXVIII s.wi Jx; pr3:.'.p.3.IE:d by
#i <]iZtZÃ`.:Ci< 33E; ~iSf~~nt,.~'Ã~t~#.~tÃV?> t3. ;:: ~.c.EE,:#;t~~ .i7.?t?i~it>.o~' -.~ E~`. a ?d;"~3t?f3:?:Ie ,:.
Lto~7 *:Ã1.-.E of ~- `'i)`. ry.Y\l\ 2 '~ es Ci s p1~MnPr !R>f...A ~(]~ i 3` ~''#.~i~E31e1 at.~'i~A''~~.kl~~~.fit.'I~`~.~~ ~.?. L:#~E12L.f, #.'.1.'
t'4$id termna: gà 'oi1p 0.r~:= iI3tiL pendetarly :1et.SJL:tcd as (ac t1.3C:d
Any :ani t}.iS1d of a:n`, z5pC .mi.ilg potymo{',}lataC3n can bo ;..sedi for th9;^ .. t..:aio#.; For ox>.:T1v.Ã. `he ;,;1~ ffp~1I3I1~ pol`{E";:zz.iizt3dl:t'm iTla"S .7w i.13:duc:,; ;3-v H ?t%%l he Ãvth~ iÃE$~1. xIs O t or2~ibt1d1l,u`_iit, t..e roacfiom zs t a..:ivot b:r a :lll:tal a=~~lalytiC, Ã.t lf. VMs ` ;lG= , t.. ick.lt?l]
c..n be ?er:i$,"i-ned m,Ãt, i?i- 1..} dw pacsLF:iii of -a solvent, sliC>~'~a
fj] di;..rtf, il E..dhe1, :12.~i rCSta:.= lif VL<i(V4' use@.s, iKor w.}IC2,?;i.pli., =}i4'r.\2~ic, \`t caA\Y\}aSat4'
al#olri.>z.~:far `,o, >2#irtc3l1<:. i.l`l?nf1me. (:;a . bG, I.1. .~;.
Yv I ."~y 1 ,~3K E 7~ ~.S. `~ :3; e. 1 `.~.
i#1y;w.onit' cc:nbfv used iz;Ã' the polymerization shÃ:>rdi'3 abt~ve. As s.aow'#1 by lot:t,
Eli,,. ..:i::mw c=::i3? J : a ,k f;riFive? six, or 2ifa'e'eFz m,..'1:E3bi;Ã;id
\\ ':-, . .. -------_.W..We,. ~j~,.., f=-f` .`ti. .=`'1,1 ~~'. f'~J...
\ . '~ ` ~ ~:Lnf' \ .=t! . . ~.~.r v
fE . ...............__-----3Ps'
~i ' '~. r,^'~: . f`\, r=L?.{ + <-= r . ..... +,~. ..i~~ ==_~. . . -r`
~v",:Ã: ~ z=~ are tt: .i=. ~.. re ,~ i= e, ,.tit ,r.~1~..3. PEi. :~~~ :Ã#'~= iÃFt ~_~f'1'1i:~Griit1~' w+..4+,:.L..t ,,z, dofiu:c?+:i ,
As dzown %Ãbfj5tfi,'.. Compound 17 fti prepared by '.?E?lj`Ãrlet,;l: Ãg a bi.li`:%li?xt L?le'Ã....AZ?: curbfyi-wZ. %'Wh oxi.:u.:", 2:-onw. CmT3t7C>1ti1i~ 18 ~~ ~~rep37cf b-,, .- p:?l:ymci.z:l.n 2 be'n?t C.xy
L}.~~~L3 ii~r} 7 ~¾ p '~ as r t`...i~ ~ ~_ :~~:?~3di1~tc ~~.~i~i ~.~~~.~~ r `.:Clr, Est x .. . } r.. ~~~,^ ~ i i ~^~.,=~:'G. ~,.\. L~.L3 A:. a },
tfxo..S l:'.3 t >.Atw; 'sà b;F.1't ~ 1o`4` ?,ly e e:Ã3l carbonate E=6'ilb tC #"ah4`dl +_, ? 1'~.~~1
L.yz or 5ili~.~ ~~~ ~~. ~`i ~~ . b3 ~ a ~ R bE.t ! e; l.. i~ s,
F :'~I~~~_. t ~Ã:i by F i ~;<"t'~iC=Ã'3~:I1~ a Ito ~;E~~~ ~ .`su~ aÃ~?~ <2aa<.. ~;_~~~, t. 3~LA;3al1}"Ã;nfi:;.
L C-he.~~-i"- ~ ~~ckifficatio~~~ of liners of Formulas XXI - XLVI a ol..>:Lrs i3;' Formulas XXI`.13.3,.VI, W;:3erei21 C1r 14 a protecting ~g*:soup, can be i".F .i`~.:.1~:`sÃ'Ci t"} ~# 4t.il:zsiii Ã'l~?it; `<[~3i:; e~;.Mof1'?s ala:~~ p(:I3T.a"?i For t. tarn'sic,
G' cea;-, be wa,v p5+.`.tei;:``, g,?ii'ol,Ep known 11:i o-t7.; ail: hrl :tis1mC . e:x3b'eDd:i]vents.. f_3 is a Q[hcr or rotL%ctII7 ` fyrC31ep, Any method knC1i3 n'#.?1 the art of sa?~'#.ing a 4dc: i'<hc31l: 01"
pe >.Z{hfa g~$.-}; to a ~2. p3.d.S 2wc:~.=~' 7~.f~d~2 }=~~=~,, L:Z. > used a.'or:.='l~ p k,~ f)=~ ~~~'q q S2~~,~.all.~,k ' ¾j~ V ~T~) =5=y ~c~~ of
!\s S~`3=~ ~2k ~.y=~ ` =~4. N~_ IgY. ~ZiLi~~. X.L;.J j,
I6r example, a #3f3hyz>.L.'F"= of Fi7i`Ã-ni:la5 :''i.xI Xj,VL bt.`= ~iiCjdÃfit;i~ to ?Ã~,. .. s'fd< ,tY?.EÃ l ..f,`?;i am]of?g a straTg~~':~ 4)#'bI'a.~'.3chwd 's:lh.Gl, ~:=;iCle.""alk2 : %E.icy olGfin >3lky~sÃ.y:,
<3Tyl\dy . .Ãaii 4 li ~?l, Ã?`4ii~.lk~~-.~ CiI .~l,.[i~I`~~L"-.Ã~'}?i?F:1 i2111 of ~j-5~i:wcÃ~`~`,'~,.,.,s, ~~ ~~:.. ~.. _ "'.~~ i:~~. ? l~i`,~~
t yC.aoCnc3<yl, i.~.Tyl,. Z?.Fn3FÃ`, sdyla ~~lkF i+1~,4. ,Ãyl41..0 alkd:.31'yl, arj'lalkli or f.uof"ol,ubf)n a.,~3.1I.:~ is ~?a~?`3C~Ic3#:?~' SwE:~`w'FÃF~t.:'t. ~#F:`~..#:'F.?+.3li~~ or to:1'tI':i'#is'lll4' by i;.ne or .#3,m h:~Ã1i.~~yr.Li=a~_Z.,}r ~..f~.i(~'{ `},,f.jSi'~. y t- :~, >,~r~, ~'i2Y'~~.r`.lci. amino, mono- 3:3}.di sui,fJtÃaacuf
>I131#io, 3.hYE ' .33F.3eswt, `;i?i. aEt;'., pilt#s??h4itG`, phL? .. y~~laÃ3'~ ,I~~., . ! s~. ' h{Ã,t3` ~~, _ ~` ~ > }._
Other ..ÃÃ~._ ;:1tà .. t Ãe'lIp` ccÃ#-, be >Lis ~._A fta?m a. +1-F.iJnt3 z.Flv`"E.l 'yiÃ.o'no gj3`C;+..31,j. ioly(eth},e:xS,.o.K.d%);7oly(3~ydrox)'i?S,`.id), :~ C:=aI'bi:?h~t~i3.t~3., a 1+:ttc'd` a ;~f~ Z`~T{~,~~l~`i~~v, ~:t?.
+.1'#Ã1:i7.`l. ,.16;a_ a F?Fkdc.ÃQ :Ãi:id i.l.i+ ...ot3df:q a any DNA or RNA
lzit31uggical i:_s;.op.ur_ Adia:FtÃ:>pm1lv', a haÃ;c;F.clnas 5idt: chaÃn cap, be Acac-orpo.atest into a polZ~~'`meà of any one of ::oE'I'..3lrxh )Vys.i"..~i=.LVI. '."~F.t'L:h i s a phC,:<3lni?tiskn,ÃC:bhp {3i' ÃL?ni..c3.l;~.y aos;ifiI:kcab3Ã:= Maemp,
i.l?i]e F:14ij:~(:sd of I:lZ:'dÃf' :I?.,',, a poly1:23'u``r f3f Foa~3~>nl.tl.~
XXXVIII below. Ta3o beÃi.:;y: ott..er can ix L_lS..w tied tf) iÃ.ffi5?'d a hydroxyl ga .Zup, AaiZ izF.i t~iod o% 4 f...ctv-lng a bcn1 Sol ether kà i57}'i,, in t,w art i.'=ar, ?e F.1,`'s^d '~.i}Ã` "`.~.#J ts'~.iS'~ti~t"# :'~Ã~sil. Ff'EÃ' v;~.a~.Ã, ~# the ~` `+. Ã
F:iI"ic i :7.~4., ~c~.t: a;3^`;:Ã'
Cm be ~ by ~%i~#g S cleaved ~~c.l~~~:14:'. ~`3i''+arl:iso3 yo~~2ti `~wi >lm.r ..~'~v~uYC.tF,~`~ iL nt [pT ; qy`r{ to: x:.t~~ c}~Vt. ' A~4=SY [)e}4~~.~f~ Y
J .+ JA_q~ 26~~2.iY~~a r1Z~_ ti:~. ~"~-~.,'z a i,}LwIffi #'i;actFiun l?,
C:='il,t,i..n,s ft3 ari',dl#i;e the polymer of FC`.+I`.ln.ilc3
X<`i,5>.~~~'ill with a f:nt1"b'z r..'.01 Za.~r\~w~=i~ ~,:r ..} ra~s~p Any Ã~,iel:.is}f.E C~...#`ei~.~i.tFl~.~. [Ãn alcohol k~ Z~+'~` i: i' ? can a r+s<:~.Ã ~ . t= ~:L ~{'Ã t,,:,3: ~.,~. at 3t.}.
Chi .uL<ll1i\1r2>. }ni:\)n.
l&XC';
M, Ã:#::' ci .~.poz,.n& shown a:.move ri y, i=, and the ternl:Frat. group, arc. Ã .idc<pcnd:;silyl Selected s'. s >~~ <3> wd hczeFÃa.
>~5 shown 33C`.lE?~,~'õ ~~l. p<?l4:3S .l` ?:~. ~.'L~.'311"alcà XXXVIII mZflt=i <'
c(2 n, by Y iii.`:> ~ tF. 3 ~ ~ y.~L 3 . ~ a ~. f.w 5le~W r with vi:Ii'1.'1kl;i ~ ; \? is: 3_E f?' .~:~r1 '}'3~i Zr. ~,~.L :~; 1_- {.. k ~.
3.~..~,,. x \= ,#:.I" E#~ r~~: ~ bi.my.iS.:Ãed s., %,':irboxt ixti~ air,tL such as ; EcF3ri: 3c:d, o:ec aei", or t2 ae;ia: I3':
Z?:hLn n':=3t3d:#:iel t , bw c13ii3ho; ds, IGELti d with 6 b<.1`l! 'lo?t.y e?zcl.:].?Fc c?cF:Ã, }wxc.t.na=fi14?de
L`tiF:oe,, C?F' ala~} .-:)v2~3~~3?ti}-~~~ 5<f~~Ã53 aGlC.. ~.11 t2l"f.t}`a.3S ÃtiT.* i';%":3up ?~sa, ci?rb<?n< c+'>, ali? ester, Ã3T al CI1u.
rxr =~;~.?' r i ~?=.Y" ,... 'Y-=.- ~=:` '~ +,,^~t
>Δtj.,~~Yx,Stolfi:. =~.
4'i" to'}-..r'.y` ~~ _'~. '= =
1;i1 f.le ::d:?nwt?.7mh- . inf}w.,? ::bÃ}ve .',.. t e; and. tht~ tC".E'F3::3t..zl group are i1.,d5,:pcltle..it:> >t l;C;Eed 3 wLwi~~~ aLh+~~ h.~~. i.~..i4~ tf. is .~4%c4~~l.~cZ1 from ibit Slip:s~~yYsa
As >ht`iF:3 below, a p+?lS``:ai:i' o4:Sl1t<.#itiz7lg }..lydrom-4 }F +aAS' i,a3: be n.,;,d#fie'Zi to p.dulce a po3yirwIw.i}?':t}i'I> l~ : :m1p;i, For exaiTmple: the aloti`h:?:
Low] bQ, I:=,mi`.d ?i,fft. a s ,..bw'.YhY x3uf~ such as `'tea.l."#i, acid, ?lC:ÃG acid, or InyFitiuc n;Ã.Ã. ?.l? o.hcw a~ with Orn ~~ i iz,t ~it3~Y~ 3 ~~, Ã ?c~, a u~ i ; ~i=fÃ: i?~(?i~iE>~f+
pIm4_...., ae.Ãd. ri;e bc'.r"t1'.yii}'S.y,?:'37:i5ni3"3C:?'Zx4vl, and h%ios: p:'C,tCctaf:g r'"x3up"s
R 5 v:.ln be ml3wv `iA E3y' 3.r,LIhodti known in wi-f.t: art to pr>d:x: an izlwhol, a Ã:'afbo} Z'be acid, Ex:` 3:? unn1ÃiL ;isp L'QA .='0,y:
F:i:.ti_ - = .: ` : :YZ:i n ti1S:;. 027. 3}:i)..tnd:i :i=1own %Tb(3 ve x, Y'. 4} ~ and fl':c tc:i
wlvcLf:d a~'i %si '.#n;<3 h%iweiaI.
I M~~~~~ods of ~ ori-i$~~~g Particles aud.Fil.ms v:?'{'ttzus :-ypi.y oI flm: emf:f> pa1'fides can be ;.C3#1ned firf)m pt#lpa:?C'.Ãs of Ft3.in.tahFs h.X~XLVf. Astiht?;' :1 below, various type;5 of fibus and p'i3wF.cl{'.s, s`i.Tchws m::ei0- (?.i' =iailt.'i'+''i?TtiS at:s. ~+ ~- ~+ ~.,{~ a . ~.i~i~ be #.71^.{~S 7?T3' l+`$1~.+:.l~;o of "`l?IFT3`3~t~` .. ~X and ~k~N e 1, ~ f ~:I'3t;~
}'.III.C.Ts,.. ail:i`..4 .,:i3~ ~~a.It::I(:FlG.".s Cif Jv:~."3`t,.':C~ `t'.ii2 i:~'to."#~ ~~?~,. Pillai.li~~, `L? #:.~'L`'di.?i};: :i..4 ~`:C;i twt.~'
t1`3;.~3mltc4, agma_s fh*>, polymt:rsll"1.:C:tEa'Ã; t(? j`)TFdCFI:e a 7NCZ'i2#L :'i:3S.'f.Int i:3mnsE.EC,-'.X.
l iy''mlvthod :-uw,ivn in ih3:aft can ebi.; usi:d tf, {i3 w y=.<~,t [.t..~:.~ ~r~~ L.n 3.~ } r. ~ ,. . 3.~~~ Ito }Torii..1~ ~i.,t.~-:. r~>. Glu:.-
L=l~v~la~~;;~~L.3'l:i7.May,4~r~if.,=..~`L.glycol.
Δti ) .....__ M.i?.,nii~~i~i.~s#~.+.~.:
XXXVI I1 1i1.~1i,'.~ L~.3~#1#At{3F.F.iii:4s~']<3~~C~:1 iFi~~.3~,'L~, i;:F.L~~3~ Q.
F'. U. n R?; y, t=; ,AFId tQ_U:>,.}nid .~~~4.?ur? <EF'; 1a,i.dÃpC:n<.:e1>t:y si,'lC`c$.:.d as dÃ:l7F"ifsd h3rrw.la3.
i'3iSth43ds of Mil.~F}:hx3Li
>?cpo,.y"#ilc.F., described h,Q-iein can be [F4oC`~'e:fr peti.?dlfce,. õ3.?.i4.i E.`=t:i`g tt-.;hn#.ques
LnL?wF:F ,n tl:.; art. Foà om3:npze, aus sh,?wn Li:.fE~ve, a p3;41#?er of
F:>> *?ur.: XX ~:= .:XXXV'I; ` dl stolveL; .h <da? {SÃ ` x.i# }cell #:3~. ~~?F.c~1~<?Tl~ Flip y~~~~ `c
L)S 42#~4'~. L4~kz +Vr {~:=; .<)::
q.:1E',`+`3Lt4 SO..#,.:ii7;.1 iE2i, dct?L?sF'.ed i.?i3:i3 a solid surface, such as a glass sufacii:, 4FF .ei:iF#:Fn ithZ? ~.<<?tyme:F #s d`eSsolbM in 3 :iolve`: ukC)ng !.#`.'h ..<:F ;gf_l1f, `
i3:?d depp<FSItQd onto o, solid sL?rfsl+-t.., w.-#b:3.e as i4dc:Vs .#:#i E o,
st_.1.'~.#'~'14 t}a~:,F# ~.of' 3 3 ;i??Y~S.:~;1 i.i. cab ~~Fy~:?f i.=.i~: to ' < t,zip a ~.Z,~`ci'#~;~ '~#l~. F a L:e~~i~.t :~ 3 tl.mpS:.na;l.F.i \ or prot'.wuo, o# <li .l'i' vc#.to'f~ or ~"t'(.~#.lL.~`C~
#I~LF'~3~' _~?rok s~:.:`.s, .:#.: certain unboi`aimleIlà <. "h::= h'Fol\met {,i#li1ta43T1 is deposited t) 3t > the so.1#.{ s::Ef,.Fy.L: -ws#ii,~ :3 # iQ.>?3 i.]?:="s}~ xt~3 i:. 1-i'~otheI 412t.i ilt~g~~'1r7 tLm.s, ) ~ .; G `,
by,yxF'c> for ~"=- . ~' ;}c}~tiÃ:at ~. onto `c}Fa. 4=diii ~mmk3s'::; ~::g., gls3M>. #`.lk:l, pL)l-vIlder. c<)flaH;'.i>l,f p46:C;a'3'dh.#:-I.> . tt"L llf+,.t,::l :Fa~`:e#a u.fla? 4cd.F~txid.. or :~#:: f:4..iE~sq .L~Ã#~e}~., a
J~~.i~i~ tffF õ ' of.cZ.FL:C?, 4L,i.~# #'Zs .} # xFx.'.EC, ~1~3' ~.
&vfcc, Fo#' w`1...?mplc, films E;=CIiÃ.ci1nw::;:3 polyuF3eF' 3;F
Fi.fi`?#Wul..XX or ;'S.XXVIII can i'Fx. 3i)FF:3'~.`~.i ioL t#' k32Nl,.?t:-r in <3F~i t3? Fl11ic i}:` aqueous 4<?lLsil7FS, i1`z ijfgi3#.1.1c w:L; <'#.ciIwous S(?lut'#i ns.. and a;?~}l1# i`? the :s:fll#t#.#:?rz to a sa`. t 11 other imi?ix?inxI1.s, fillli:i cirn ttt1:]iI1<F a #3ol1m1ez of a oIm.3lz,
XX {.XXVIII are fit:i:iii<'.Tfl by.mc1fing ti:?epiS];o:-nZ:i. ThC.:.ii.?`.`lt5:d pd_3ly~.iiwi can be i.~'~}pz.es to, a~^.53l.iÃa su? f i e 4itt.xl. i'* g.a4: Tother L'`=iriboc:zinr#..'`#ia.~'i, t}li: pi#l'y'nner 3 s i::i7pl1L'`~l tt? a soa:i ssl`azi:#?.C.{.> and is then ;n;.lti=:1 tc, ioIi`'3 a polynnwIic f:11l7.
13: ct;"ia?n ::Vicodin.i:nis, slibiltt<layered fihn5 are prepzs_.itl:i;; 1. or exanr le, a i".`o#ya.i3.tS. is d'::i`,E~~ited oI#t<? a 4i33.id suf-faGC, as described abC?t'e tl`, pr?tt..#i:o.i fi.i#:''1. A second ps`+3.y,m:urk ziAl.itFon Ã~ ttlLÃa ~t3e~.?f?si;'L's' o:7to tile first film.
Polymer fil`.~i.s iso :. 2, t '), vt, 5 ct1'i.iz 6, (;.t. `?'lctn~' la'.,L,`s b:: A;31`odÃ..L:l:.d by this l`.ietb13i3t.. hi L3i-iiUi {.i ?bE3'tl.inmits. u.ti.h p, ~~nls:,`z ti .i# ::~ ~3~5?~..lti::~.:~~ ~'I'~?f7i i3 i3S3~ ri;.~~=~ f3~ ~`t7~al~i.:i~ i' 1r;~.,~'i,~.~~~. II> 4i?.+L#;~la~.F Wifi:~~ix.~~.Flf`i:?f,- ?Fo4..aulÃ'3Z..:f'4 i`i'weudo a cl'-f-i"'eItz?t polymer, such as pi?iy(hai:.tl a.4id), pt3ly(i? ycoiaC
?t}z~;~,<3i.#..~, i.s.;? ,Sut,#.~4`~.;i..z~. cii:i<Δti. 3t)3'v;vi1~?'CCy~~~.:~.{3?lf:. 7]C?~~?~~iir.^t~.#:~#~f:~~^='v't`~L:T"~3t~~:i~} A i i~'.ls;A:r pozyea.;boi#wi i3`- ptiF = 1#.=x1de.
zi'.~ . '~r~s ;C~4 4ziY~. d ~'ir.3ers :=i~.#'#. 3:?C. :vft.NE<:=+.=a<:i to ~ :. i l Z y? . aSi. 't3'i., {. # ) .?`i Zxi:'.= rz.~.~G z~*
#'i?tQszo L3i,.`d#:et,~. .eb7t e4 h-i w.`iii:3 i.{#fft:Ti.t`Z a,Ito;L`ntse:3:i":= :i'#ilud4d ;F#.i layers wnd i"c a ~ t ~ aii ~ t, =. q c. ; in iii ~a.C#w~ta s~. ~z;.a tif:.t ,ilt~" `i~~.
For C.?S.cit -;Eli., a .II'att ~~$L I#~ Δti . ~3~'. #.~~~:#.t~", ,Iz a .i#.4
E 3v-e?" di <Ã;trwd to mZ .tiL a rapid r ~.li..aSi' t;.g., within a iew hours or sav i.#; 3i3 s; "+:.CoI'#ia enr can .'.3i ,i3'e~A~:Jird #.il t3:. Lcoil layc >F t.lesiga-3ed to
PI'oS'#.de e.fit,.at.Fear. IG,.s'~'?st`AT'a''C?i; i&
< t>I ~3L~:.~;., -w. `. `~. 5 ~~`C;<'.~... ~. .. '' ' < tE. .~~.ltE'=~"Il~iti i`i:=~:~, an ~ `~i.~l. . ,t? ":ci+~~:3a''{~~~ can b',
ÃtaL<Ignti lii?t: :v i.lÃ.closes:in4' zi.-i:1.iE, bill tC; iT?Carly `~ia.l".ty i'elea\Ã. 7..if agG .Es Iiw sue7SC"qLiia.i:`.
` #F'it::i ~i= r ~ by 1#'i Y.:'a'~i.tc-,#;.3 ~'i.~..~tTd#:~#~o xsl, s: ~c~~.:~'.aFi~#.'~%ll '~.~l.) z#li7 c z~ is j~Js'w`t.~.<2#4f,. ',r~ Lr' a.:#:g i:e"?#..LIu'~`i..l.i t3~ a z11L:C`~"I"# w?~e. lC5i i:x%i 'npEe; u.i'{..tt`( 1111ct #s's='i#.il;;0 c_.#l be E.S:,i?
i ~ ~~ ,a = 3a F ~,at,. f( ri M+ i
L; ~~:+~?~.s#~ <.;:li?a..~#Si~`i ~.~?#~?.t.#:~?ie:'; i~.~~~i.~'a.~~.hrs.i ~.~,`~i 31i.'~~t a~~ii16~# XX L.r. A 's~ 4_t\.:'4. ti+~FF. !`#. ~..~. a ..w~ia#3i.
r~ ~-= ~' fli::' s ~..,~ ` '.+>#~'~..L:i:=f T {~ `~ ~..~=}.~. ` `+ liz such <13. =3..4..'~ r`, The CTl: _E:I'~D~3i"ii2~:~` ~S:I' #.1#~..:'t~a~ #i>d]~~ ~ at .,J a .,~ '* .~.: ~L1~~i:I1i..iz iI% a cof...s.,s.let manner to A"Yrly.l pa:ti,'=: 33s ST3C:h as stripes and:`i_?.i' &?ts. tri:e st?lvt'#it iS
Tet27E; wd bi cxa,wL;l't$i`.:fn: T I11'.i 3meth[?d can be per.;t?maed with more than .`a~#e i:s( i-y.i"3.Evr
=:7l~iiia..<. ~c ~ i#4l5l u:i ,. ~3~`i to.?za c.Fuc ~ of q.iii '~ ^i T~1~~
#I3: y'. :~. ~C.~=?iF:?~ a ~.}~vZal~~::,-cZ. ~ ce ~ ~ l~Il t] L.. .iE.:,~~i wC:TiL s13L . ;?S 3 0}-;?Z+c~i~`Y\f :fed ~~.rtS,3'#ls.~, i?1%i~? ~.?4. fia~`~':'~1i.o ' onto a solid .'.#t facE,~.'~b' fl:'i:i
~echmiqtth to ::ftbT'd a rt3_:f omC'i: ao-i=~ i containing ~.7~:.3~i, Such ~t~'ttzi'iii,to can efi:~`:Te'~:'I~
#Is Ef3 apk<in>~ ~?1.~33i`4+,ai~`r.Ã3 .~~ ~:'u'`? ~Ã"IC~ ~:.ssLi~.;~s as deiL'~n.33i= i by the pei1.,.f.: pal$Llrf? }f at l\: ' iW\2 ~ ,~-"#, Y;t,h, a5 ~.~. a fi1i~~~i
Mt.Shod'\ of:~v~`~ak 'i?<fP;ra?L.;k4:"i 3fT.?f~ iC :?#.1F IC? a P;] x#3~:?~:#~ls.C~
IYi?. ~3i3~ F?3i iLti \_L.?i=.`,rfbi..::7F'.#tiin i:<S.iI bL'= t1SW to 3,tstr.~; ?~. 2'iiz#:Ãs kÃ,sa?t=Z'n in fhQ <3rl: For t.x="s~mplG, a water 3in, o.l, elt.Li::s3o.1 t#.:chi?Equo s\:ribed bs `"AWnd &ad ;:o--"vorkf_.is' (see 1:d:(t:nza et al < AtIv.
Pol4ix..eà Si;15";6; -1``'
A: ,=,a~ i, . s s i3a3t .> 3 ~, ~~zl`L'a'f3, a ~~li3r~>l. ~ ' 31+l. ?-'"~
4 1 A. ,. t i:3 ~^~~C)~~'(? ~ =~`~.~x~ 3FSItt >avo. a at.?>.m4'r is i, fL4iy? s i.le #3? using a \'f3TtS. .}nltiy device. 1:il \:i'=.i't`t.l#.i. fi.ie
L:?,\~ is \si "'i in tll..' an ca r ~`r such ~1 ~ '\ 'S:=i ` ~. t~Ã 7 iso.t Se at'-=: s~~s.. . ~~'.~ Gui i#. ~tz"iw_. ; hi' z~oh.itr.ÃZ>;.? }'" i#.ÃC',f;=d in a 5% p(7ty-k'inyl #3lc(~hcil sE1:Ifinal:#,a#`it and YC37'ttx.}.(, (C3r 5t`r+ycaAi.la ~i3.FÃg < }:iÃi bfv tÃp sonicator) m3d 5$Ii'iLd ffzÃ' 16 lie.?im to ;~rc#%lu::4: F:r#t;aZ?p:ÃrE]clu1. Iffxc mi4=Ã'o,"4?arf.C.C_t 3Ã'4 collected ;.i:"is`i'''...s}.1ed wTi:e3 d#T~ilAeia`d:kion>.:;Gt water and
T+. PÃ`#"3ducL: :3aa.3'Ã'.?sll`tÃ\.:t:.S, fsT:te oan if_?I exai31pl4_ me a m:Illit'=dE'si11uit>3i pt?xy-,t-#.i:A.ir..<.#b':?Iz ÃT?iths3C?' (st`o, 4 g . Landfc-st[=r::'f GI/.,
N':<"1Cr<3i?';t?lmuies. 32:5222 ^, 19fr+k+ ).
Bi4flyn a :.32TEa~#?it;}i C~ I as C..f. 1,\'Til? ,f.Y{l 5=`; ~i~~'i>Ã~:#.il initiator +'~ tls C> ~ t, 1 l
^:7;#wt ill. t:#:7'to #~ ~x.. :~`: x.~~
~mp1onÃti-ill..) or fflbs;..`ed#t::iz:3d1lZ=e:2v such :1:Z< i7ir.Xi:Ã7?w i3ei7:?'C.#:o' t3li.#t.=:3e, diethyl f.ho$ $
C;htot;i..f?i`Ã:3., dhr.cell :Li,C.~~:tÃ:t+::='
3..~~~^i e1#.f3:C:ii1.:, `tlÃ1 ~~~IF) bicLtot .<., ~(MCCN). (DW), or fa3ld't:t:hyl SIlIl-C3?::iCz=e, f:i: C.S..itZf;a.l an nt, `'suf..,.# as I.e,.(:fi:.:x4l >l õsl4Ãj d:Essol:'4d:d #.i-} th`\'.
S[3lvf;:$?r. Thf. ;,olvi'.ial is t`u.#.C?\ 4%La 4 i:i ao , ry
U~;?~?f~ r ~i~.;<3t' ?;a:%1tc ~`#S~~1L?s ~#.#.T?~:tÃ:l.ei:.~ Ã"i:=dllx~?Ã1s.
Z,~ 4'`sJi~.?i.,~ Ã;~,Ix.EÃ~':, .~ :?l$~:s..a with a
Et1Ã?a 1.f.ÃF..~ ; Fig.{ i to:iTtEv 4t~t }k e#~ co C3~ ;~i[?1i +?~ i~?l~Etitfll ~~}f}at C~`3 Ã~ cls ', 3IA `sà ~?ÃE#.~.~.:à zs; l..#df3n.
L,nSÃ~" ~:.a~~L,-flt.,= is ii'~?~~i'?.<i~.~:i~ Eiii } .~'~. i. ' i ~ i a 2 ~ " at ~ ~ W t L Sic3315:~ pulses ;~'#ti OL<i:Ã L, E3L,n}' snV2 Zvi.l} 30 ;~Z
power, w-hicb a+~)##.,~s ffiw.' mÃni\'.~~zÃ..~e`~iark <3sid allows the solvent to ei'..#poic1.te. Tl1,,.`= mimim'W`3:f,?n is .'siÃI1S':t=Ã"Ã"e~.~ iÃ.1.a? a iÃ.Ãdstu';:;''s: at 65
Cft}Ã' 21 .?oi?vi:-e .i firce--ri3d1Ls:3 pC?lymer`z,..~.Ãti<J23. Optionally, the
I:s...lfifà . Ã+t: d?; tI3:;#.'#.'~:
z, ~~i Ãl~ ~. ~t~y~~.Kst 5 ~~~^~:; ` ;s~?~v~:acts buffer, .v : _~.: . i~~lfr~.i:. :~ rx ~ . <?~ .~ ~a~I 8 ~ ~~1~~:<,::F Zuiffer>
Nct1rb<?.aw iyL:.,4.I", sC?La:ÃEi.,v.l i,:ltri#..e :7L#r`atL e.i' fZ'.'c# ti~=i,J d"svwJ, riW.rnf,3v= #%ce:i430 `<Ã% fc3'l:iaia and salts.
Aft..e :1:Ft vi:a y #3aÃ>%3puft,dL2 ail, e?~=' produced by phi?W .,:i#i_F...
Fi?:'#, For m<funpk~, a nwTi~?i1E .? as O,,s.:3'=Ã.beCa li%F'e..: ci;f, be dAssol,. =::( .k"1 a st)lvi.3t, st c?.# .:is ~ ~a c3 3t ~ be'{Ã zcF?.t;.
diethyl abE:>F Why[ e3#:=otatf:, C.'s.fchlf?foI?tctbief`s.L=$ ~~;3iz S4Fz#i', (THF ~ :oi_t ~s Ã.i, ;#:L=i~-fg?1Ã~3~~~'y~s'~~ l.`~3, ~Ã:I?C7~ F~ ~~C's, 2Ii3f3'l#e~~ (DM2 i or d#;i?C',thy: 4FT.['i?.YC'.Fl3i:. II?. CfeÃ'tiI#.n embodiments, an agent, 5Faf4:i3 as px3:'t;=litiF:Cf'.~ is ..lso d.bSi::dJi;d in dhe 4i;ai ef.e.: `F A3L:= <,ohr'ent is .ie-mC?-vC~d VÃfi ,"+`E?ei.s?. y
Ldi'apCi<$iÃ(:>n t1.E1tÃi a i'Fsco.ati #?:l#lt?.il'c >t.1.3:Ã:f81t:. ri':`a.': vIs.:=~.?us mixture is Ist.fxL'd vr#th a
S~l})#.?fl?F#.~ ~1'aF?~<# f'<fl#~ solw1 . ., scxLh :is sF3d?F::mn doZ..';w'`. ; .#..Ãn a 63#.I. ~,:w ~.4oit.16CZJ?, The mÃ\.tlf L' `s' thC'.s1 sESÃt>ci'eic(> tor ?0
Fif:.t#Ã[Fli.'s 1s4:'=oon<? w1t,`F s2 sLZ'.i.Fltlf d4 lclv) I4'#tb.?0 W
kF#id {3l1t>Zi'13'lg the solvent to pf.d;~i:F;.Fl v evapeSrel.:.E-. :..i34F,?
pr'#`olÃtrtsEi.. .z3`e i,dd+.'.:ta to the 5.:3'?uEas.ÃiZl:. T-1hL'.' nn.F3t#t!`e :4 thÃ::.n o;Ypi.?s!w=d icj H#,rM ftC?Ã?; FF. soff.i`Ge such as a fneÃ'c:.#.F' j t3rC l?1Ãi`:c while the solution is svi~mxi vÃgof of.:si.~ Ti?:` Fcmudtz?Fw; pxfl"d.Fdws ~i~~ s:ÃaaLi.i wvemÃg"In ok3eFl to tho <k':I` to xFfli3w aY i' "eF-F3: sFI3:I';....'ro3s``i?i:a?: to 4vsfpoÃ'iiu.. Optionally, F_iIe ?t?~~Ã3i~F`iG 33<?~~<3:.fS ~Ã'S are tl'fc>i. dialyzed against a ~~".~u,,ft'i'.+?.
}~ . x .., a ~...i excess i y r~+ ''~~,..i14 ..~~ t;? iS .C:?F.f3 u a= .'~'S..L`t~#ii t3I3d salts.
e pcs be a y "5 =lt~ ~fi?=r:w3~.`>~; ~~1Ã't.C,.,.w: can also 3~.?`t. ~?f~ ~~?aev~S..di by a ?ft.C:=.~F~:Ei2tiC?Ia Ã^tl~.t.~7t~~a, For 4fimmp+e,
a potv#^iFa,F of Fi?F`113fahl XXXVaIa is t.~s.i`'s4i3l'L''cCs in a solvent, sE3cF :4 ..l .: .: ... 1.h.~.: ...,~. .3..C`#.eds w a.h afl w gÃ,:13::; such as pe.lti,l1t&N.t:L I l?'''~.' '.^'.i]l`aFiF[3f7 #:1iidC>i:i~ to an aqfa.L;FÃo.e, `. Fà ~~Is I.fà f
L d:.#t:C?7l. 33.1da e.Fs si?dluÃ?l l'.~.ittdC.l 4ri ;tf.Flfate in s=S=';fff.'.r, JIC `.'C:=.1'.[1 -Fno,. mÃxtF:.3t-0 is ..uÃfs+..a~C'd :o, p.{.xd?F%.. an The .1n.,:i,ttZ3`C: f~ sfir.iii:.d while C?po: to the at2't?oaps.::S. .ÃP c:=v:1p+,?rai`= ~i.~. i ea.c>. . . ~ :a < 'F? .. ! r -~\~:=i., <f.>Ã~ x s4 ~i.3F..k3 as ~,~Ã~:~~1lrri~#`~etx'#`ck`t~#V> ~~:f~= I"iHlt..~Z.ig ~ t~FÃ~F+~`~>.5::s are = z~~.a~.~.=d s:,3px.E-mii lyZa:aF=S z:,=dusl#'.w:i3:YF..C.F?i'<3I..F#Fe w3t1? tf:tz't.%..i5vC.vx.i::S 4i#1'fat?t:;:i at,
x.. _ :s~ià t ~ 4Ã:~:~} ~~n't, the diameter ` ~ i.~i` the ~.fi x~.'~~. af~F'Ã'f?~:: i.."J`" ~ ,: .g ~~.`~x~~:,~? a I f~ t, t..?:, iz: cÃ'ft:
iO fn.Fcrf3 I5q e.g.a :?etweeÃf 1.0 T2t.f:i~ and I a1'Ficrfl:Ã1. ~evtvmI] 50.~. .fm Yind I bt.t1iz:cefi eL`':.i'#: I and 50 Fan.lc?`oIF.`s. 100 ..1'i"f'f mltl 5(10 mm., or bC'l~:'
F~;;~tF#E FI t'Ff of i117 ~;fF .lf ~~ 1~?11I~ N":2?.~#"I4 Pt#Ft1s`.'.k-S
A`#S= faeffi(?F kÃÃov Ã1 in th iÃEt for o"3t:iFA}itflatif?g aF# age:'3t wFEilfÃ~ a P+? yf'f?off?: pc3.~..=.elL L<i33 be used tfS folal a poa4":11S,:r:`agC:,13t vs)mpleA. For
C.a-,,,a:i31pl4, iF3l C,.l : nyFfF..sim;
Wi;bf?lqt..? :F4 usod, tt: fz?f'fT: pachum> containing pt1:t'~ici: s of
F?..7Ftiaa XX. A P;31y'Ã ^?et' i?f
Fot't-nuia XXC".FÃ-. b~= di:showed ir, .. solvent, ;;u~ch as di;e:hlort?mu?haneY in the pze~sefll;:e ofa:l a<' e.Ã-., s...Cell.s :9Ti.~,~:its.F,1~:?; ~~l-F.~ ?C1lX"aL~!'=`~3vFe:i'Iti~.i(r~. `~s`ti#?i-fit;.~.331 Fs +. ~?a:E k~.:~. A sFv:F'~.t3.~:~F:kÃ~.Ã~
SZ#lEi.Tota, s:ach as 51,Ns p{3ly\tn3'` EcC3hnL is added to the and the rLslÃlfi.li: ?t?lfÃt>E`Ã,, itl Y<Jr`~ex#~d fi3a a-b(?u: 15 ,3'1)FAi:Ãun; followed by sÃ:n:tFk.: fE>F' FNnF? 16 bi.ZF.F,r:i. The rtisuifi:~g pi$r6c:C's ii:E'Zi colli_'.(`eÃir.fit w`sFSi-iod willi. w<ilC,r, and 1}`i.3;3hi.FzeC:. Ii3.
E..LF-t<'diii r.=i3':kbod .'¾'3;x7ts, the m)GapJV101lat.Fi?n efficiency of
PaZ:litFxeE lbl #1h4 pwrt;#.:C:s t.SFi_,~ th'Fs ti:i;l-lizÃL]aFE,.' is betwE'.=c'1=a 30-99%, hi another etlibC3dÃf?1s.'.F"i~ tbL' ~.~n4,<i3sL..,:itFo# efficiency o,"
Pn..cli ,aw'! by fihc Pi#ifia,los L3s;?,ii; this tecbn't;11iÃi: is )i:tw+.;`m. 60-751.';i.
< .~e FFaF~.i'~~k`lc3 ~'=d .i#3It3PE3l''~eIfc IF ~ c1F3\a ?~cF TL~~1
Any 'CGA7mt can bV 2~5~'\y~S.~'V~Aii~~=W ~i,,ril~~~,i~. the polymer flSnn1? and \J4l.F"L.n4.4~ d\.sZ.'5.i[iS.v'd i3ert'ii'#.. ., a>;' e,.&ixF'i3fq4, r: ;?i]ly'#nkF' fillf;"# or PartÃ.ciC:
LlL`sct"Fbed bebG#.s; :z,rF .Fs`iis?:`;3Z?s:_Fte a pl.`ÃF3.ns.cU:iL.Fcaz a;;o?i: s..~,.eij.tf#. f;ao.m a;:Iit?i.2tw (I)
F1m??zsteFi3id:?.: anEi 3.F3M3tiaai3 a.i=y i.E`"u::~
f NSAUDN,i i:i?zFlgsõ~,11'C, sud1 as t`Fic$Z3fcfEiie. 'rbi~3'I'ofGIln "~.Ct,apaof:,nm :i13d n<l:pF:>xeI~_ ' # opiate ii.?Ft;Fk3ha ..F1Fg-t`sFcs, such exs, L,otlE iT1e, fGk7lauy`l, h4'dF'onwrphoL)tn.,.i:=1d I;?t)i:ph-in = 81i
~ci~ÃE ~`~i~iL"= zÃ1~~3~~~ ~~~~, "'.,tz:Cr3 ..s a~~~ir11a (ASA) (L=nte33i:_ coated {TSA)?. 2~~ l+ :}.Acker antihi4lGF.~~~inW~s, such as c:vmas:h2o tÃ~~~~ terfen:~~ine, (5).a2 ' blt?Q:kcr k:ntÃh.s4amtnÃ.rs, .'iicl.
x.i ?:'.'i i7F1.:Fd3I1c and 1'iliilÃ3dFx3C' (6) SFla:l^.Tl 'cÃ:_3b\' Fgsuch
InliPAe`x3* 3, (Md ) iFnFi;i:Elcir:?`f3hii:: ?liiti-i`e3f~.'i::ikYS,`s,., s"e8t_h as and Ni:nC{ myc:Tl:, 20 (8) cFl'i~l~lÃFi :i~: i3nt,ibÃ(kt1ti. .:FÃ.`:+,Ã :m'oo.lv4ti. 4LFa'i: as n1.F"1photC:#i.E tF^, sb> ciotr.in<i,z_'+,3..~.,
llf.Fct?i3:i..}lc, itett?Ls,i#.F;;Fziz.L.; (9) 12k<3c[:?lfdc a1ziFbF4?t"a. <i.Flfi f::fi~~:'SvC::i, ti.at,, as azah,"wmyc_Fn ,.lf.:i bet;Ã-li3clti:FT? <xFsÃ;fbioL.c i3.$,3:i-FF,fev6i i;s,-
SF.FC13 as F3a?d (11) pse..,,iUM :Fi0bFotic 1uL:x3 as n:..ciffir F3xai kft.`i`.. p..=ii;.el.il7.i3 G. and penicillin V; (12) quinolone ,.in`.ÃbiC3t.... ;~:Ãit:".
25 im\:clivus. :Y7:FJh s?SL.'=iprofloxt'.2eiii <t-F.nd norfil)x[il-iA1, (13) tvtriac\cliFio aunc.F.b>. fil-= anti"
3.i>rSõZ.ti.t ,}, .>.F+...., as do.~ycS`C.Fi`,4,, Ã'Ã.int;cy4linw, aIId teF: <E'E yr:.v.iFfC : (14) t;nfit.#'.Y:.,=.of'c#.fl{3tixS s3mi -it:ÃfE'ct.i4'G~ such as isoniazid (INH). and d'zax'F`iipÃ,,r; (15) aFnt3pF'C;tozoz3l wsFxi_='Z .., ti.,CFv`t.FCi,idille and C aps3:Fi`FC:,
L;6,Zr&ntFiFm.anei.l antip?'Eit\?.Ii?3l z3Fi1i-.i#.1f\.i.tkv4s, such as u,:=hloJL?quÃI'k`v' a.#.id s~3~5'11A3+ t~Lw:F27Ffii=.. (17)...k}Ã f=?`sõ3} Iti>;
Ft^t > [~5~ty..Ãi Te Y i?~.!=LÃ~~;s4= ts7 ~]tS =}L:;.-~s as , t* (~,eds ';
[ttLtA ~,+j~! )}/t}iti~kLrn }-s(?y~ antiviral Anti*.3y=i.i ~ {=A C;21SY .iy~ 2.'=v \`~ s ~s 'Y t>
Fr C`~ &C?S~Cd\~. L~ LFLSY`:sF to \Ci C].igk,t'2t~~ ..1.FAn ~iCi c3`'s rFcyE,.lov_ii, waTzi.'.Fc:.ae7L'=#.r, i.Fz:Ãt'.rfi'Frf7:'.F alpha, and huÃi:c3:Iii,.Ãdi.l.kG (19) <$lkZ`lx-3.t?i g wat n4t}")iwstFc and ~:is~~. :;tÃ~~, (20) -nÃErcÃsouÃesà t~lk4l(xiis~g '111,611..v;_Ãi<asAic aAy\-nYi'!Y SLYc#.]4#s cit1.!mF.vCiZl:~ (BCMj) (2 1) aÃJ.timehCibo Lo
CL.SS:i?i eZfp:.4vLicL2gVtF..~. .TuT.^ha+4.}.e
(22) p`orÃnnldine analog r.l:niti;l{:'=ti1blS.Sili' (?fl"sInL=op,_Es ts`s uaga l-l`'s, 3.7t,i: as fllxr3l{1u,uou,l (<.' FU-) and g4Ãiwii:1b i1LQ (2') h,`?ri:37101`1c`2] ;:51
SY3t'Op..>`.s6..s, Ll.;~a s 1`,,.p".i?hLic. (Ã:Tt3 (24) vial:Ei':1l 43T1fink.oplx1stÃ.t;",s, StIc}. as itSS..t..~~~x:YS..z, d.L3p.3sSdc (VIA46.), TI3'.eFf63.i'o1R>.'s~lpha p.aGfitc:{ol, and tÃ'aInt;)iÃ: (,.Sa.+Rs:'s); 125}t anLabamtc ..'.i>i.in4opi.a,4CmSJticik as 6Jl1:f.s.glycinyl d..{cF.imm>yZ:in, dauno. L:Lrif.eii:, do.='~C\~rubit+;ny:JATa miifrml='1.nin (26) vi~ilLsac}ikalolid nG~~il.ur.;w any~mmiA'a(stwc:`, such as i iFÃblc.#:st3:#e .:3.iad vi72G.I "st1>io: (27) :luto.r,l:onnIF: agents, tiS:ich as Ã#ÃE",:3t:3`.i+. =(2` `(3.i,Ã.dc1'Ã3J..x-It'.=x'_;:~ <'r.utt3.~',1t3t1i a i:lgio1tE. ~.. ~i3Z.h as ti?e#:lil'i.+p17...' iÃ.T3d ti"Iht:'iy'pht n.idyl.; (291) >?Ã? _Ãm':asimriÃ'?ic zt~ I i5; ~.31 ~ ~ r~ . ~~.. t3~i`I'~?~,.,.J1 as c ?C and ~.~:3i +. ~ p 1 `r ~+~ #tj'~~:iÃi, (~ ~1' ~_l 3 ~1~..` ..1~=Ã'<~. :C= ~ y L.~i~..\, wi.wt:xl a E.
ill,k <Yc ..ts, si4h <38 : ... ~~,c?E}i.: Ci t?,:rx">S t*eirytFli: <3~t, Y~ ~iz7G. [: .: ~# ~:~?tJ~,.c~nl~s,ipaà (,."~~~Ã;:-~~~i~?.?a~t#Ã:i~~=d~:~;, such as ,~Ã1c?~,w'~~irÃ~.; (;~' )
\'i;iG hi.[S pyi7iaSi>tigm.3Ã1LY (33) alpha'bt4iC=ki.Z tiESch a..4Ã::t.~~a. ~. 3y,i i~.f~iG= "Y- ,~y~.~.~~.~. ~ ~w.iv ~.~ U ~ a 4~.Y oas pn;im^=Ãn, (34) :frits.i baf.Jf:ker s~~~V.~{ipafh~;F3~e~L,Fvs. `s~~A.~1
=uxYCla)C>-~~~Z,.`a}>.::i5.i.=~5~:?1.sWV..'S, as aSR7oter`}2 waia dob(atLi1,i>t?L (36) GS..nhkJtas4uSCLr L(`r-..c_in.v, ssuch a^..
i;4pSi'1#.i t W:l}. p..wvt-N (ClC3..~I6i?g.i'C.l. bist:E.f{i3tt:') etl (37) bÃ:ti';#-:Flockos `.suoh iv4 i:l';LS`aiS;.%S. SFio,p op-anESloSe ('8) ca:5ct:Ãm tll:armel bli?ti;kt'#' ca.E7t:c.Eiw f>nc',.zs ; o:o;. (~..`s n.itC.'d]::33:nC.`,
L~.i4.t V~iiklt~~3wi.dt>.2l; *3.J ~ 5?S.'Li~.~.ill-' (~i1t1(Y.il~fi.fiiil,]q
M~~iy.:i>. as ix2;sZ~xi.~Ã L'4' .S!\}.t~?^4t~b ~a~\ "1'4t }. 4~ }`? r
G~CtJ:~A23.it=
glycoside on>ia.rrh3~tbinik,sy sus.,la. rj\-, d,gc?xÃn, (41) class I . uch as i.ocaz;:.,, ÃnuxSleta?.7i., pheI11 t<3i.1-I, ?Ã L3c-a3~:na13`iÃG.~e, and pAn1dSne, (42) f.l4tss 1:1 such .,s :i.4i'<?loi, m;::opF'E?lS.Sl, p7~5.>-fyra:nol;13. tÃ1I7fSlol; (43.)
L:,S.i3sy III >tSl'.h as ai:i;.i<?daAf?ni:=; (44) ..-S-aws IV ;:Lke': as dalÃÃ 3zcm >t;
vC,l ;~.>to S2 # \' "~rtC. '~~si~`~.'i" .! .<`4IÃ"a; (46) iiiÃ~? "~ii.~I3 (451 i~~t ~;iS^~L>:f3~.:f`s&t.~ ,'y~iix Ã~~a ksi:~ ~i li:."~~ as i"fr
4L9ii .`t:ftiSg unf y.me' imilib;:ti3" t'ACE is3h1bitt5; 1,InxSby.^u. ioÃ1Jti, us, such as i.x.zrt;>pi .i and immia-p:iA, (4-') betablt}ckcA antih.iporW.Ã1sive,i, Such, .:s amno4ol. and p>opw.i+3lo;; (48) a._:lcSi#iS?-%h.Z.7n+.:l Mixt;:ksa.i' it,ntihypoXu,1;five
EMoat8, such t.Es firRxlÃE3t..`..'.q (49 central-acting ad:'e-nLk"gc tÃitihypc3'te.ISiv;~~-S, Sucl1 ,.s c,lo?3Ãu. >m,' all >
mothyldopa: (50) dÃuuoc~io ~.~~6l~~y1wÃionwitre agents, suL}~ as 8rnÃ;<>ri&5 .-
i.HC'I'ZI aÃ:to spironolactone; ~~~~~ pe-6p~i.o.,al v,;so.>flatoÃ>
i ~ pti.``tE."ii.srtvE..4, S:10h, as hZdIe1EAid:1#.3o w>Li minoxadl:t (52) aTAiF."`pi'-rn:cs, sooh as
Ei71~z~3FC3r.3i e117i-~ ~}fi~~~ #e.:,~i`~: (53) b7`L, wl'#i; it,iZvSt;.EIIt antilipemics, ; LEvEt'3 ;Es cl.:s~
(54) ~ ~~"IG- Z oA n%h.Q.asU Enhib:iLt.'sl` sti:"h as I~.~vc?.`.tt?~in aÃxs.a p1.;vt3aiclt`;Ei; (55)
F:1L#tE'opL ., such t]s, zEmE`in n, dt;bEtWu11Ã3?1`r EzEd dcp::Ee3]iF?C; 56i i~,zixd.ac ~fycio`1;,::C:.
#.nolE"f;pt. r, 5::i<h, as fiiy+.~x:ns (51?) fliE`{3mb'i3rylacags.,nt:9 or n':! ET3E'.5. :axF+. Ei?s ` JtC'.;,?la.s`5. ~ T}~~ ~.r, amme.`cEikiso, StF..r7wk zi:`s4t:a :1Fid i:lrt}zh#.xi'1 e: (58) d.;r.eT?cj>o.z?gEu faw .3ts, stFoh n` co1L;:.31QR'>i:1
Intl:i.?x'1dil, tw:nt3111 Wi"R-Ai (',T)`~) dormatÃ?;s;i..v._,.#?;;Ti<
%o.;b:cC;,.i.zw.,t`>id, <#.Eiii iE.f.ti;.:17.::#att?Av aoGni.t, sClcht tiS bm=cfhi;<<'Srw and ; .. tioxbE:rwf#:stsor ~~_'. J at:t i1.i,.~fii iHS;v t;3p%Q~{13 :? zd1n.3`'L'`i;lvi.~s;, sLEch as amphotericin B, f:;lo`zelmc^Z>.''f 3li;', m.ci?twt~lo, and 61 ,2t,t;v:.,.k top:imt <`a:F7ta-iE7~ectZves. such i$4 ai:'trUl;34 ir'~Ã %)
0 czal E,,7eC`pzii_;,,.:t ;, Auo~' 35 x~.8::+)","f)'~i'wti.El (:?--FU). (63) L'~ki'.'i.#EI`C. ~1~`a `EL; d T z c co:ta CEiili i;1 `s. EV a.`s h3T.,ElÃ##.),sf..; (t.`'-xi-) loop d,uroi1cs, such as filrCr`sei7;idE, (65) pfftas`3'`mn' sptzizir3gg d#.xli"x=fiLs. svia:i> f`~~ Irian1tei'i I;f; ( i`3~f ~`~~ 3~:idf, a.~#:.~~',1s~:S, ttii;'? as
EaiEE:i?4E:E,E C a~ L F E~~ E.i .~ as p= f3*:3f,',.E-at;e1dY. (68) t:.E'1_ly.T`tE:,s such as RNil;ic 1nd.DNa_k't (69)
a.~e:1ts, SFa`'on isFi L'yI;lE:z`3ptT*a:int..,
5- rc`it.. <'i.rtn, (.70) c1nt1o n1i.i1 ;s. :eLEdI Fl4 ~~l:i?L=ilE2i
F~f~'.<?L:(70 :i~AEq.,`Ii3.tt'.
c w tA ~ w `= ~ ;c~7 Z ' . #2 ~ 20>14?+..Ã1~ti, r ~.~ r~4 `a~Ez#~":i:4~`.~'...c:~Ãi~t.. ~ to.~~?j#."1+:
Exp:amp i:?.lIb`tt)r, iElti-okeI' `i,lge.n:'R, such ~$s t3mepxt'E;.~:ole> (73) Hj `+,`_tloctiC`, ~2I~~E Ãc:iLr c gent4, 3u%i1 <~s LI :E:3~ ~'{\~E~.i::~, fE.EIa~~'Et.;.71;f, :iTf;:~.~.3d.E#3~:~, and x.':~.~'Z,'~Et~.E#.i:.'; (d 4) +~#<jt.s'~za33 5. such as
("5~, # TrZtr`s.iniAj ..>ti viit\T `.3.:`1.:f2 as ;:~~ItbdikmVi,=in. (76) t.FpiLEti. a~,~,~,o#a:.sft a.n,.#avcv,+Fus :ns.7fhefi~.:?
20 ~~ such i~~ ;~ i,' :~) hi;f]Fi.ItC;poi%fiL <33v_ f:C I<iFc~ ilk.1 such T3s,
C,'# >'thl`+!pt`a~..;EIa, i` t i:st:An.E
(f_# CSI`) wnC S zÃt;nuI3.i?si#.lal (G \.I.-CSF)? ~~7~~ t(#i1f~ES~='t zf?il <F?fe.S7E , as Et`.'zia3#z..e3o PhI fa{;tE?rS r H; (AHF 1 -10,,~; (79) f:ill{coa,~~;`i3lwats, such aa -wnfarlE3,, 13C.Ps;t:"Ã.`.+, and i.EÃ`gatI'obal1;. t801 growth Fif cLpii3:" 1I1hi'3hE}i>,~ such as LI'li.AIllxb :2:E1d,
M,0fetl8`zEbq (rt'.~~21'r ,E,??,3r.if~wÃi`IlÃs, s;ii=h w" Fl`E ~.i3 w{ p(~'s: ~z;~) 1n..i t;z4~:Ela_`~, such cn ({i t"~) ~., `~~.<.:i ~;.~c.# 35<' 'E:,. >. '~"`v'lE t"~E E:3s`.'.~1~ i3. I#.i._E~~IS: ,.~1r~~.Y~ E:`~, ~:: 25 :#.S L.`strot":Kfz ;E's.wt =3'R3gL'sC'1.1z; (S3) p"zJz ~ 1x17 ~~1..~', as v v'()IE:a?"s,z;;:~t~'~:I `E:1~ t`rgi:<sf7=el (t46) s~A,^'ogeI]s s E..h. as i,:f?I3^jt`+y EEtti;d
SLmgC'.E J, d.i.'Ih`r l.11bC sta"e3l (DES)a v,W<3` .~.:i;; (LstIad:ol, o4luof'o. i.:"1d i:.`stI'opÃpaiic); (87) fertility <$,,;<>F'EE"sr such as i lorlt,A".+hs w hEl:`nf73i, chorionic k;:?.'`.?..:+.FZa3.Fi}p..n (11W), and 1'S.3t;:=F:oET'f3piE:s; (8i)) r'zE3ra,hyE't#xid cz4-#=.'C'.E'ars .aLich~ i3~'s t hEz3i EiifiEFE , (89; pizu' 3aE'y hormones, such as dk snFd1pr4 ss:EI1. (?St =L=.dÃ, >3:{vz 1~~.iAA c3-Ild,
30 vi.#:i<)pr4s;sil:. (An...~i.); {90} pi:?t.:.'C;st1F:s, such as 113edz[?xyliF"+Fk t:s:* on and p`' )gC.Ste.o31i3; th t ['i?Ed hi?1iF'li3Ãte>; 4E.lL 3 as lC't' (9,2) 68 z ge11t.>?,. suoh as f.3tez'fefon e3ctc3-~l 17 and ia"ltt.'fert7: ga1;:uml
I ii (93.) ;Ã#.iL~"::
as rtmalon,. I<?btrhÃ: iM, ÃWG, IGIM ai?<i xm~~~umo globuhn]V, 1VIC. ~~IV; (94) waizdL. local and ~thode4, such as ~i(iÃ3caine; (95) ost:or Ão:;zd t::?esthefics, s Uch as bonzoua#ts.; anal,
ISC.t?#.?~1S ~A ~~,int ?m:#sc3.#.lZ?"I&Oi:Qi.al +i."i:?,.tlcotite.'(?Id ilt3ti^1.nfli?F3?'#?ia{toiy e:.g``_i3ts, sf,cih T3s', 3t;tafa?{:tbaN+.?Ã?e, a.Txr:I.`ti.'i?nU. d.v.4.cll :C;~a?a;iC3'nU hS'drt?(..oS'fi:iC3#?v, and pri dy1l.::o#iv; (97) :-?3.[1.: m..1o4;k+'.>.l''~'.it:fl 'i#.nfi-i:1lhEn'4:I?i#.tt?f'L': l~b?I71E::3[3hai~~3Ã ~ } ~~, iF .'? 's:S 3Ãs'?Ão?pr3.11e, v.`dophi?spb:?#1:Ãa.ii;} alta ?n3eÃhot#"ta,xa.:C'.; (98) m?.t,.ct?:.E,;,k~.'letG:. ,?=f?stt'Ã"of#;z?l
?n`L? '~~~. ~li?.~:'ttc.~, drugs # .`4Spy i~ t ~+} >s~.2~.~5?5i~..~. to ~d v 2: a{~~ >~,?~ '.ai.~1. Se ! i~. L}?. ~~. a~A~:3~~ v'112~.'~=2 t C?:3 ~~t~~\.~;.~,i#.v~~E'.~i:a
=t?~`~) .~}~+..i~,ti3: :ill.:at'<l.r E#'n~i:i:.i.i4, such <$.~ ?6,;~?'~L.~:i+~.lt3rtsie.?.. .#~ i; dl 3 .e;?al .:< Z'= 00) Ti.Zee.':s..'. ?Em7'omu1cula3' blocker skeletal f`a]Lascl[', x'L'~3i3,.:3#3t... such as pyYri (10 :'rri g;.rd~~.?e. t10 ~ ) iic `'..#.oEo=.,;ci~~ agent’, such [?S mMG di~~~~.~P,0, #~I lvo1x awLtii I-?~5,. r_.n3_[
t14lE:p?dÃ.i?e; 02) r#?"f~.:c}?ÃES':73y:; n ts, such as, c'41Ibatn<l1::.p1ne: ga :?Sipi;tifin, i;?n-loaf:i'?glÃ?e,
?#:d vraep:i'"t)lL:= aL'.=idr (103) b1:i'bi'ti'lir#?ii s3;.#...2.3 as
I>:ia5.;..#.ieb.3..xb?tc.Ctl ::.#.l-id phtniLaf>m. 104) benzodii:nZopil?e :IÃ~~l oL}s:vu1sanRmfi ask.,fC?ns;zepamry d3uiFfvpan-?, ;a2?L:15 Tirat.cp..`,`?, (10:9) a:#.E>:.1 pa?"k>oZ?i31#.in awt.3`1t.: e, S#}.cl? <#k `i:i'c?r:?i?E:>ipi3i3c;.+ :t3dopxt, cw.7ddl?~`;:3. ert ?..:do.. (306) ank`!"vt.'#'tiglZ t?k~iwn~~`.he, such as mtiJS: ~iAnc, oplt.c g.:Ãa:islt `s..ich has r^C`,,a hyt: ;r ~ ~~.Z>lTI'~:Ã.l>=3~1~,>aÃ:, ~S?>~..~a dt>ciC?``v'I'ii~v atl;~?S'?i?oT'j?cl~rtÃi?o, (108) op,ma..to ,av `~ va.=:,>..s: ?~'~. -. .. ~;,~;c.~;~?>?i.;`t.;.
StÃE h, as a:tialE?:SoÃÃ.., 0 091} el+.'.ta b;.oLkCI' anti-giaÃ:#co:Ill:l i?ge#?ES,, 4ud;. as 111,-w1f)l; ~s 10) t:?;3.lot;.:% aliii^g#:r:;EucE?3-na ?.g-OnLS; s3: c??. as p4lZ?t:tl.l'vt<iic; (I 11) ophthalm.IL c3il:?'1.Ã?or',ly i:.os3&
tilÃrf?Iz?fCs ...ves, s,:.1~.iii as Ã7e-aszÃ:?lf>iÃ:, neomycin, and %t?'bFamyitl?, (112) E.3pl1E.iõ#. :].a;.c such as ciprofloxacin, F:3o7"floxaiJhi, anduflt?a:al i.; (113)
01,11di?:3:l.?3?i= '.:">or'E?ct?;?wI'i?ld ant? t1;flammt1tt?rr' ag!wea, s-uL:7 as C?L;k::.`:':1L:h.st`ne.: and pliA>.3isC lo-z3e:, (114) opl7ffi#3lm#; nC}a1.`it%?i'o1d.T3S ia3"`zigS (N;:.MDs) 4uch's:ti d#e koff'7?a0.:: f I I 15# w,`6Tmi<L:=h+?t7c4, :slit:h as d1[?z#.?p#.Ã?t:, hi:Ilt>por#dt)>. and ni\pu.d<?IlG', (116.)
2 115 bo`,..nd.z,.`.s.,pint.. ,a ax:Ão yl#E:.':;:., sC?'.di:Iti4=4, aIiCa hypnotics, sb.cIi w> d...k:'`epy3Y?'b, p;BaL.C'pas3'1; (117) p#sy:h<t;A1.8t.F lan .; such as and a3e?il<?la?:c-, " 118) a..#fii:l:s5avE:=s; ::lu4h as et>deiI3't+: (119) ba?I1ohC?d#.a.awas
tht:=C;phZ 5li3~~, 0 (-'} t?dI't;#?eÃ'#?'ÃÃ`, aLw.114t NZ?n~.~hod1la.'f[?''S, such as x.lb?.et::rt?z, E12;i ~
3a ~~?s#'iI(C? i i:.[j."t.iC.oStt?'Ã3id tmb ??fl.. .yniT?alf9Ã'y :lhvll:i,, yt.#t:.h ei:? ;(1,~~,'..2) a,3tiLaf?:es; ;I3d,., t.E'.1 fl#iTlazt.',ml c1.I:ld i?i.#l(??:(4 nc;: t 123)
r?~ 3~~ . S1t 3i ii, a à ~?~ ?~~. ;k?3à 4; f `~.^~) z~r.',ieÃ"T'[ .3'Ã~. std.~lSte .i1L:G'= ~3.:?1.[s~:.. ~i~::t t . ,~i:#t,;a as :~.1s.F3~F~s.?Ã1~#.,
f7.FltI'exmnt., z.nd nF~~C3fi }c; (;,2'') withdrawal sE.1bsl 3.#..+..w clii3.IsL=. <?gi;m*x N?.Icl, as
(1 21Es) minerals, F;,ucl"i as #.3't1:`l, c<?lL:3uF-.i3, and i 3s ?eS;E.#.i3, (1.27) v.itwi?z#.l B i"~~rn:?;?F:#za~~3' , sL#ch as C 4'aTIC?Lobc$I m`.1ia (`t'3tt.#iT`xi? B 12) w?lf niacin (3'X ,.i,7?;#: B3 i y ( i ) 8) 1'itt???F;.11 C cEfmpoi.F;':tdSY slid, as ascorbic t36d; (129) vitamin D cÃ?r:"sp.m#wis, such as
<'...Ile-#:`'#'id (13,01) vitc?miF. A, '4']taillii7..`.., <Ltid vitamin E t.,iS.F'aip;ut#.ds; ~13 : i ;?C`.FSont^, stwh t4.<''. k3.; ~ ? -. ?} <?F.?~#--~3~~(:~.~#F~~? T3r `4~"1~~< :~F.#t;.~5 eE:~ ?t`i3~~#11#1;:; ~ `? 3 '.~,.#?~#f#:~:=~f?z3F#~3,:.F..>F x#::~,t.~:~'~~~. 3` c1dd:t`.t}.:F to the fiE1rew;ill the f:i#ilob3`F#.?g less t,oI'I..:3't`~ i.. dmub s can .k34i} be ...sF.'.SFi:
S.`zrF'a[aliA i>yp,s,'3dlaif'. F .7 S3iI: estr .~a#.t)l vaatv.Ia:l% in t`;:: fimbffÃ;>i:
fluidic.int ..a.z3 tit??iiÃrn: i1..eÃm.,eCti3:#: Tcvt)df.+pa; nafari,lin, &ndGo1:3;fz?p#.i. F,?n.tzet', th:` ft3il.s;i ;fFF dtw''.. :aFs i3lso be i.#.:;`~.'d: i'eco#:21biF';.:3:T3t bet#.3 Srlf.:cc3#.?, bc.Zea.i;c ?~` ~its#it~ ~(?~).# !1r cmFtxIIt.F 3lc; bi3 v#ne Su;3E;'.xY??;.idL= d15:1'?'i1tF4C; the fm'itSh-MoII c3c`F1p'n"'iikg c~~"+#nephF T3c, and bovine collagen; recombinant b1mdI#' I3,IZ= , I 3:ET,:AaFEF:#.?;Yb',f:; h,u,I??I? ,~F?fi ]FA.~: `-` :~#5~e1~`~t?~:~~~; FLirtt#?a~5~#Ft~#_i'#t t1.1iF~.~~3 g~'?'ski'tx? ~1~?~'fF'lt1~Fe .~.i:`:'?fiFi`1~?c;F~~t 155 Shi.ii2?;<3I1 hu.E t3:3:;;ol?i#:F (a f I.e ct?i?_ib #fic3.nà hLF3'm332
IF:eirei?imil F E#;-=1 GJ F - i.r?; i"ez?mb .2?.?Ã;;: ii"#.t C!'?''.r l3ri ~c ii ? a, ;wij'.i}z;.::lbs à i i? (G- -~~S F); <thi :Iz {ip ii3z'.; Ã:CRc o Fi?b Fh?wn i. ''1zyk- z?id JÃ#lr3'.#la `.:3?? hormone (r-T:"+H); and it>poor,4.,an. F%Frthwr still, E}FefE3alf3w1#iM' 3:'3'a! v,xoa1.s i.`+Iol%:o;.,~ e,'=an be uw3: :?.~g~ii? ='.,# ~?+~: #1??'; a.Fed4siiI3.~.C#i, t:teda61fi?l:; bleciÃztw i ;iulAawr human t,alS.:io#.,.v.i; i'i#~3ili?'J3 3wi?~+ I~C3~2#~; ci.l$rbop3z<i.th`#; eiuF..~#a4lf?`;; di3Ã: sF#3i?i3::win. dc#I..FI3e Fb#.c.iF.`e L:It{z,E,.i1xc:::
da?wsf3i7#s.lij 1-i3:1; ~:,F?()L:1.n alpl1i1: d :C?p(?side (VP-16) flu;3#"o^.#=rs;t.I,(.~ FU); F3?~:~:.5'rb'Ãe
Sc?dFEFr?'t = L.?'?trJ.T7F,4:i? si.#ff3>3., ÃntL;rfiI`ir#1 alpha; hci.#p'r(:}iFL:t.
tnCi.hadCyi?w i'IL`i. . ,?1eflxw4:fi:s.itl'.= ;i:?diFta:s pacht~.#.,~e ;; #"s:3n#ti: ll1e HCI; r 1z,.b.iz?wt...: : :1..tilt.iu,`: iFI?i3 r;d mal;h'}s = Z ZTS
~x,~?~a, b~~~3,w, Aa#~: ~::SS.i~Ã`#3;?l;ti of ~.~ ~~ ,.=xa.Eli ,~h
Fl'#~l:i:C~LFfi:.al fFof;~3 the abf3vi: t,`'ate~f~x.F`L'..'a il'ly?3.#C~'=. {,to) o`:ti #.i~#~.zCF:~f~`itr u such as 2#.Itch'of:};y`4vi#iF'l~~#.~3itt?i~:+, ~;.'i#?.,~,'.$~~'`l?#.ItL`,`'s: cytotoxic aF~~'rfi.as receptor F..~ 3.#b'.tis.'S. and F~I1J~ 3"~C2I~#~}+ i~~u4:C?F ;b) eini.F-tiUSs?Z t;',,,i such zis dV:}.?i,ome~hoipiEan ~~`.v 4,t#5,7b#t?i?Flde,
FifJscaAf.a?~~vqca.bY'tap4'n\4}.iii,. c2C3G'W.
and .`=hloi`,:}lck:.,.#.F#Ãsl hvt.aC?c}?,t33fS:xi (c) @ii#:Fi?i:it$#?},vi?.e?r such as iFa<3leai:e. pbwa3.il?i;t3y~~.sft'~o-~ w.#:riFt4, pyt?hlm.lnC. maleate, G.3x5haFI:h1e succinate, 3?'td p} C.FAyew.1i xt3i~`?1#:.#fi:" i:..iÃ#`cite.y (d) dlicof..g:;SA<3nts Si.'.'~.:.~~.? .%#q r~icd7ylE:ph'lyie h.'tI~~aos"h:K?i' &
hydrt3<:h.s61d'1, a;:eeIktriS`~.."Phti>d.i'FnC,ah,rI.F"oddE7r1d. and ep.ht1d'I'FIxC; (e) Z'i7t'F\3:3s ,.F..is.F;:lz?idS S:.#c;.i as codeine ph{~sph'i'StE. ~:=3:3#?#:ini. s13lfatL= and `1~a1t~5~zli1~; (`) afit1Q.,aal s.3pplLmLiY`ts :4E$d as pt`io3asnt1ml dlt3ni.,c, t.M4 L"'3101-Ide, {.c,aS.gE7a1l 4=a# b'#JTa.itcs 3na:t:i#bti..m.? {3x'#.{r~ amz3 T3t.aci a? r.: Af.
I?,;ac3l and ca,k;:iz?.T3L earth metal siilÃ5, i{?;:i fi.'x:Ã,A"#.;FigL:
I"SE.`F.3;ii such UJ
) i:Ein.t7.~}i'#~~"{ w. ?YiE~ i3FA:.3 ~3 ::~?#b a :i3:.:f..'.~I zAs N
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L^=S anti: m's:l'c?c:*.Cit:Vss svich< as ~~~1eaT~,'lat=4tci73-I`.i1o~~'{e .#, aS~~ ilfa i#.ili~ F 3E7 `rL~fi=al., # co ? ~
Gtit~: :i.~.~~)IE.`s>iiaFlws s31ti'
prop,a.Flolclmi,int u#" iycll-Mi~~ (k) as ggt.Ec?:,a`.'.1.,ch#.i';.~ (1),:ai,
Lai:ads ;msy'h l6 `r#.:EIma`~.~'flm tl j'T3t:'i;xid{y 2#33d 8?1ag11e4ruÃ`t,. hyd'#'L ::idt'.$ (m) b;Io t`,t..l.c:a .s J,:ich a:i p;`ptÃdL~s~ pt?lypLp{idy.s, paAclns and ili3:iilta acids, hormones, 31lenfi.ic3t:.IJ or cL';okanesi #.ia~i f ~ 'T `i'i.l .i4.:i:1.:., ~ 'c ~ i ~ ~ ~.=;?.#i~ac. can ~ t23, ~ i-e t3,t:EEi;da; such 4.<i t 1ilEei`lwla~,t t.#7S 1-18 3.31~:.1#~ ~ ~ r3 inU~. a~'S aaii{
#lcalf3r;Li4s: ,.<Nawi.'., DNi'i.`'sE'r~"; iE]tett`,=;Ii,14, I]`<)rIIl<?214
I{fle I:sIn`.j ='a`~.{1 "t731?n'`.`~ (LHRz l) `i.ia'IE'.i
F(;lcc1:Tt{;an hL7nnoIZC+ tS,,;fIiRl-Io-.timGfo3"#'?E..i#., y,.o15='u'#
fibrt3:?It3sà ,gowth a<tc:or 0't;iI-0iT turno: :ii..oto`i~ tac;;ot'- a1;)ha & beta f Y NIT ialp.ha e~ bZtiz# iic'I'i`i', ts2.`aLtt:a (NH3F,~, growth hi?~~?i~~~>e releasing factor ~_B1'f growth `
<-3r ~'rT 5 fti.Lr . ~~:i,..~.~~, ~ '~3.:t~~=)> ~~ ~~wff.~lE~silgr'L~i=t`3 growth c: ~x`~.LE'i_.to'E i'}7`~#.~ S r c <3T.~i ias i 2c.:: r*:~~ E{3,~ r.\aEi~.~~=~~
Ext,:::71t.. t ~jF3 ..
5 hL p4T{?wZ'tC`> groYvfl`E f+1d(.7i' (1'KF), 1i1s3_il`i2] growth factor (IGF)~, Ii'1Z?ia4.E#n Mh#.,.Kitlng >;.~icAo;t ''
Ill. -2)0 bom.;. i3#oqphii gC,'I:C>1`.>i:: proteins 1 ~7 (...`.+mp 1-7)-. sft.yli:E4_3st..atFl` flhL.3:1o1F::3-alA)lleE-;,
iE ~1~~xiE rõatt 3Olii"#., ~~Ã'r'~?C.To.S3ds. {a3s.inaEc1:je (SOD), iol 5 fOac
Lc;.ll.# ai1i `., ANF, E.110 and ,inadin (I3) afFfi"iÃ:itl..+.t13'`t' lN;t'3'.IL' :wL.h """? AiTtt.fim`?;.3.~4. .`a16=i3~C i1ii~~ :wiE' ~~Ef:\ antisl~?ti~v4 imd t?n.ib#C+ticuv and knt oxyuv{.Ito l`C'#.i:x.'ag3z3bEl~.t..~ nitn'v' 01,
a tlrt fit:aItim; t:i;inpde4 l3fi3-anid c:.itl:.RoIivJ i}a L#S.C.a~.:;~ phi$nna..r'..'s:#cc'l agents #i7ivAllde lw f(`la.3wxi.1=,~,..? the;:+{dapC:#_3i1L~ s..atk.<,?'{.~ilLti; s3F^t_lbolIc.ag ;) s. .a:.3L'.4ta3G3?i: c#tf...;3;s clnixis::i{as. e'i1L. zasffi.1#a#.d1. agents, Lt#1~:i ~~C?~s3~.C ii;:{<~I :~= and aeltlvlf 3#d i3gC.iFts,
S.~^'d`i.3at', Ya1Lc#E:a. ai1tiC:a~#: c-fit'. ~ c` ailtirti"a:11~+'..s,=stiSi s i`g~>cflt''`z a.i` n:;:i.~'.Ito. ai:ts F 3` =~ '~a ts.3##S~,3, a S~Ca#~~E:).. ~:.~~i }
/.".~. :i#.#.$ ?,`:lE`~~, ~:~~,''ill.~, cl:Ã1~. t~s:`.". L:.rt:; 7 atFl~rtt7.i,C?.~~i~~~f{, c>~;L31~~S, ca:~~d 2'~.:5#af ci`,.~,:,rt ~~. t$~i}I
and i ~c S i ~ ; r r= t ~ ' ~ r ~ r ttF = j } ~t~ ~ ~~ t =~. 4 ia{AND. x .~i;a ~~4 c .l~}we~i`~i s..si# .i. .cÃ.# 1# ; c#;~i.{l.... ailt.i a'rlr?#.nail ~,Igs.,.E,Z.s iiT#t1 t'u`_i'Li$ves' kA7p!`.'fite 53..#.pp.re4sani:)., b olo3õ>i:a2s. ce,.obE4~l d,iLao# 3.:o}!?nar~=' dilators, dei.-o #gusi-a'#'its, diurL6L-=`i i1`agpoisdv ag ayffi3'+'_+pj,e:.iw a`:z'ri? 4x,3ctvtc~I'anl . I:Z'p4I'wt y+.:.iT.-.r.: w>s, hypizoai#.ti, l>L'i*i3iz L'Sci:m:c #ti,'ciats~, '#i;ta exchange t 5..::dF;.:i c..?i'c3txvos, t:;'~E1ae.';ii A,ar pz.cilia{tilts,
i 7i.lcoly #`L.. agoE`#.ti, E>ouromtl.Eat;l.da{' d# uggs, pC'nphf:1i:El vils~.)dil:e#.oi.:s; pychL3tr`.3tt:;r, Eod ?fives,,
s4itnulCbS?ts, tJi}rof.{'-an'1'. Li2ttY`fiYy-rt~id ti~t~'.~..VntJaÃ.lth.ltin+v relaxants, 41taS2 12i`.aL2d pi3').iLugs.
EmiFt3pl.` of spt.a.afic dS'ilg.i fft;it. can be ti:ie'UIyiL'.li#de: i5pslra`?.nasf;, bE.:s-..~i~ixi-a,
E::i 3C:4;:.itci=Yi.3e., i:2.1.iib(5pl3Ãii"i. S:'i?..f'in114fi"IC,'., 5::hl?':?71abui'::Fl, .Ispli3fin.
dilLiFrortPbii,bit7.:. dE.Yi'z32omar1, iif#co ,..:gel.
`s.lo.:Z?n#."32:i?:, <,w$?t?4edG:,, I-xoxÃ`s".idfi=.i6,', fl:ldaI'ibi1"ff. fl:iÃ?F..#i.i..:ii ihyi:i'3xy:,#.'::a_,
i0.54>.idb!`-Adi iJt..saS3L.ia2dZ.. AYSE.AoL'i=4'a3i, 5.~.~2F~iR~L3FDV,..12~4+r~~1.1t.=~Sl.'t,.iAf31S.1(! ~=',.mV.[pÃ?,-2At1a?.)
n?<?f:'i?.~,"it{?p.3a`i` ,~.? inetho.`re:5..%lt'., mitZ).iT?y:llf.
Fl.itotan::, #:11t<":wntri?i?L, ps.fjhftca?:w~As pL:mt?`t:it a?, pzi+.:t#n?ytii=i, pi-5.'.ili:xÃy-ed ?i'C?cui`ba:1i7?::, rir.h?;`.a.:.bi.., Mo~f;.pt?i,+?L)a;.. te;? 'r,'`'43`i.1d. $hi`Mm3i13ni, th:CZtq:a., v.it?plsistine, vi:?`.~hrfSfinL., ?:ild- vf.Ili:81'cibFn<:, ..Th4 E:=7::Eai?:..y pi,#e1`#"eC-j drugs fos li)`.=.?.g ~'. ~I-zt;:'.',.a trccdtme1'?: is pi.EdIl.'ia?i'':ly p`t.'l.i?'.ÃT='.:5.ed,
i Ãi?~te%un. (3:deriva{ti5 iF{~th~,:4e.:i1e;,C'.=:?1xts,
1.ili'.::33os of <1.iIfii;wnc(~-? ; a,xtl#.?Eti3p~a!~wle agents are
Cw'?ptoffice:tns. ~ These dm,igS t?:I':; i:'#ti;.lcqp..c.i k ~z5r vzrawof >lie3-r ability tL., ?li1.iib1t t(yp(ilso`l #s`'.'.Fc1sG 1. is :i p.aflt zilkslEo_.a isolated fft).n t.ILL':4 7.,ldigent?ws to Chfiai3 a,iid
Pmdo`;s ;h.reof such zAs 9-
3l::1}~~:~?~?I~3~~A~GaF~, .`.~ ~?>~~ai ~1a?~~+?~a1~i i11. ~~~ ~~~'~E'7 4' i?F:i~?~t?F~~t #~i= ::z#, ~ 1mei.i1yl#.>}ect::.i3iY.,~i3=l1,;3tÃ.;th<`%I"i, 9-i?.tP.'C?-IO..11 #l~~~d#~'.~:?C~?~'`t~~<~` 9-ckK.ii.`SC?.. a f -~~`1.~.~ ? A t'~,`.~:.~ ?~~a ~ Y~ t::7131~?sL~3~i.~ t.G=a.~'1, ~~ $Ã'$.7.1i'~? ~ ttc, ~ ~ ~.?w~.~1~,`~~I?L~~i `~ti~? ` 4w $3~~?~3';~,Ã;~~y:a, (C31.1.? 4722; C), and. other analogs (collectively 1'#,`.forred t"L? ht` 1`4,',l3 tEs, G:Impl.5ffit:`dn dI Lg s:3 2 C. am. p,'.stiffly under study worldwide inrf;~oarC:h laboratories fell"
In4,x';2?'14i1t c3; k:cdoÃ?:, by5 aai:, and t:;tiai..r {`.is:3cY<i`f.
Adi.aFi.:z' na;3y Ãile pilt3.imm8:ccLttk4lal i, a:.t?t can bc a riid1c)st,".3s?fi1.C . -,oic:'`; as sbwnsw:S?i\:e or ~ ^i.Y'\r%~C~ ~ (l1a nul. (3ciure4< by ~.~ S ~ ~, ~'N}~=~Cy)
i5[ Et2.:a~)~~'S.S. = . ?~'4 .VD. }l x (made b; :ion), RSR1r (mado hy Alfas) THYN41TAQ1:, kftmi,Ic 11by AgoÃkron).
olai7.1dcilt?>e oT iirb lgÃ#-as:t:(m;?Ã?ufiac:'urcd by NyGt-n7.Ã.=d): gadm>Ili>la?, tC:;mKph:"1:7. (I?.i:di': by 1"a.amnt:3c4clec:S): B*~~,.1DR/Br.t?xE7('. q:mado by NwPhurm)3 iFIdR (1?:Eii::sc by Spa"'"-ia): CR24 12 Selke:l.~w= by ;.,..w=la Thi?3'isteÃ.`aiI?..)) JLIX (made by Te_iiap.il),, c;gent'.~~. that im:n#.asn:ix \ hypo:~;`aci-, and `._;: Hkc.
The il.'`a.=.a.m ca#? ~.'?c selected fr`si:tl a :?PÃ?if7:,Ãs .ily ~.we:5'e h,.i:3JI.nC;c. 11..c biologically uwÃix; :SÃ.#.bõiaunL, can be s.'=lef.ted from tli~` g1 ov-p Ce.1i;i1tiElng L3f pi.Beit{i'.y, pE {y..; i.:p.xf..S,.`,*'.: pa+.?ti3?.`>s, c.#.ii.?:T?Z xit`..idi'? polZ'h`,k':L'i`'.`xiiTif.Ãe~'`_''z, growth fc1.S.;:i?'s. ht)rmnt5nwsw ll:~l i~ 2M s3~~~~~=:i2 fLtclZ?as, or M!ir#i34::[TZs, and pao-dS1.4{w+f.I#I weLL2F t.~ÃSaboR.Si:.~iioi^ ss fl.W b,,O1Ogia.a?:`Y Fa. t~r~ SU~~~~aDCU is a t.ic..FapeuF#e dni:; or T,Ãr, t ?xef..mb}y a i>.rug, f:'f3i13 L1C: 2~i:3[3~? ~:~fz141 ~F31`Ã~ l? f :IGI~#J~~~li'=~"~.3:tF.~, zi`'+..ts and (?:.l?::a i'~Iat#t:;4'x.t+.i?.::Et;~ Ã,t..fz as p<.#S.aÃ:ta:tiel., iÃ:FÃtib#()ttiLS, .F3'.1t#i3.t.F74F3Iti 3#?L.Stht"t+'L:4, .3,.?fi~nchnn..Aflas. ,.t.it;,.
l.F?d c,ntFf:i?i .qF..fl:mrs. 111 cC:~A2:1.Fi1 useful L#F3~3~)C~#F37F 3',`, ffit= ~kk?t,# :3C'3_t~F~= i$?t#+ { or pF'ÃS-E : ~,.tg t< <õaG.,L:cA Fro1''F tho gmntp consisting of
LlheF'?1ot~~.wi<.peÃ'Ã1:= -i.goiFts and, other 3I.i`'iÃ;L'.E3patÃst#C.a :ti:3't;ii as pa+;=_jitc:mi:i, +:Itt'boph;tIrs and c1:#plitu=?r 1,..tF"o4o:.#.zE.,a cilkj=3i:# :lf:1g #xFi`.F#.t's.~~~4..e~.Fl: w,C,.~'i?".. staf.:.3i as a;EFl3.~F.F<~:~.1~3: i~B~ya~;~J; ~~OS3aE):#i.Fc#. fw``'"~' U F ~1?# `'t:.FAIL#...`.S_?.Tf+.', hi)#`mC3'#'i". .3Ã:tMoopli:`.iLsi s3.s, gi,31a#`oaFa. l(:.i:prmfit,3e, and
F~'.'?4Zx.#f:%n, -rC>.=q put,i>
?#`.>.:h#tt;::^ ;;LlC;,, e:Fs tit'lo:#..F:.``,, fs#.,fd,`=#]I Fb, s1:FtS:;3?t
S:SF' aFJFta-=-kz# :I1hib#t[3m 5.-#ch ia.,
na-uF-Msz's aft..~Ãr-coph?tÃc1, such asaldesit>13k1F1, InwrMAÃd1 .=~w, doÃ..e`zi:lxcl...i7px??id:-, fVP 1~-~;,
in¾Lr'fZ::4EFiF alpha, pawlir.FxC+{, i.nFairefinoxi.i (ATK.=f'~.).
hi caFit'sk.?eI' iz?e b:t?lt?~4;.c<3llv acttvc iÃ.1b4tancL F?liviw=.c 's.34Ãd, `. YFIF~~laFu acid sequence cm b`' selected frti31'na s.lz oÃkg) any
DNA or RNA 50.'~~~:ei~IC;= I?~ i,~'#~Ã:<~11: ~.F#.:?E1i~FtTluÃx'Fs, ~.iza, '~#olfif~, 1ca~ly L~,clvve s. SsE,FnL.L. is a DnaA se;ixI?i:e thLa wF4,.Adesi-i o4nVfi4' w}1i2?ke2 ~,?t.,.(e4.LVd from ti2.iifFt3(.:.=%uCaE?ase ge[[1. g4#:4'.i z+'.f...#'i?i# L'Qin It.S11."'IjiILF#Ic6:., iaaa[i L:haof`i3#':'1phorkol zalt..,~tt`. 's.:'a.E3a4`feF,v`if.'. Im, cert.%lm c.~'iibo1%ija"3`w.st.s, Tho biologically i1:d]v suti?4t~an<'e is a DNA
S'L':.quE.`~#lt wÃ.:i:ft f.`z:.z:=odes a a ;
~o r > 'c c}t In a.ckl:iF:t3;~`~..z ~'1:~.pH<):", a Jzu:l?:'L=s3#.. or a t'~.di`i~^"t%1F':3.z tIaI~`'sc`I.i:f,F:= ~ <~.tsi1w factor. .3a c':`twFt i;F.i:?oi3Ã azolyl,~s thw b'1,t3lo"~~,:ic's3ll"', iFf;f F6 ~: tit.IbSt,.3$lcl.. Itti a DNA ;s`a'.qF..5;.F7:ce flh:il G#.4oda::s a RNA `'sE.,.ea..teil f#;(t:n tile gYO..p w:la.siÃ.Flg of a SG'R]4c RNA, oil. :FEFb n&~'~ ~~ N`,l, siRNA and a r.! bi?i?-y-rn's::,
B#. 'C`:gFi.iElly c3ctF vk: tlgt..i'.:`i cE1:fm#3.i?l5.: for i.:so watt''i the aIWw zdL..sxeF'Fb<:.d hQ.v1.n z31o3mk, w~thoi.'~': aii?'>itc1t:to1-F, #Fiedli.tdm=.::I:ts, viIF:?mÃ:i3i+'; Tn7i#ex::?.l. s::pi?le..`f:.:.'.`1ts:.
s~1.~?ti~<:a1i,e:s .,~.F.. fi>`i' E3~1~,. t.~::'i~~i#la~~ ,i'Ã:-. p.Fiti?t.n'##CF3I, diagnosis, cure Ã#'~:IF~~~~\~. v ~~~``~... ~.,~ ~~t~..~~,t<~o3~<F.'' e S 1 i the structure ;F' i f.,#:~~:#i(Ã'> i e of the ~3~Dcfkt2 #'!' Z.. ¾;3.: . #a~7 ea.L.`i.< {.~I ~'; ~ FÃ ~~F~ i. 4I'lfÃÃ;b ?;fi,t.o.;?':Ã' bFt?lo;? ci3lh a..t:iva ;2.F`>.1'3{??'C aG$.1vr. after thf,'.-v.I3C-C: been p%:t.ud in a pfi:..L>i:t4;F.#`.F,..:=s'~``. phy; # "zf=#.i E;1`3vitiFÃ1ÃileI;.Ã', t.T4svf3tt', i#cti'E6õ .c,gf'F,.ts. ,F?:F,C,.i?..3b?Q ff:t:F' EIse#.y1 the iota iv c<?2].p<?s:{t.oTFti include 4Fd,Z~ ~':=t f;3.cmoI'a, sui:i3 as tf'anSi[:f.F~"tI71.#i a growth fLFa.ois (TGFS),
~i .. , t platelet x ; e1'S ..~~_3~:: ' -~ a:.~} h3t~3:'Ã3~'SFi'il4. to ~7~. ~!'4t~.1 L~'ilti:tir#'s (F~l~'~i), 3le1t~=+.>~`F~'v~~ . .I:(_~ itFi: fit:L#~. ~.. ~:~1a~~3C.F .?:F3 ?Z+y~'t~~ a.a.F~.:Liirs (A CÃFS), (.t3#1IiLct:vi t1s-F1e 34=tIviiwd peptides (CTAPs), ost<ot?en#S wid ti`oloq z<..~~ llx' i.l's:ti:Q : ~f1~~1( 'z; ~ i1` 3.? @ ~ f a,~.t".i~'i`1Ia~`~' ~: ;s f. \~Z, a ~Ã:~? `,a~.~ ttc ;r3;. ;`L . lsl~~~'a) -
y( s\)}{- ~ f ~j? i~~~)C)v.t~~:}.:.t]~ ~ {~\1!C af5`)=~ \}to) i tl j {}~`\~[! {F ,) ~~)Y` <r~ Va> L~.r J.:AAS. ~e S?.BlyS 4 C)4.1 t~~ti4~: C~.~w w= _~~i~i SSR)_T\.~ R}~~~i.4 ~~]:bi1:[i~ 4t` '~`\{ .t1A.at}:' ;,~[ ~^. M?f4,.4:t.
fi;#d~il~ax?t ~?LF.iI;IY} di:`:Fla.~t~E=Z% 4~i:E ?31'c+s are ~YIv~.
I'~.:to.. ~'rRa;:mb`r .=`,,,,, of 0::E TGF Si.ipo7",`-~.',5:;Ile famOv <endl.idG . te- ~`L.ti1-~~a"?.zs$C,1~~~.3I3..;. ~?rt?:Z .~'~ ~ } '. i'S.?tr example, k(.3.~i- b a to.SS{ ata a~~~~~~s b,?,i'~ind..
~i~fvF-~?Y,. bone morphogenetic pi.,t<:ims ffc~a-i~xamp`vz BN-I1-1-I, 8MPI .
BN3:.3" :i. BIMP-4.
BMP-S, ETNVIP-6, B'~.-`E'- BM;'-8. z~~~d.BMI'-9), s~epzr.Ij:-b.}T:tiding growth f..ctons-, fib; ex,3mple librobltlst t?.lu~N.Ih ..#L'=~w31` t FGF;?. '.p1dL`m1al ~.~Ã'owt}] f.aC'Ãox ~ EGI'; p.awltt dk:Iii`ed yC ~ (1h ~ `~i..+..~ ~~ tj 'k . ~ ~s dXTP ". t 'C4 ~ihÃ.:Ã~..~ , Ã .. F~" and . t ,~J~v ~~i..~ It;~:4~ ,,I-:}~i~~.at.1f~3:t~~:- #~I~;iI"4) F~.?.~~3 E,ID> ~.x.:a tpae,
hi.>.i~~in A, anhibin 13), growth dlf.f:reiifiating.1actors (for example,
C=DFr :, andaLtivin,::
(io, example, AUtFvi.ii A.A+`..~~vi~.:i B. &i?i3. Activin AB),
K, ApplÃss3t.i~~~s for Polymer r Agent Compositions a Elc t?[}l472-:t:.i' provided 1-:;3::1'c-.iii ciiil lic Litili.zt:d >z p:rYmf}:C; healing or tr:`aE or i?7`it - ~ ~ ts~Ãc...~. ,`:#:. ~ ? } ~~i-3.1,~ Y i~.as,vl,o'f'i_ < ~x, to ;
C?L,.~3 and t.s~. `` Yi ~ c co *.,r~#lv..t>,~ 11t? .~1`s~:c:~;~ y~ i }~.... . . f:'i.~,. ~ act,;vx;4
B:"~ provided i?v`=.`e3.. ci1n, ...lso bS.: EaS:a fi37" i3'(='cli'let:=ty for ;)T3>1 tt.l33~ ..~I~3%[to 7 S :ft,;f >14?t hs;,~i:4~i.:s to, pa'?iu8...TOi: Ã}fr31ic-ri1- aund n<3`s11ps?rsTC:lt.S, filI31R, cf1ati>
L;.`..; :tiE tur:ss. cLiY.~ #`. E}l~~~?., ,i. `t3t:; 3al,. Ib4 pohT1ae:i's à <:r a;So e'3 used ll. various tz;tlrt~i?i:
p8.ÃL?at..C?3is, iuC.:~~: as tissue FLug~nC,Itti:f-.lf?m Sl]Oh I:.citk t'Fbi~s can be .ti5..=d h:. #.qp%.:3r anz i ~YCllp~ ~h: fi<>7 '~ I ~..:ti..=õ ~., õ ~:,, .,13Ile or ¾,~,:i4.,1ta t`a~ct, Other tab;~';~ of the t?{tl4E7.'.~:~ ~:?.<2vIdtd he:r6?i ~:i42uta~..+
`irsilww.~, of <:lily.; late, Ei? pI'o;.1otasl1' xl"-i..al;d #:ikalia;nisin:ÃC=s or to 3.tzfii"1; 1'f .tkr:F'onG.: T3f t_ have bQS.'.1-i ;url I`f)1'F'#(3`v'i'd or locally treated, a?'C}?d.1s3:e of aoc:`rcgiZ?r`:fl i?'ar3ph node 13>t=tatit::sis, <11qi?'Zt;nEiltfr)n of local vr'43u?i$ hi'<3.lI3i.; :if2i3t <{em05 in ;.1.,f6::1.on, ?;ii3nliz3latia?n 3f sziI'if:;`:uI`' i11.d tIbt7.i,1mail scar fi3."71stIt3on, and .bI= l:il trvc#t'..ieÃ.i ?fp<3`s':-
{ 1 p' i a:ive p#.ik.
i..a sL:??'.I]L eI.~"iii7t>dda3"1'nt:, ttze polyrr>Cr:i provided herein t.,,,E s:sf.f..: to bwclt .riÃ:ct ,E'. For emimF:3le hw pt7ly'a2C.1s pÃ`ov1kd herein b<.'.' tis:[1 to ari'i:d$. h2i1F;,, i,s3lf}?<2, pr..zswt:, pafw>va:zt?.rb14.ckst Z:,At.E:er., IthC`,'d i.:i'SLLil(~ also t~='~'~' 13sE'.~C~ z~ #t~'1~`Z:#3t'= .~T3i~rI~7.~r" z:> n:.L1>iil1. ..1`t,i?Ã;t:<?
tc?:gvtiretiiC.u.ii. thegraft, i"+uch:,:s lZ%mp(fhC~n-ia`i and lLuSC.:l:.i'{.'.:.. The po..4'?riG.?c ''a;.'t#clos c.z'r. be ,.7~e~tt.'.C. or indILI:iC:~ ~.'23t? iS;` ari?l`aF.?t3 Iizt3AZcra3:?lÃ:= tfa>2C?r4 ~;) L3Z:cttt.v dt>iZ'er 3~Ã' 3;s. such <`zs, .hi>m:btA3<:Tti p-.,' or sensitizers, ("}:' i# ie~w.Lf.t. or 11,.3a..sod a>.a.:1r the s..i:' of tlo. (7pu.A#i]n 1F?a1tiToI4 to d{;.l#4ei' agS3r1.ts, St,l:h as i.^ri`ft:Er~`'3iotiCs, -mlSti]vfiL=ti, o gi'wE i or
E:t. .t?lnlg i.he.ebZ r1L'o3d3Ila s,dC: (:Mf,>t#S 'i$4Sod.:z`a.zted with sy<st{.'.:II`.ac Ciel>`c ai` Thi`,
P+I.by-Mi`;1'Ãc PtÃnIcks Pa E,sY'l:aed herch. ..'c?Y2 be adtt?inIstt?ed :l[ a s1..C: of N,,wL.i'=Er' w?d; the intent of ~,he pail.cAe4 beiiig camed by the 1yFx?p.? fluid to lc?coregional
particles 4s:33Ã b&:."L'o?1ic tÃappiAi at i1hi; lymph Ãiodt'`i, a.~lobZ`f.Tsg de,.#.v~,dry of i#f.x,cats to tumor 5C'.C.fE+,~'i thL+, r,'~ .+ w's`~~,.dt$ 4+r z ~Ã;~Ã~~~ ~s3I Z' i?#1g~.~' diet tl l}'I3-lp\~ti;'l.tS that T~'lSr "`?rT i#' #~. .:.~` t {~' .NH:~ ~ a 1 t1{-. 3~ ~C'3 . { ~~ E:C t??~?1`w :3 ' I?~, +3e:
Yltr&~ :i,LlI1dS;: tt.B.E:3.or cells and ?7:Ã~.t<Bcl-#Y<E.I~.~'.c cells such as or d-e?'#d??Ã:x<::cf,. IS. :3.:1d iha3s dired. o3 un3i:en byi3ei'. v:Ã.rti4'..ies 5.aÃt: b{:: utilized to enhance the i>iatr3~tiiiÃ.'
4wt `;C {~2 > < ~ ~'t -Z.q,r+<x 1 } )` <+r~ J! fyn .yP } py-)5`.{ { . }~ ` }
SiX.. a?il:c~$, L>i.._Ã,tA...S't.Ft.=~<Z.1b.t.~.. ~t+ C!~''+.C.f Y1~ lS
V`L5" Lt-S211.Vi ~ E!4 t.LCZ..(. v2-t.-~~ Y.~'i.~\. ~~[2-{ G+7i]..t.~~,
the Z,el5 directly t?: b4` Ã.IpÃ'+;tfi.#..l3ti:3?tf ftw #.e.#.Ã''z:ui'#.c
Sy4ti',m iC:`'figi7.t li>i Z.EF'l?:Ã1?`,
?>>wy~;?Ã'>#tw p%;Ã'tÃi:.ii',s and fili?~~:s p;t.3v#ded herein can also i;le <td12z.I:Eti`.uÃ'wi Ã'o sÃ.ws Ly'h.."C. .E..W"?l?y :C=git;wi:1h is l:#i~-oly to occur. pi; ;Ecl[:'s and -filmS .::..i3.i? ht' i7dÃ?i::?'lls-t.i'><.d w; i:. c<3s whae, as a L.f3nsE;=qEl(''T7'+,:e x3f qii&lh as CO.PD or Wfit,.,l??Ini1t33`"y bor3., di4+ 3>i"..`. or sy>'``sw#?zii` ebw;"#li):i?.C,Ã'i#.py> poor #ilec?lÃ: 1 lT'1ll result -i:l rni3ji3Ã'" i,;:rEi3pliccl:t#E:s"lti.
In, aditttt3n, i1h#- } ..+int:#clo5 and fil#'i:t3 c<ti:i bc adt.i?.."rk? ~L' ist[:3`f'S ~ :s. 3 r~.. m.3I .TFs (ià .. a 15 or or tt) s.tesff>llowÃ#.sg local ablative ÃheÃa pY:`. F<?Ã. 'sÃpplÃcs:tÃo:tis.,
iÃ. margin ?.a4 tÃ~.' P(?:y#..ei":e ;3,aõ ;i,clÃ' aloe prepared to sidniea"`~..'~ tf.? the
S..b gif.: i or c' ~ LC. .~.:~L~,`'~~~.t..~~t:i within the L't?na#.?.,e:+ .a#`d 33oÃimL`'''+e: of t.~'tie r?.<1sJ, In other cmbZ?t,?'ÃI?'. ':?ts, the part..Ã~.;t3e ;i Or 11:171s,. adhere to ¾he pe:.t_a:f:"d#E :ai, i:::.?n?li3gi'.; or cC?llagi=?l f3l":..hc
L.i'A>wry of ailt:-.c+,t..+.:Ã:r or
F7i?tx7ik:Snl<;4tiQ .w-e :l:i. i3-i oi.h4? aJl.".b;Jdinae1`ts, th.^ iiEI-r.;s
Cc`?:tl bz ,`.'..:43lw:d, 5:3 f.redv +.3'ld,'t::s"
24 .::aLwCOLii place Lti
In t?.3:i'. the f1kC:3;i and pitft.C.fe hl;;.,lrA.Ã can b:`, used :.:-i w== ttL ppht.;ti#?F:ls. hn such url:i3. application, :}ic swofl.iTig %+4`Ã}L#ct :.t?d with pH changes c.Ãa be ::4d-v:>:Ai.i <L,t.`4.,#.11lf' i.iffl#:zt_ta. For 47a:'c'-:#.171~.~lv. 1 iili?y of the ::iC'.S yle:#tc poly-m.esR d.i;`ScribL'E?
3t~*Y Y ti~~"~ =a3~ ~' +...<~.r size 5 i ~,:.i#; alt>.? :~=~. i>Z ~.:~y~ to a ~1.``s;ail. ~Ã.`v ~~,?r Ls1 i:~~~~ la.<.Ã'#:<!.'_ `~ 1,3 ~T~ :3E 3E.. e s ;~ :# ~ ,.~~? ,}ad .
25 ~ ~t~;~? ~X`{1'Si t~~..#~:~ < +.3 fill Lt'tÃ".~~t,~ eht: saxe of i i'?C3 ' ?`N b:. = a~ ?.l;at,to Z~.'Ãt~lZt;la,Ã to:il;: > '~it~~:l,.s or
iÃ4suc, if g., .Ã:~liAZ lips or dceks. Op7taE3.+`it#.ll4'`., the pol'S'#'?,1el`` i.'(s:.ÃlLa deliver #> ,#;b*::{tic ct,,g+~:.'ÃA :s s`31.,.odhÃti; oi iwciid t1`<`,":3L.a. In, st}4.3k et3'4bt?Z'f7TIeI1tSz fl-w p:.`lyx3w.:y edsC.ad for ti..#c-li an appliL;=afi13#Ã Y3A<:c ?..F . .."r`t~-E3i~ and 9i~ and 111`i~.
30 Any method Ã.sf iÃC?he1iikg particles to b1.ologÃu3n fis-S::ie can be used
4:tapl#Ã;.tsÃ#. Few np le; the pt?lst~ wric ~ ~~'~~~lU~ ~~~~~uct herein can be
Plu:'oiiic 1 :.w.7. .3: <3;:3otht''r Ã.`.TibÃ?i#in'.t;'.n i, the particles a,".'c entIc.>3"a?`' ~4:at;.]_i#l a at,.~. h4dÃ`;3+~,7~,Ca, :WhEr43Yi.:õ \4..s.aii,E>e or :+llrw;#ci?l
I:Aal~S3#~:l.E7"?ZT?L strip ?-nc3d4= fi's.D pt'T`#ciFF'E.3_iÃ:FF:,
rE I k,.~~~'s vq iih."4k$ or o4tiC,'.r #i-latf'.='{'ii#lS t)tpi1.rtfclf.s 3.izuFi C,i?v~ utilize a spL. ,E:TrFE :#C:h }J .3Ti:fi#1 . ; ac3i n, to h14} S.:'a4e the:Ã'e.} t.hiÃdw=Ji t time at the
benefit ~'#'<"?I~:1 ~~.3E. Li`~, of the ~~.`,<rl;"~}1e?'3:; en tidid#ÃiC?n. z>thL7 i:y~~L.J s3:.~'',i#~`MUÃ`~% can pwrtÃcIe: wid f.~,ii.n'itidt.sliaÃb#;'.d l2vre#I.i. I'~of ex-'iirnp3C%, flinn_: and pa3't~iiõos i;_iia: f,,.t,iii:}Y,.?'1
`i iY tltiÃ.\icrie\> _E L ) i}jL ~~! ~(+ c> \ 3tSt;raty k ~{L.,.' Ft<at `~ ay+e <~ ~~ a Cl r. ~ J4}{r~~ t},f.. 2 wc)> )\.5~~w.) YsZ+ T i4.?i\:cca of iia~yty . a vniÃ~ be L(:~..L~~~ L4kL ~yZ,4 ~ \ Tn4f~t{ i 3i1.x~- i ! 4.. The
CFS wn.&o; anz .=t.;Ls..nc;~ can i:?C'. :Tivoli,)ngto Ã"tid?#t.C the r#.s~. of p<3si-n q,`i::pili n..ed#Ã? .> b.#t.:. as ~: z???~tT.~.;'cs+s. 0~ficc'k Inl'.ct3+?Tl. Th};=s f.31efl-l:.ir p .movies :.l}a alii.'.##..wi vw; tf? ffis, use and risk of s4s:4~mn8i: .at7'i'fblo'Ã.ics. I'l1t films and p.}:f'ÃI..le-s- can cmilc}i}? G}nwstl?Ctic=`, 43a.#,.l) a: local 'z.>} 3}\:o :3a`aC.s:hLtÃcs, 50'i'~ wu'E'..C?fif s, or [}I2a Tt~~~ }F:1}~ 7niJ"~ t!ag~= ilÃ\. ::Ã,;i:hk ::4 az,efZit. ~ iIs_ ~`..'~, ti? rC`~ ~c C~,1..~ t.l~i. }i1sE:i,. t1}3~.5. E]`~.
E. 1f ~?extlE.:i'~ `:, .~ 'a+ a:: i.is.. c. of such .~.Vx l ~~.~.:' ivZ\ z aY.
tilt: f`.utor.i%ia:+ va:l `.Qdus`.:E. 3i:?.33)dlty stF S,i,.dili=y to dt.4Ã}'F::#Ã#.i i#.i1d E:t3T1St;pa$ÃC;I`> E.,,..f:`"C.::i:;e th<'. length E`,$ h:?`;'?.tal Si='s:iSs f<3'I pa..1e.23t5, amd it.i.F¾iC:'}:.
C3vC;r`ct~l hei}ll.117..zi"e \f?5t'S>
151 Ian ceila}:.[1 t:n1:i{#d1~."'+eIlts> E~`a7o p[3lym4"I1c -fIlIIi4 :ii?s:i p2#,i'taU.C.s a}t. in E:=w-~..i#.'Ovii:1a i:Iqi[ef};us C}:" organic io.}#~~on5, or cS37nbii.Yul}loÃ"\ thereof }a ~~4} aqt1C'=E?.,is }+)lut.i.t1s can be sE,leCt..',d ki"t,m, .amL3.I1gl w::tiC::=1", bi.}..Fo ."ed sC3 ~x).:ti ili.six''i},. 4<'dlfne. b2J'A~Itd `iaa`.#t.., s{3Ii.it}on.N of a>$li.i acids, +~~~!iug:5y'.', si51i.ftAol}s t:.:.~`~o=itc} zl.1`f;>, solutions is I ci)I`z'i:1iÃ3z.Unit>i?:`t E;}' aixy ti'vE,' or more flwi'oE`.+f rri7i.'. oI'gaTias. S:7?aty+}S"tw cc#n, h:'.<'wli:CÃ:E:=d f:`i37al i':f.nn[3:i7.~-f DMSO. S..tr`a~~mZrlT. nwth<3j3C;~, T.Hi', dIchlo#Y?37.FE?rh2.i3i`. DIVIkt`, 113=3diL: or l<?lE C:T}s.: or cira7bÃfac irttfn'? t f3a;Jt"S'i? i:>, ayi;JrE' thf:#"L'o-f:
i3'= ps.'33Z i'%3C`'kc particles : a1U films a%iin E,a)ni::in w+. i~
I4.fic n-I6A w'f :`.s, `s. ,h,, ;`u}ciS::C: acid ed'.., i l. E i?'ii,, \3 e#3 : ,'t , ~~';i: 4S.`.c:o~3E.i:',~, Such ?I`e<3~.t.:.1'.}~?lC can ~?;.'. Tsf Ã~ to
IiÃ~Sfi.`+,'.:.:~.l..s <.3'F 3 ?>
polymerie particles, :.nd films can ctwit<1irt i} recepko-r :t..c;>:;t:i.z.ng tai r>t't;.big tnzfÃ~.~Ãy,
i.>An of .~ ~.'~,, iFceptf:r or ~ltf~~F~Ã.7 ~~)~,:. AND. z rat.t.~=~.=t; .iii;~ a ~.~.(i. or t><<ratic~~~ or }~~ ,ibi!
s.1vBs'qExa3, antF"s.iGelli<.3l ar s::~.?l?%}iÃngF or apopototic $,?aEh`:3.}v. -affiÃ.;,, dhe po: 5ii,4,.;c maÃt:Ã:'#.<l`
Cie;:E:.`,'.E' hkd .. c:a1-.', be i.#3+,.'C: to :+,,.livor nut l;.'=Ã:
IL'ldhq%i4 ,iY..t:'.i tf_s :i E,z'.ll, or to EiE',.3ii., .T 2t L}'}i be t;'~#.I~.::~3+?t.+.'C~ }i? the i~a~BS;;lEii\ of a C,~::.al or r..f3~.f.t iI'E}s;.`a('.~I~i~3:iC'i1 or E., c. ii.i'.x~?Ti i'. it?Firk a such as ~~~I:?3E> a or specii.#c transcription factors.
The al:t fft.3.3dJ of using ti?E> pE1lynn<:T'3.C: pi:"tlcic4 .}Iad fi`:Tl`i dt.''sL'#"fbed ht:>e3:1 Ciin btf t 4Cs \ SÃ'~az..}ta~~. A< ` S 2.~l4' or =F~~ti::lie bu E:C?:i~'i~: i E?'~:'. t'fi~i31"~; ~. XX to ` Y ' = ~~~~, v ~?~Il`~;L~ l'l~~l t,'3L?l. .,Sii.s~'~i\.ti 3E: ~:se.e . ..i
p<7:t.fn.1, 1."or exilmp3iy, +3ii:i'~tic,es c(3fT'?aa.11.lf3g; one Fypo of ti:f.`.:Ã'z3peut.}c z1gcA:i be de sg11ed
L3f results Ã;Ã' ffi3 p~iltf:less b's ir127Ãf`g fi'2~Ãa:~~?~?G{Ã at
nodes, ~=.hi::of'w.. t}thE.~ pt:#itfcÃtes or filt-T#:~ that contain eishe: the. or a dff-TeI`cz7f: rhcÃ:3puÃfic, agent can be a:ppried to ,~t?~rgj4,:=3l #:t'1aTg:.Ãi.` or 41.#.tuxc. s1::::5. It :`iÃ??~Ã~.(r `Fllh~.? t.3.i`=
TLcE??.T.Ã~.Ãt.C.~+.h. that ~~[~'.it à r.;~?aFi besides c~aE~=f313st~1~.i'i~~si~`~lf ut F'J1E1 t'. g, cy3:f:ikrÃf i: 3'r=+1wth 3 ~2~.~1 .f3 ~w.2': x~ itxffÃ',: 't~3 +'~Ã~.t:~, .;~c3.d'~ EF.4~`=Ei 7Ãf a~`lt...~_~ .~.~.~`:r[zh ti?~:~ 4.tfill :~lf?<~s1~:li of
~i~.~.~`.1J:'. L:Z~%itf~.ÃfÃ:i~} a )`;~1r.~fd=t'
T'4I~Z:~~~Ã:(~~.3~\:=sC~~~i`'d,~~.2:~,~.'. or other i ~a i~.ex5tt! U<Tfn. be
b3}t-lik} i ihi)d a.{Z.L'.ÃNl[.>o Ll<~il~we Δzk: ~?~3.y+`Ã:.r.<. ~Y:Ãic c}~;~f=ii,.1,..~, z~t~il..~~>sAAA..3TIFL
)-rov-1f.`..t3 can bS- used ..br:n viLrls :$n1~ ~~ ~~Z vivo ~` ~'. a,.~.a,a"lw } ~ , < ~ ~tÃC;. faÃ.f Za:~i. if a ~.le::~..tiC 4,s ki~i~,tlf;~_
Dpt'nkh#L` E?pf?:3 ti-fC, po1.ymos S6xff::d, ti1C`> rt1tF.. C3:`drtFc., ^:el.;-.s4.= can be Lai'.Ãi<.f?<,:BLa or
Ã'fi1F~~i:.`=~::1<Ã.~'C'. II t?iC. ~~C?l~=~'t##~~"ti provided :3~:I~uiÃ`Ã uCÃÃ?. b` Lso; ~.E:}?' af~ii~i.ewj~''. C~Ã~LatiF '~ji:f.:LCry` after an iff..
F~ tia3 porff.)C.'1 of qu.:'v:lt.firo`..fa<e to peÃÃsift s:.Ã git~.a~..
of.tJi.:i", I3a fl-wS... ~=Ã~]t }~7tt?~~5 dhe po.``ayme:ÃÃl: pc3f si{;lft'.s, p3'oa'':C.i(.d 1:etÃeM p.ias r:d'Gi %E dual i3e+.hanfs;Ãki of dt'=lÃ'v'L.r,' ~-~'J.`sE:a`1:a dr..F1.:, is Ti,:=lL.=ased ftot'':r the p+.:Ã`:,Ã+.:1.,x and :}TaC ;,arti=lvs. swell to dSika.Pbfiif~;:= or destroy t_tl.: Coal or ci.llÃafsÃr c}mpartnir=rA ('g.. C'.nf...osom~.'). Aitean:afi?i `it''a kcz~'~ 5~~~. :~~3C~ : - t)'~d, S. 1 ~, ~~~~ t ~ ?;FGF a. r.~~ ~7Ã..~.`l~.= ,Ã}G:~~,+~ '' :l~le}~:=~~i:i~, or t3,~~ _~...05<~. a f1f.,:TÃ~?~.;. s.r>L+,: at a c.a location . i? Ã3i_3 ~ t.xi'Ã.+,'. .f. t0~"1~c:+~.,?LC~x size ~ ~ ,i i) ~. :ili:~ a~.klt#:=le, .w .3#.;3 ~3i~,
i3aÃticles can bL'ciAÃTi7t.= lodged {33. 3:`.anb'[.Ã.d`'i :a':th$;1 a L~ Ãvitj=', node, :`LÃ.b..Ã.,5^.5,:, be`3Tlch`sÃs,, or ap"llaxy and can be Lt:ed Ão cwclude blood tpow a4 :::.x.
C.rr'bs}li.~~It:oat .,gÃ_nà for ~~~ecding; Ãt4e =i'lw?v::1Ã:'_?fFS l`Ã..cl:faberii.1t"r'l?ns, or wJ-n;7'r,"
E.~'iE:vi.s=L3le33Ã:i`.2:.t3C?fà E3L 4kÃÃ:3 :?l, used to a3r.'.veIit ÃfÃ"flm% to a specific portÃ?,.'. {)f the IL33.3g w* for tndos:Z3p1S; lLÃI g..'Ztlam`', .k,'t.dtxf.`.=~Ãiz}Ã"f sÃ.lrf. zx :'`+l, to a'.3Ã=e only twcs 4=xaÃa'pl(;> of potential e13e;i of Ii7f;a prtbpi`.rty- :
GÃ1mgred by pai L:.i1.Ã age firi?m an Czx,t~ont]u::i agent added to the pixlyrnC'.Ã=1 a c.taÃi S S.E71~'ix i:1 z ors fty :n vesse,'l as :tut TyC:sLT' iI? 3 .s+JheI72#c or :f'?f;:"ted t:YsE3e or C:tv..4 t>z ~ `~fPl an olÃ1Ã3<fi1..3E.::3~: si.Ã0h ws an endC?sk?:mG=. ;??.3ch particles can
#:1cfÃa :~3:i#a=~ 1~~.~ to ?'k;li.il:eS3 agents thatH nI[3i1Ãpi7lÃ:ltL` hc<lll.l~..g or fibrosis to faa: lstc;tc. pLÃ`Ã:3w13i=lA or teInpoic.i''y clt3s;.::xÃ. ai,~~the oCciÃ:filt',d lÃ:3.ÃI3m;'.=fZ or e,.`.Ãvlty,
G~.....i,Ã en,:t'hS.di:nUnits r3>?lht invention are directed t?3waÃ:tias pt?lvEaS:Ã'li films thi-l.: aa;, &~iLnw:d tCr deliver c1he-therapeutic agoiits locally at surgical sites, ÃÃ7w,?Ã'~.~,:.`fs .iC'?n into the loxeC:t$oll mwuA".Jl. Thi:.psi:= films c.ai~~c used, in Ã"-hc) Ã;'c.:Ã :ÃneIft E?l-,
cilili.;e7' pa':f.S:?3.ti, wl?eri . Laf:.lv3..x3#sg dtugs lt?c>3l`'s'y l~~~ t11L c,1dv:3.i3ti.lgC=. of >k~t3;aat>?u$ side t.`.={l-(C;ty i. }.?i ~~.=`:'t\ at >i.aic~.
L.=tY .~ ~S Eõ t 2~ drug l.~ "7~ ~'e~'~', & F .iL1,=' ;\ 1 1n lf?~'1=' ho
i.S.=~Ã:>C'~a.. ,~i: :.~.#y CF.air ~.~L#.F.SSW i . ..
00,11Ti:i1tAa'taf?:`#ti :hat ilou3d not othe vvi:iZ'. bo ub$e\ c.d- o-.Sue to d.r`i.ig toxicity::=:, a ...c Riia3s,, can jet .<:Ese,as;eni:4a at .he site of S.:#.lga:ll-;v' and il~=C: ~i`:~Pl~'..~a4'~.l~S v:af:}.
St.r.'~ Lc.#_ii. i~. .~~ c~~''E.'i.lti~ of vl(#:i~~ prc2:C#.:clitZ ..<? t!#c `:np,,. Ã.ta-1ioia site and to :h ;, site of Ã.t]etaS tt#= tumor g:'&swth. Cl3.c TI 3hun >.d : i?`14n.nut'ii: films f.,. : deliver one or ia14?t'i' :at'at# iM:liet.ei a-gt:ills'K c.&, '..:ti d:st:.i.i:?ed ht`.ra':-n, i.3at wai. a4. L3PO#.3 cci:`k:ui or 31ati-astC:tlc (:+.'.3Fs i.'ma1#l::ilg .3t the ,u#&.3 Ã 3: iIMLi14 aftf... 3.:.f.-mL:r oxi..;sio.i-#. is pS.rr3SJ."'imied, Thus i.?iC; fifltns
Can .eduE.i: the .'inv#L.ie;:>{-o of tumor rS,c;.il"remaw at :v rC.a4=c:'i?3:a3 n?<3.i'~li% after removel of cs7k'tZ.+,Ffsiis iS:iLFe.
c ~ rli,a ~h p.rr<? ' i~tÃa `4'~~ herein i.. ~ i.E..t. ability ~~ E~? f..t. :..`;'; 3.c`s ;fG1' ~1..iW.? '`s ice filmS o.sil c-ov:? " tl3o choSi. W,:ll to :"t., ; dl1ot..isc~* 3i.;#;i';?`nn(t For Cxm.ipxe, t1w, pol;ri..3iri such as InC.gi3thC.l ;.on3;%i or in C}th4'=l.' body +~::v+.vli.ies fo-r
Zi:itl.LisGS such as :'t k'S,:Z?x3m4. In add#;im; .1.~'. ?`<~~iT3I~'.1'3L f3I~37s ~:ilx'. #',x~s'l?:i'pi.ii3.'(:~ local i#:ia...`:+~.~#L:~~-r or IV ~~:::`s:;t. t3~.\ and be <Sst ... Av < a,A r113tv . ~'!-iE:;ll < a.i~a:=.std)~1 for ;:~~~## ly ~'~
ce.k: .t #' i~.&: i ~ `w;:'`,_\.~.=ati:~~` ~i~. t~4 i~:T3c.i~,
`õEt`.~'~iA ,.?tat`,.:ir agents in iP#'~~a~.r t:~? Fi3<?l~3{?:i3~t~,
a~#"`L:3~C+I?t itl A3a'.~''.i\33Y~iti.= ~.?# 9t,"'i~.3.Y15y.r~+/ 4 f\.(~~i71f3t1f?n.
Px ~i.~#' ~~~~~.#ir' r c :.i3:1t;.~r=i~i#a3 T}] a . ~# ai`,t1l~3 or `~`a~il#3f,: ~'" `{a, agents ~:t1ia Y be c.'3 - ~ ~~ ;.~ <. .,~x~ ~ ` != _il#a, k ~#, s =~y. #YY tx solid
S:#'tf3L'=<. in a Q(_ri1.Eo<lC.'d 23:aTIF.ei' to ft5rr-i3 p#.3er.tt:,mS 51.1Evl7 as stripes z'kF-ld dof,,~: SailL`., or multiple ig~m~m* ...".=.iii b3.. Ti>:f;:i?.-p4bi3:~-i.r Ifi mlyp'si4a.t#:m tC) cia..l'#.3vve pze~.s54 tF.~"3.C.'Ã .peu:~~:#< d.>3#'i<L::.3r of #undt.iple z ~,G3#ts siI7'1tIhmLC}l#sd"'. Nutt.xl#~ than one t)'`;)i> of p\?lJ _3ii.:#' fit.,3i7. (.t.Ei., be u..4f., to
C \ >!z .Y v~ t' \i ~+; r .?~` t ~ t",rc. \ tune or t~=i;~`Y?"e)~ ~~3L ~z.~~~' of the Li1'E.i>~,. A ~ u3"~~'k~,: 4i',.3~3iY.f1?.3iE-.~~ the :ilE:~,#: :;3 is:.= t ;3ii:#.i~ i t \r ca t;i ;,#3I~:.. : a,:_ ~ `~3 ;~~~~=.i' a s rely:~~lso of the ".~?c~#~Ã(s). the . r(~c:~
E s..# e:?;ami ser. a 'F1l`.~11 ~:at}~11~3JSoC~ +~f a 'r `~ t. ti,i}~:t. iE`s acid
Z qt ( Y+ r> .r~-.;tY ) t }t> e5>,~,r y2=Jt,)p <}dry i~,je sr such \~ ( f}}{ ?r''9 `Lq ft's t~` "`~T~ i:I{h t `.-,=~t=rtt.)!_.5"stl.L:ti.,sy-.`.]i3. i..ti.i% ~ \..=t~..t2S.2j~..+Cw with GS''uit~? .. ~Fl~'~u'ta. T1<J b.,.^T.421 ~S 2:.F~.~F-f. ~aL~.S...., ..i,.
i3.nn.1e, .t::i:.dL The fil#..i can t>3ei1'iie cdRittt:c' W7th another h3oltr'f1ler of ths<. Ss;ic.,e or i?1fft,,::'.:#?t coz`.txpLrsifi>>'n 4hu.;`, does '^o`, contain J1`s: e:`3.3+,~, fi3.iii'f3i23.w`~_', <7.71:iilt3^le-# fi,.`:2Ld 3':Tfn, tE?p
M iii',# , Ahach Sxf3L.a .iiESt h%:vc t!'ke dI ~t`g, aLt as il s.:i(:raa3i'.liil ~r`.tye E the. . 1?.i, E 333tb~~~ fhc reli=aJL. ,e~~ thf Coa.+f'::t;f '.#'onn tl}o Li3ideri'r'tYtR #lf1.:, bt7.t <3tt the Tom .a!'er .#a`.ghi' .f?.eS, the ht;s`ioa7.i lii:a. sisi1`t5 io `'Q.L,_ist:= fb3L= i.9::'3.z`? hn f.h7s, fashii3.i"#., delayed m3d controlled ro$eci~.~,e e,Dn =3cct;.te. 30 i3.3d a.<i::3 bx to in1:Iill w<3[u3.d hL':1<%1#'fk; li'. occur bt...b3.'z'
>#L=~`=~~3thaa:'J ~~.~.zv~`? can Ã~~~Y3.`.t 24'c3~1TI~3 a.~ i'sli:ilv <3;i f~z#.~.. 5:..`~'.+zf';. ,.SY..ioel.tt.v:=l~r' ~ x~:ak'[~~Iii drugs "L'._.n be if,.ii,'t1~ed ti{;:q1#{:3-LiMly and i i~~lf?i ~'.Iii.iF:TÃ = E sr P:r=i?lC3;ilg ~l-iG` ef-f`+Yo. i?~ Ihi: other drug or 2f`xott;~'~`vs "normal" C.i:=3~s from t"^,ie. to;$+..Io eff`v'ct u' of t1c second i~3iuf.: t?.. W `:'L`:sc-:i:e i'.f?llti frtSnn the effea,"4 oL a Se{.>oI`Sd aÃ; :nt, for t'.xi:#;rnpz4 pI::tll'atmi*.34 widi tC?õc..tw c:i#.l 1i1Jl#.`
tt? :ii;=]to {#3Y3?o:til.u.il t:ells to aTitiwfi?liEe +`;.lu."I7io1huc2p:i<`>.s iilEzi t`vt Wii:1iZ`a TC<:i;s xert?1::#;#.~ susi.::~}1
Prov1do-d hi,.cl.';, can be LiSe-d tC? wor a#.tv G#.gi`=;?t. t~~~ aC,.3, ca#?
i.i any p.i.<rm?:icci&Qafl'uJ'a=::{..4`i.)t:.#i?f4 ff?~'"Su',; inc3'i.#di'l~.;,.; ~i~~'t:a~l~::if-~u..~i.t4~~si ~~' ci`..'=#.C.~:~.::~~?,.C
l#i i L nwm.i S a of ~3:Zt1ii#`. :li,t.4A4 i.#.i'7u k?1oI'i'.e]. #.n the #.iri and 'i3,io z]..#;f'".i.. ,3lf; fÃ3:" t#.;ii.:: i#:`1 the ph<3 i]{i.i{ vJi3i#.#:l. l sz#'.1p{"'Si##o;K>h of i!ic ~.3<)lymt"lii:=
Mcitert`aik d:ser.ibc:d I'{eas..,.:n.
Ai,t:qAe#lfl#.. a.:,e-nos are i.>.i:TaC:rtbzad i~ ~5:.x{I iflie$"W..`.13'1. #indiscludi.. l.'t.t a.c T':ot bial'aFtCC, to. i:=hLmÃJ}hi..:tgnu.Ãt== agC #?1s,. uiÃ;h as i"~E~iC?~~~1``:;i~ i=F , receptor kfflh:butoi.S wii($ Ã3;..i#~~'s Oa" ot.,e# ea:..#t# Ã?eitpic?.` v:t: {3.t=,.~,e à L, rm`a nl7.tit modulators aiii: i?3oiaIvt igi'#3¾ .s:iC.i as ~ytok 3?tis, gy,AWth factors or ,AÃ:rolds 4; .th (}z With13:3: tal4' or P<r"ihow;z'3'i antil e%'3s et, ..:'15.,,;ti4e `.l?.e c.i7.ti ne{3i3li3''a~ri-it:= 3eSptF.llsd'c3s a mf:illf:;i a?e v's,3.i.{.:1#.1:'.= & s`el{s3q37?T{, :-ft;
I ~ lo+Na;.a~.3.L>Ehot}c ah?t:nt5: anffl?i(>t:ii;s,r or nL3clo?c acids as a m+::We of local Ãrcp-at;= tY.E?i.r-ipy,
TI-10 b1i5li3gicall i .ii=t.;~ substances and agents are tied trz amt3un1:
L."'~f~`#~:.#..#{õc_i~:`r t a~t=~~A~"i .~~ '~.?~ii: C'..1.vi~~tl~'iw
Tx#.I`3#.2~'at ~7~' a ~.3-~:i3 f a:SZ;afl `v active ,w.> .a.ince will dqv;i`i.d: +`>#'~ thL `~,~,~.t1I'tIi:::ular ri3i3:eii.ib being i:EBk:d, f#.1'a3C?i.E.i'#:t~? (?f ths' b#F3aot..:.it.zt>; t' active
S t')Fei-#f I Ft fife' tf? about {.,~e Rvk,. S;]i:a ~, ~ ~~ `{ u.#,}~ZF~$a.\ can 43G .a'~~"C.L, ~ ~ a`C C.#~3RS.:rI~C.a. .~a~?:~l e1~ 65% i# Ã.::ET.~ E1 desirable. ~E7 to aio-~. `:~ . .<. =: .=~: _ tcl:=;:i.~ ~ " c#:..+`~: s s 4{ ia `i..i.<#..i..=eJ: {,>3=,,:T3c..si.is L'~'`OlJ 3t{. ~i~~t:iii;at.`~:. I#?r' 4:i:~' : 3 thw amount of druYd::~~ve#=::d per mea o ~ filwi ium per p_u-:icIc ;;.a; .i: }ezud z?x; t[:.c: t}.C.:<lpt:.I.fc r>i t1.;e of Lt#.c drug, r:, toxicity when dct#.vC.iC.d lo+: `ffly, and the olin1oiil i the patient E}f:if.~i?e i.int.'.~'to:~.S":3. ~..s~i~.= number E1a
G~i`ticSC.s or :'_?4~3"3.f of ~3'3t 1 ? =. a a ~ = at \ ~ .. . amount . q ..~~ fi <~c~~i, _.....~ ti? a ait.4 is SL=l~~.ti:li taL,at.#~ite:tllg on Eki:tC?~";i ~i~-F~.~s as i .) t A?c`. iiF71+:?tua~; of .~~+.'i:.
{ rZ>r y~r f ~ ~ 7, '~:. 7 ~{] ~ f3 > .~.f. ? . t~~" ~. Zr :-#l t(f~.5{.=~~
k3`~.Ã.i~ ~'Y~~ ~ i_.~.1~.~}c.iy~i{d~iC, "_.~ ~,~C.. ~.i~"#~~ ~~~A~~u x~i# w'~= f. t:~C; to,+4'=~~ the t ~: . . '
t b;''.ir~,i, ti'i':.ii3:.`.d. Tliu L`aevelz5pax#:ca`t i5.?~ f{tsQ and 4) tht . t:=h:13~.`,;,i3. C;l1.xra.i;E6:'iisz1e5 of the ~''i<i+.
di;sa4 i::s ?.itie4.3 Ã5ii ;h t.4t'= p a? ain, t3tel,ti i s i"o1.EÃin:? l?r pi`rit?I.rn4d by the,?ti. 4k tEl L~.. li'~rl'i~ . ~iT"t. ~?;.
#,~i.e.~3:'i.t~lZ><F` v and LtJ;~3C~t;. i?`i~',t~Tcl#`i~:. For ux2;iÃTi.~~i l-'~, :?~.tZiG~~;~:? I. iiJ' and .% i C.
pczrft:;'l':L l:m L'. i.il be iidr3 :"~i"=~t`.'1''c.'~~ to a ~~+:1{.~lf~::-#.Ã
Tthe rt'.lo:ise kl.nt .i5;:s of a ~;.i$'Ã:?z i`.FZf(';'i7ti:r fia'21 or h?itrtÃo].Q i:an be fi.i:C. ~=,.d iiS:lÃ.3 atzk, #:+:G:`.' b-y".=,<3aL'lnrT; tl15:= i'L#txC? ~~'f l21t3nC,`m<'"1` units i :iEb~bi by ::IiCS( ifv.nXY the side s;,;3.1#.s Ã1f given 4?ti o.y:IIE:>. &Ã:, this ~..3<7.#'4.ns;<Y'r a fi3#37il'r, L3f
G(:pt'>ls''#7,.i.r." with #'.''lc.z;e kincfic;; iiiii bC' t!^2S.d ;.Ã} .i t S :?lA3m [>iiaic the d t'.l 1ves4' drf tiC:veY'iii #eAffi.'.1'ei-`at dm g\ ?i i d: diS.' d ^t'4FrC7d #'C,lÃ.=usr`~ k?no&:s. Ftr:' c:`i:iniplt:j 1,17.1:LiS.?23g 311f3?"e Si1C` chains along txc "Foayi::i.cr ttic1,t utt hy d'E>phÃl#c .T'.,d] eriÃ.nl<` ~~ . ht t;li" p~zy731~':Ã" I1:+3rS~`sZ tF` or `.`:~.~~.'..#c m,`cF G:.: ca !d b''Ã"l. also gone1%#lli Ã#`w-t.i..:ie the .t:,h'.asc à LiW~= of an agent ;'.E'C?[i3 thlG p?Zl'c'3?i(:it m S:E~#~`3.F.#.Ã#3 ~:::i~I3~?t?d~2~3:1C xtwi, i.ia&;= ~)+.3~.~'';x1~wa'2C:~ pt$rt3'wi'Aes or fiI1.;.3. Cir;.`xe:?{` rC:lc: s`i.: of a,,gea`ts. The dL=s~.yUd Ã'Ã.Hiei:lsi' can :;o1Ã"i.Ã.'IClL= wf-Ihh i~'~
i'3..i1ai:`Ã Z'?'i1bt1d:1 7e7:is. drug kic]iv$ary is dl tl <.l' 33r a period of ilpp.i'i3miT3aIi..Ãy 0-6 In other eii?:?E?ialt"1cutM, the drl3g ?s released over a pG:riC?d of a. 6 win:ek4. hz aÃ#:i,Ã.tier i."11bod?.I1eL''"#1~< th .: drug is released weeks. over a ~?~'IiC3C~. of 2 (:ek5; Irl other c`1Zy.e1#,neÃ.tsy m<, pa :1du's .~ by iFi:3?"S'iÃ4g the T:A3o of t;2iff#M#"e3?t.,m(?.3<?."Flf:.r units dE':r.a?+
"s)# a .c3i;,E3ttf .M0:80 of glycerol aÃ1:d caproic a.#h:id pt>lymo:"s and Ã"C. *t3lt#$3g 1`:i3c"#`?.?ps31z3i;=le5 dh<3t :'4"ae<i`: dr1.3got'cr five days.
Provided }1Ã'I'47,.# are p..:Ã'tÃde:i, i.Ãil;lUd1Ãig mu"C;rf..dpi.vehicles and
i: a =~I,,.~3C2i~.l.c .l<zt~_S~C õl_ ~G size of IIi, a ~3i3l~'I7..f.f' ~ ~ particles ~.~.~=, ~`~ ~`~~ $" ~i..;iu..~i"~i.i~ `~?S..f? ;aÃ~.. 1~~~. i,,.%
100 I]Ji; in dbwY`ÃZlea. III o#;T1C.r 4:1T bod1.~".`."3s:zaõi, 3,hÃ,. >ir':e, of the pt3h{llatt#' pilit3+..c's t `S; bc-tv,;C:=i:':Ã1 0.02 . 0 iF., i ?a#.lc e'{'. In o:e}loÃ" i.,mbC)d1:n1:i."nts, flu ,-du of tl`.::= pol'4, ;SDS;r 3 #1i1C ~~= ~aF`c bl'-.i~ctnn 1-50 ?"?11L'=Ti3ilaG~~~ in d3ii3;.icCC'1".
Oflaer poi4`Ã'ias`,t.<z p>'l:.rcl<:S i,,. <3 larger
N i8 4~, 3'i.it uÃ'.;.pet.Ffi._ 'oIi`~..`=s, iEIch as where tw;^.T:of r'egr:S`+4 th 1s pr4='viEir;,`:~. For p+. +~L trxZ tiii.~ ~~c y ~a~r,r.iv'#~ C7~: size r ~,~~.. ' c ~:~~t~-=ti~ul ~g 4..i ~; :.. i<f,li ~.> ~~~~ii.3~
C~,\t=:~~~':ET. . . a~:}a.>t.~{~~#.i+.i`L:) ~f~,t. # ~.:~~a~ i.. at to. ~x`~i3:Ukr . +~Yt~Ãa~,
~quau.ÃÃ#Wg or stapling has Q)C;C"LiÃ"#'~.'=id, f?Ã` within a Tzi.iTVe or treated i:i-. .iol' Si#C;3 as .a;i. i.RbaeÃ:Wd trs=vit't'Si;t.Ut#:da?"S` to md.ofr':,quenc5 ablation t}". other th<.#':ipy +,?I l=Vh`õ1 .:: a.Ã3t7a1`i:inci1u'S c21';.tar such a:~ occurs in :iq[1a#.m"u5 Ci,all t. a..io.i#1oI21`ci. P?<3csi`i7.i;?3:' of r`,olyuieFi.`.. psi-1:Ã'fiC:"}G`.S 2 5 within oflhe?~ ~pont.-met.?.~s ca,iÃ~~~s could be utilized to xcsii1. M actc.<r:~#s i.:a :it:: cavity;
C:=#d3ei wath i=L';TGase of spcw'.ifi"S.. ;selcios#.jig agents : #.Ãoh ws m.#L 3i+-tido#"`, :Ior do-x:rc'=yca..i# as cx: a`;Tp>j~.5 or other 111?ti approach d?eTl .m .iii.fin-
in ._`Es. , tie<3mntui'#1 E3f bu:.ut?=s d4`..page :31 emphysema o.i' 1...fea,"fit3u, dIsG..lss;..s *u4h as
L yS:4. toi' :'-":{ampl'..
I }iL new i?"?t;3"<3I3..i'2's :#i:d polymers can i3l5t2 be used to p,co;':3ie bÃtrzl gF'c$dable tr~TL~+?:i.S 3<5 ~~?.'?~ T7.~~~, f3i3~#i~#?1ti3~[C,13.~~ r z xd copt?ll'mi>Ã, using s'"c~E~',is,iid ri :[ ;]I3Fqt1e4. ~?`.ic olI.s ;?`11`~...'t . `34:3lymeI's> ll:c3i +a3~lks3~E ( 13~i i and i.:i:rpf}l`Ji71ers c:an cont.3; n ..k~'3. .`-.t3& chains tr,,:3Gis between i i) a .33t.'?n{.Ame.' f3: :3-?kcl'i`5u7f?lt'cid;.3;' i,in`#t i.:ok'I ck.i?k#ng at 1s,-z7s,. one functional side H #i ta r 12_ <3lky3 dma?A s ConIal .u ; 1-5 0 carbon tk?"?tS; w1 d, ?:#. :.wktskit >
[' 3 a sÃr:3uteiaa: 4' dkftZ.li.l':: 1':1 om"M4.I or :'k]acioft"kG>lC,i:lk3ttt
L.Ãiat. 132 's:=o>tain e.nbEfdid>1o? :; ti:tie ca:k be clLk3tÃ.c solids Cxr t itÃ>oe:[2s'?.:< ~)3l;Vii. ir, v,.kl'o114 4mboan:>k1.?4'ilts,. the k2;atckkal;s j9ris,f;dcd he.e.k,` are ..?ydr4?pa?obkG
hyLE,'3phlli+;.. ~~:I3 ~?[hcl' ~.;Il:at's(~11 ~~=I::tS a provided .1#',t`1n u?k{xuigoÃ-.`_+ a :,l? ?ngt'. fr':bnn 43ch4J;:)hobiQ to tiyfb?"oph.`allc t?'` "k:.;+pon4o to a lrhang ?I:?pi'1. i':i i ~t~r~ka? S,iI?b(`dzx71Ã:uis, :.Ix 7n clE,".f'C?mole`,::E"r:.7iG:k` f.71e.',tk:.`.F1cl.3s Pxo.`{L3E:=`.d hf-.i=:'.n ..wG#s ~s} a :,#.n flxat i.i4:+ .ab...l`.I::ti i?a, tlsõ`?fft:iy8 a a:'.LÃl oI' cÃ:llLllaT i:r?mpt?nmeI`a:.
EXAMPLES
T,it; invention is further {lt`4crib`:;d. in 1.t1c ft?.lÃw:`i.kg d+_. I7.c:: ~innlt tile seopi` of t..~i:'v ?a`?Z G;T'?t:on described in the
Pre.~.f:SFi.~; ,,;. ~.~ =~~j~-~fii~"j,?~.~'~'.,?~~i.'+~5.}I`aP3i:~1~~"~~ { '3 ~-~`.~ÃfS;~.ilfa.,'~.^su'4"^{~'.~.I.f3`Ci:kikr. i'vas p.ep'~.:FeTi st ~. i'3c<3l.CCin C ., 1~^' a p#-OvlÃff.kstr =' (`Lf ~El. ~1'a h . { 3 .~,~:
` k`f~~7.7k,'`~ :~:=.i~a.~~ t ..<.. vCH k1Q3:i7k'dFiv~g, a xs~~.3~~i: 1.`011~.~ .f 01t '?004), First = 1,1y :,-{=kS(hyriro:x~.'incÃi~z'1 )eÃ.~iaziG=a.ld'~? 4.t?.. wQrG dissolved in tcÃ:`ahydroiuk`ain, and 5 A rzic5loG.t<lar sieves wL C 's3~i1~4~ i3~ a to. 1 ~.:~Ihõ A c <1~r:k~~'~k~ :k3i'~.f)`a.k:`:kt k.?f~i^tt33k.Ee~~i'G'`Sz.l~~i?x3.li. :L#i3 ::.~,dt>z :~.i3=Lat.':C~: to tite miilurc, and tizc rLii:c:ii3nw13:, allowed to pIs,3C:ci:=dut I"?:?,3nn iempeI'fkltkle. Whc.i?~ Cie m.tY~t?a3 .~,. ~?:~ ?.:f~flr-:<a-x;.f~kf%lxk~~13i]~= \=4 ~ '.<5 added ~ ti"I ~eSGI.t:.s~ ., i the . L':i'~=:~ ~, t~iL~;.(;~+C.~vt?: Acta _..?~7.1:~#~..~ ~a.f;:, ~~ ~:st_; r 2 .; xi<. = ; i~cxe: ?omt?3'k; e us:Tlg IfiliÃ'11tio71. The solvent was
I'omc?vt'd- .'?_k r:>ia%'y e+;kPo:iaÃli#fl u:i,dG>` "edw;:~d pÃCsst.,,c, i3:.ld fl:c residue taa
S4i3lvt,.d in i'r3is
` `x. at~~`~a L '`Z < .~` 1Ã. 1 :i~~s, <.~ .,k_.1w:~ , ~~'#. tl7 100 tw3 i"v~i ~;`.*I s'?.~~ )F?t3), '~,..~t4 ~?`:orf,.k .:i~:1i.# ` .
over :uia3vdf"i5tt;, ; 43dla3Tn sc.aii:lEc?. The solvent wclssi153sequm"~k.,- my3t.t'Cta usla3~ ~'s ~~.<I.ti'
ii apoi`atAi,?n L#Ã-W+u? reduced prL'1s#.Ile, and the residue L, 3s pu;.,.&d using f:=hro I2'latoi(~ ap;-ti=.
Tcffi vl '4 14,6-:rpi-neffiox}`l?l3~n yl) `.,3 ;-5-di5x-miy1meflim<~l and Ã~ ~~thylamun<::.~ wu.: dissolved in diehls.romGthuic and chilled to 0 'Ã_ :
chlf?'1dL was then added drop wi s% to 'rbL:= Blt1lixl-L3ri.. After m:x'Eng Ã31 16 h., , ii. n'%.txfiiF'e lxas then s;`asscd UaTf:e times with 100 in.IVl pill 8.0 phosphate b'L'#ffi`.r a."`1d f.....,ed oi`C:;x itnh,ct`::+13us
~iSi~il#.~~: J, W - ` # e1"8L ~~'i2 s `~l:#*t'q~.L i~tI~'.Ã'f tllf`''t to using E~~t. at pt> ar:_ w'.
rod~Ã;:~~:d ;',ris;5t re; m>d tffic residue, a: xI tbi: title ci3t~~ipt?und was isolated his.,atg <~ihoa got } \t tIy~~(
4Sta'ih.t`at.~'i F}~~i ` hve ob_.~~Z~..~~.~Y"~f3:~
(?i) 3~C:~:[: dissolved in i?~43. ^zz~f\\\ .t ~ i.1~I 2,9 .i e >:~. ; ~ ~,
C3i.~.~'C~<: ~~.. ~ ~ . ) aniLa (03319 ,`~,., 1 t~? i.F i~~
sz1rrG.'.d afi 45 'C} foi I i. A#-th:ti EI:i-ne, toti.teE7.1,`. ( 1.0 i1:l.) was 's.tld.v;` to the solution, ,ld t3?hE#,'.,1G4me.` s r!-N distilled Ã.va of dae mixture at ~+~, C. :`I'f::Sh ti?.iui.ili' was aiia(3.ed, and d.dstltli4ly:<!h L..a.~ i.Ea e==` ~} t. ~.l`f ~~,~.et';'.:i. I iris process was repeated Fez3:~.~ :~s~,., was 't,~~õ+;':`Z'S; .:i#.
in fit'F:ti: di :A.1;.%#te. SJd313m bii,iX,bfn1ate was added to yamwh flao acid, t211iz fi..?:z..50; 4fJdh: x?. bFE.s:I`bt3nc.fto Te3T15:+ve% E;ivi..?g fits.-rai1L?n. The':ia loom::i.llll?3g to.i#..m<.`=mas 1::.move:~d: ~0.a ;"(?i: atoi
V2p<;rafiitn, Ic: v>.nÃ; a sl#glztly yellow oil. *This mixtuiri.= was Ãhm. sopstrated tts:ng ~a~~:;=~:
g*.I t?'iF"f) Tn cbtY?g r L3p h S''; T b ?:, j?.f'C?du c : "+-v.:4 (Yb t a iii e d :f.`s a ~~L, 3t o s 33I ifs t 4 1.~ s'. ;'.o,.~4~.
3 a 3F~1~`~~ ' \ f' ho`, < ;3 7 Med > ...of ` J liq
(0.504 g, .2.42 :mn:?l) <.nd,
in`Lts3yl i:,.3?`lc (0,68 il,.l, 0.49 4.8 2T?1ilol) wci'i+ l.A.l,sol)i`d à ? and ch-d3::~:
$.5, 0 :'`..~`: .{~ `t';i~,~.L~?'~'l.at %`~'r~it'iii't-.`~ (~).r~s? ~'~~-r 0.:~7 :'~. 3.tr} ~Ti71Z ~.~' 3~'<7~ `t~~.`?C:Ãi ?t~tl.:~~".~~. drop fh.~`, niW#..aY=. Aft.t<:' 1I? xsng0b.r 16 hi3i.ii,"i, then3.;4.tuwo ~4as then washed 100 .?..NI pH R;,?
p 1C?s~o;:e~~ ~'a.of',~ ~~~Fa~.{iZ.~' (50} xlt::; X 3) wll's dried over . j r ~ ?~e~t'~:.LtZ~`a8 ' ` 3~c v[~t3~1::..71 :at<f~.G, ..,7es?.,< a'ikt ii`as 4{.E?4eÃ,ue :dY^ .L'mtJ-v{'d using 3"S_3~ilii t c?zlptm3lbE,Fn uIidkr.rs::duced pFT...~a,_.c, and the r?rt?t>txf wa's isolated ki ?1~t SlIci3 gel at 83.9{' C;'1fi; la,
Sylthcsjs of ~ i b]4bc-,zvIOc2_..y....m+.:`,b t.`y'late
(OA5,mi.F.. 0,50 g, 3.8.nini?l) and ui1'+aF;.: .;ivJ._:e f, 3.73:I7:FY]i,~~ \i`C'3:"a dissolved 1#1 di.<b:o#'w,'riS3:banL', and cH_
Ei~x: .:~a ~i'3~~~'~i ~F.~~i~_~.'i(f. 3 tm a 2 'r~a~3.:, `!F .. t was ;i t1i{~ (~? cF.~a~3 3.i ft` to Y f ~ pi_r......+ ,`~ +. 9 . ~.C~.~~.~~~~.?f}'. L:~:3g.3 ~ C.~~Z: _(?cini.Siturt.. A> 3.urmix1?c7 for n. } 1 s#~~.`a..'= ~~~.ixo-to.niC.' Z~~ i .+ t~7C~~ niL'el~. > .ET EL ~ `40.;~ q~' ` r # L1>. St ~~ `>
btJff\!2 = J;to ?~%>, X .i)Whit} dried ~l~~~~~`.r ~~2~~ ~ 1,. tall'C)[~4' sE.i
SÃ~ ~i11 .~ 1i,.iC~L<:. s,1 ~ ~','i.> at was st-b:ii'q(1a,;fly removed u6`:.1#,F;ri?till,P evaporation t.Fndei'1ed`zced pz`t.ss..#.c. and the p;'C}dLiC:t
Ww.`.a :3si?l...o-ed" using "I ?a, 2. gel 3tiztF3:t?aliAgwcphy at 8 > leld.
{YciF~~~i ~ ~~Y3 ~#~5$'[??1~~?{i ~'by'~~f~s {eti~iDllelZw i < a 3#iFic?if yF!''~"ti,~.:f` `.~..f''..~ `~"~-Mr`f ~ f'=~{~ + v~` ```- ~' `?`{..
Ã624 .T?.<F, 3 Ia 11a1:~ ,.3~ ;i^L<~Y~?i3 <.4$t:s.ix '
``= ~i1~.x3 S$4 ~ t,i?:.F ~ :~:.it?~ # ~; ) a af;>. ~:::~i~ . ~ .f ..;. r >~' i 31 i?r Ã` 10,0 ~ ~~.~?~-~l~ in a 10 ,? ~. s~~t~;7 ..~. and
?bs~:q~,r ni~~~ ~,y~~~~u~~Ã~~:~i .;~,~. l~~.:a~~L d with ;~;~ three trti?z:s. ~:~,:x~~~c?;~~i.~:~, t~~.e c t ::~~st f=5 L. 0.02 ?l.:?:71ol) tt?L?slff 3aii:.+#113~_t%S~l?I ratio::z 50TS) Z'cEs in
fl41i3C 3I. ..aUs. Tht? SC',bj4??k flask Ft`:bti PaTlÃally 511bma.rtsf=d. in a th'wA?i{?5t.3t1ed of.i ba.Ã~~, preheated to 140 Toluene (400 x.FL) was added to the ~:.alai., st aiid ho. mixture i=4}1s ?.1eC.t{:d v"I'a s4'i31g+`. :t? V>C mt>11E.1'2ic;[.sz. The
Ink.;.3C<tioE, was S.fl`red tt?{ 48 hours, a'L.iT?E?t'{:d a'::om bt.cli, and. to .'f7T:+II`} te&71poaatUAC. The polymer : <2:s, i?I4solvt,:d in dichloromethane 0 s> m[..) and precipitated in. cold median.~I. `Flie sz~lveiit was {iecant,: .I a31E .'',.lbst.ruendy dI..4.d by i.b`ip{.{Ã`atlt?;'?> ~11c r%='iuffinr._~, polyin-c.I' foInitia L"=3.ffi`+.>.F a t .'`'sco{.E: `'~'1i or wb_Ãtesd1d precipitate depending on the ci11`bt)$`iaw a(?,la-va .o?` f1s.
Ui?po 4net'..
at.lli~~ p'*;c 4, t;~'~: ~:[3r"3~#{;i) C') ittE'~ t~`o following ~:} 1{iil~i' 4z'^. :, ~. ~~ ~.4, t' ~}. 1f)k;:.,~..~r? e~~~a?a ykc:= _i~3i?~t. .~ to.Z:T+t lx... ~.',
?i; iJ. `rk i;.501..00.
x;F.~.`k3I ` rLbIV >Vd1 Fx1
=~t.~ ~~,.~=r~,~,~,~.,,.~~~., ~ . ~ ~ ,..~,~~~~, ,tih~.,,..3 k~.
Pi3ly(~, .~~ r ~õ 2,022 ::?t#a:t4.3~.) was =E?:t,\~~C3~.t' glycerol 3
Piascik :=~~~.~`tl t .k- ~ ...L ~`#k Ã:'~,:_ ~ ci_r, c.:~ iis~:~?lt..<~r"~x~ taxi 1~.~3.alt,~. 's Ãzis P~'t' L3i ~ . 10% ~,.' `]{ . ..~;`~~ (50 t CYZ and 20% p{:(0H (. (R) ?l.f,) were tliCn i}.f,d41d to the d.e3lsii:ioi7. The rka.`:..ae cv ac?tawd <;nd, puTt,ed wi-a., hydrogen thre-c tÃmm The fl,xsk was tfcr, pwsw ~ .~ <:cd to > :3.~ psi 3<:th md sha-ki'>? f}?"' 24 3rit?is,?'S. T}?tL #"mi;tio?". n:E?xtF:E.1'c ) c3ii a;..ri.. 4.i..t: ti1.`v'{.iLt3
Ceh#c: aiW the t.lter cakc v,:;~shcd ~=~:t~~ 50 nzL The st?I-vc:rit;~ wt.m then evaporated 'm S'Yidtl thw. 3.:'i-1al ~..Vol-~;n?ib:r.`, J1.ET. 1"('s:iid13.g `oe;~11"41" fo;I?..r.} cF':~1e} a 'v`.st,..tu"~ Csl or vv.hiÃe so:zti pÃ' .i:f-pau}it: depending :3'n t61c L,al"~.'?f?"iaf:t:` s..i).: {: A`.t i. f the cC?pi? ? a?"Ye`:~'.
C a;poE-vmcs six uiuc -f3nnei~3 WYF'2 the.' ~i.`.'HC?wÃn".,; cit'b(3llaie il]i;ÃC. , ,r,:ci`,.ons. 0 f,5, 0. 10, `.~,220, ii'k t; `{+., 0.50, 1.00.
Table I }.'t('3oi! 1i:CIiLatLY: 5hc C;;.?n-14"3osifi{1n, i-n(let.u.:.I w.i ?2:t, und thermal data of t>.~ `L L= ~i ct.?po"1f'nmcisy whià n. [1.1$: 1.11 ll:itri.$tba=fi by stritltuFt~E f(}}""`+.'3~4:>... ~s, bok:~`~' dw. _,.sWc. hy_:
Table 1, ( :i._= : ct7:prola.-t:)nt, CGI {,:abt>z7ate o'c`g,.yci:`,I'Z3~ ~ :~ _= f-mole p:.'~icent. +,:ub{r.Iu:t:'
n7=jt.:of"n.cF' Tn po'cTnt i'11at1o11 to.C:i! F~~.~ :::1'f7Ã3lG por'.%flt ci;abc3#ta`,.. 1>3:st,:?F:3.;r in i:op a`pt:'T: s,:a;:_ ~i~~ :.ii"1~':Lxl~St.=.3 ~i~ ~~, ';Es.:Ctr TABLE I
---------------- - . ....... . ............... ------------------
molelulA ;:or WeÃ~ ~~ ten Aal Pavcà G=~~
==........ -----_.._ ~.,.,,...~. ._.=___.... __ .. . _. ___. ,_,_ w...~.,.f.~.,,........_............ -. .- .,- .. ,...<.:....:. 0 +~~ , ,;;.3~~E :..~J..2 or) ~ ,~~ `l. t j~^x Yi .~
c ,.. l.<..3 9(r-i,.t.Bn :0 11 61,700 13,300 1 .~~.M -54 ` ,t`~i .. 8 t. 1 10 11 5 7 ~0 0 1 2., . '0 ;: 1.t.`}~` -59 -11 ,r i':
Ciw '0 ;MFa .:..jtF ~~ 6~7, 400 1~.},2~~ r 3. {~6 49 4 3 2 1, t t.'i r f... .;f=~_?~: 2 2;3 57,400 8.60#~i 1.96 : ~~'> 0 :I .' ` `
(:.<i 10's~~ 110,100 ..;91 -47 .. 45 2.0 '010i4001 .9 6 -46 '5 :~~. .~.,.~
t. i:O t, 20 t ,¾3 NT; 20 68,700 101, ::) C.) 1,94 ~~~? `:s S 3 i.! 7 1 .E0ix 9~300 1.718 ,.43 3 Y 14 f. a. ..~~:b ~~~3`~Ei= ;~g~ 40 4.y e "' \e'?fi0 ?,9V0 1.94 i-~i ~~ ? f=>"a~:a 100 1.00 104,000 _t,6t+t~.~ .~ 1. ~~ N i i?
1- r. \ ;:`~.~ =\, ! `\r t ~` . lr \.`' \ ~` ^ \ _ __~ ~=~:
ff"-`. _>'==~~: r'~ . r \.. . \ ~.~ ~. _- r rY1 r;.;, .:f:~+ ...' =2 . =v ~,~.r ~... ! ''~-y~ ~:. \. t .
------w -------- ----=-~-- - ------------- - - ----
`~ 1~4~.:. ~_~~,.-.''r'~~.~ !.' õ~'~i~ r`~.w.~" u '~.~i'`/ ,,.~`
(1.0 _ 2:02 #t~:to.<<~~>
nivf i:i{ts6v .....W (16{e+0 g, 3 13 nlmi.?o <3A't<i (DMA,P) ((. i.f . 3
tn,mol) wei=o dissolved in IÃ~~ trrs'dichic:rÃsÃn.thant..
(DCVC.'.Z~ (UM) & 2.42 Ã#,z-n4.~~) was added to the reaction a`.{1#.:;5:'#uic ciÃ: a `,4l# r 3ri:cÃpita:t'
aij Ãa~:.~;Ã:SGi.~~': ~'~:{ti ;,~ tri. rv ~._ ..:"~~P he.>LÃ1;> cil
IÃ~t_'s3~t3 r.a~~.Y.~p4=~"i.its.;;'c Ã..Ã~a:ia ~ Ã.~~3 t.? . : Ã p) mtp.<Twm wt<.) ).oaC#.t.cd by fifltiCttiuii uY.Ãdi.he filCrList`. c..o.#i:4)2[LfCit\.=fi.i. 1,:#1.;
ionc::m,T<.S Z:d fiftt'aEe dissolved i,k diil--Colonno.h.an-,c and ptr cip:t>.tcd in .:old n.<.caan;;l
(25 nIal t.~ .~:f' v33v:..at was L:4,.Lamcd and sLÃi)Jequal$ s' {fi.-iC:i~ by evup(tlu.L2>m. ~'h;= r"~=y~i~~.>l` pa?i ymer was a white solid pI'e.=1p1ts2tc.
imli_ 3b3lz ,S ~~ ~~~SSEc#ÃI~ ~L~t~ G<lÃ~~~Flx~4 +t3 c ~~r~L~ sti~C~a~f i 11{Ay(j)G"nGy1ox " glyLt,..fC.< . Ãia3 3ll~i~t tC1H# S :$~F]i'to.~itti~f?:i7 ~ (1.0 g. 2.02 ni.:no ) ,`i:oaÃ`.Ãc acid :1>.~ Ã+;`S` . 3,5.> nm.31o';) .$F3ta DMt'3~ (0 123 g, 1:01. i7?-nol) t~i`re .. 54:3I.1..d Snz #.aiL dry f~iunl;Z#.i.`#?':set-lba#:.Z:. :.}~.~~C (UOO g, 2.:42 mYT2ol) was added o the: rofli.'. :#.a}." :ET:id a j>?'1it4 , Ãt~~ipitat.', f0mred: 'l]v ii21x`iLite was stirred fC`~i 24 13at#.?"4 at rowTÃ Ã ntxer nafÃe ;:en, Vllac prz:::;ip.tatw, cox#tpc~wid was ist?iated_ by filtÃa:i+.3n and S ,.;: ffiltiate ; as, i f 1<~.Ã'23Ã to i;. #:4at cL>F1ct,'`nt1"a=:i+.i fitÃ#'e"li:o \`b+i.i:i d1t5Ul'v~.lid ii iÃ.tl.='tT.Ãro.i3tF.'.fi+,h'<`'s31i,. 'i1nd prej :pft<3.att'.3i .ÃF; ...tyli3 n`_t..tii7143t (.c'.5 mL), HIC: 4olvf;`..I.3t was dd;;=[.c..Ã'tcd and Aiub:yequi'.>idy '=s~>.`#.t:=L3 by mapZ?,..?I;itta. T,I: "esi:tffiig was a w lie solid p;L.iiZic.t:f,e;
=-~- ....... ..........~ _ ...õ-----.----.~,.,...,,,,,,~ .,............~.._
F`o 4,''(?lwt.?:t%IO3 yi,' glycerol i:1Ã~?i?i" i1~L u.t? i i.i2:~3~17~%1?C3#?L} (250 0.43 Ilu?'li3lr w<3:.~,-, d?ssi}IvL.d Ãn 25 m, L c+f py.Ã::di?:te and cooled to (} '(:.
3ra8 :?ddz_d t3:top by dTop< The ?,31x.#21'f: ~=~i casti::lÃ'I`i?d ff3> 24 ha.~?.Ers, c#i tx?Ã3i-?"#. :to.a}Pe;'"At:eE'e tIF?f?er ?lltà s3gt:1#.. a ::.3v pva'.3d,T3i was removed t?#:1t3eT` vi3ct,.3??`[, if1i.' i:3'Ã.tah~ p=E3df;Gà w.z. d.?s-staIvf ;xI i:.?
Iai.:=Ifl1`.3roa?.`E.'.thim%'), and. precipitated in cold ~ i ={xy} Gi' i~.>,5 yx``~5,~ f~ r~F~ x.~ set,i ~y?'''t-'..?? } ""~?~~~ \` t4\.4'1A i-
i3.nd s.<:#i:{:+eiji.:5::nfly &aL.d by : S'ftporat.tot3. 11u, e'f'sult1#?g _lolym.:a was a 4th..t sE_tltd precipitate.
E.Si.i3.17;i`5~lOA]T? T v F x_ ?) t el~ pol 4 ("'<?bl?7Fa?t< Of # 3al t Cia: co L apfo t4t1?3ke
?~~ ~ of ~ `~~.=^ {~- -''f . ~"~.~ ~-'= +j ;,,} i ~~ ,+
jza
A'#? :i:?n3lts,'-C7zt,Fv1.3.:fed c<3i.':<`lZ,mi'=:pC7ly(O ,.?'Ã1=:'#:tzai)hexiS,.-#-tD?z: :.C#i., 2-0at ;. 3 dtf?x:?#t . ;_.
S=~ L4.+v',F' Li;?wf;~S i;?I'i?~i.i..Ãt?i`ia:}f ~3i?~ h3`C:~3i1I'~=E~ L~\ir?M 41~L`. ~.c33~C?:~~a-Ã1!; #?;:5.:~3t~t~';.
i;<< 171 j?~Ar r riJ ;{t<Ifs' ~w:t.+It itf #IF.ki'?::>:3G( .?t:':wf f~ rs??r'Ei/L~t +t13";t'?
i-yd,:Ãd (1277 g, 0,78 ?#?o"). (l. 5 g, 2.6 mmffl., 22 moI. % .t.)("(-' #0 129 ;;, 0,63
`i~f.tl) were ~ v~ {~...t ~ : ?-,.ar, 3 4 ti 3<i r~:,. , uth., a. . ~ t~~5:~;.' ~ ~.i~ :~-ÃI~ t.~~=' .~. Z .:, 1'aw m i ~ and ~x~` ~~_~'R (0,1032 rf +.2:` r~~
wi#.n wt?..zC'.`d at R 5 ,:<o#. .. s :l. The z)CU n`r1;: i.Ãh#'1-6.'.Ca and li1G #izi.v.,.'1 t G'vil.,~ oIi=t Md, # iair pÃodi.:c$ ws,S dli;so:ivi.6 Ã#`, f.i#.cb1oromCfau-?1t~ (10 mL) iÃx3d prec;g31ti?.14d in c:5.i1 #:'?~'=~i3.iF.t?i. 11s0 'a''#,?1w?-?3- ~A c3s d4'cwwZ:d and Si`~b4quf;i3F'ty fL['Yfad bn%
Lv%:pt33`a.EtÃo1: (85'!:r `tir..Ltd), Mhz':lÃt?:i'#
o., Phe i.An}:.f'sss<+.tL~~H=~:1Ã3Ãx w[is, deLL'.tmi):L'~by Ihe p1LsZ...~i?4~x of :Mink, l:.2#.cCh\I.L':we group LaVares:t
#.:a;)flp as wf:=~l ws thC F'#?-iot= ~.~?'otC.i..itng Ã'1?Ãip 3`Sf,.a, .3.ih p4;.t?ks t.n tie Ã'Z`2tL'Ct.Ã>?g ..
z NMR suC:c¾run~: [l.t 3. w%,#...I 19 (a?i 2H7 OCI--.k::)3 and 4.45 (s. 21:1. . .2'.,,#'.. r' ~8 cÃ?n:, t, :F?'fi ?3i~.#. ~ r=k~ f t ~3~"i ~~'.
i.... i.C. C%;id or jL:v.3. {ft~ii-L`.t iii ..rt inf'=-f;L'~i~'trt~:+`..tLi~a % =. 2c t.1..~.f r~.7 i.^3.'.''.{i1r~i~?i.3.,r~F33:`.1~
11,3,: i:>qptshy3T.er (300 nig) was d'{:;bolted in Ã1 -40 21 o.,pTj7w.. idi.w, `~16 mQ and dry dj:31o;hyj sC3'~~2 Ã~`3<iv f,.24 r?1Q and the }:cia,3C?n vvm?' sdmcd fC`a 90 P1.:i1. 1%
+ 4L``i s t.Nswerc Z.`'<#.poi <3.led, UndL r'}'.ed1.3ced p. e3S,fSi`<
da4l-flo:Cmaothad3e ;10 IT3L# :?.d pi'ek.ip;;$at~.,dl in cold liielhG:n:3l,
Thest,.t`~~.:nE.i:.~~s dcoz33'i'#::d and s}ibsL`i3uo`?dv' d"I`Qd by ei'apC?ziation (quaiit1tc3t11`E:~ JcW).
Complete dLp?"t>tecttm was di,t+;F:xllnei: by à :e abs.ci:ce of the Fmoc protecting f...`=zÃ5tb' ~o-akS ir, the El'I NINMR '`~ oe?:ruzn 1_sc~r~ `uncrif,md:chi N.}.V t'`aMoll te o G--- ---iTi?I-i:f~ --J
- -- -----------------------------
} ~. .:T f }1 f-<i,.
4~^` .~~`4` f -..~'`'~. "f- +~~ ~''+=`,~"4.`'r ~'y.,.ir S.~-~.
A -,xYa:i any xii.Z?hitl.^'di_#.; r'itl...ed c4:3polyia74.`.F c.c: >?-i;xÃ?
or- r= ~ c l z ~ t tip r` `,' ~e'" 3 f~: xc1 ??yl E ti.. =T C? .--s=t?.~:i' rlt+;,<>~t~L ) i NiS i 73t~:<'.511 ( ~ laSFt3 L.i ~s ~, ~ d ~?4. r i ~ # ?EifS ;C>.F`L (W 0.38 -#.1'io]), bc.i7:1yl :?:rt:+md.e ( :l'A ml +, a s {.>..ki), i`z-#?E$ p,otslt~tlEAm hydIo.'tkhn (113 g, M,.~:81 niC'1l) wL,r×E:, d1s:sL3Olveii:1FL tZ?l::C.Y+1C. #200 I xLi, Thi'.= remior. fl::sk placed in, a 120 i,{v ImeSeded oil badiand :-s:.Duxed o4crMgxst under il Adug. ,n-,).t\=,.' A)rf..at.:.;v Y?412s.~~~~'~i. wj4\2i:~LF~i.FA=\S \i.~SiF~~. I ~M I-ICtS (300 S1F-.~. 1.i.3e LS-}It:~cnae 20 i...traporat~.'.d f:?Dn and the pr#'.+dC1& <:o,i3.1=Wd .Ii3Ãg dichf
C3I<yTiC'th<ln:i:`= L3 -x 3f30'# "xlr) to .?ffÃ?.F'Ea a #.:ixiia.e of nts`J.?o md d; t?!':.ltea :et` 6-i2ydlo?s`:y hLxiI-nEtILr a(Cli`. ll?:~~ cI..It;'F~ p."t?Ci7::E wik~"'
4 apo:3.1fi4:.sled v,-i:3` I "I.N.1 sodium `~.`'t-vdro',ieds.,' (200 llAl_) i:lEf~i :,1.?eth<knC?i (20() ext?"....t.:ted i4Sth (HS:.I'di?:i=o.iY.4t~'':41.7c Ox 200 t11L):, and $h%si?lvt:ni was o4ap+rtrctod l.1::de. Eod3ÃC<:d preJsLa:f- to six.}Zrd" kf;.;re 6"i3'vr,.zy1f,>xy f.ic.'~~.&noie ca6i,[ f72?4 vY,wEC3y qC NMR (CDCQ :38"
1.4; C by, 1w5 ~'~~.Ã,~ ~~:.:~~r;1_ t [I t4 11 -2 ~, 2 .rtk ' ?~ t ~:;''~~ ~`Ã I>~...~:~11}, 3,42_
^~ 214, i .a y~ ~ . !r, .3 3 S r~ (or} 2a.q'~?`\~^ , a~7 .f4.^~t~'', `37 ~.^ ~ ~~}lVK~3v~} ~. ~-'~3 acid (OX' 3 g, Vr 8 ;2?nnC.~l);
23 `:iLA,`x, and. D,,kAP 0.26 Inin~.~i) were dI~solvE`:ki in .~'`~.: IN:: (20 ia'3L>, r''hL 5=3l1:t1on:
Was ;stirrxR~fs.'2 a1 2' i^E}r 18 h, TEwcD4.. E_, was i}F.tJ;:iC`ki'cll'#t} ffic Sof1'Gl}t <. : s.}port.Lo>. T:,}E.' meso;.pvc d i;: diE.hac3rs nm:~eÃ~~at~e (10 n~Il,) and precipitated ink :::olc=.:ineffianuÃ..
Th 0. sÃ1l va;:;;it Y='ti a4 dc5;',antcd ,.d subSErqueIAd w' d3'1#;d by t : <`spL)-:<Ita;}n. (W:i; yiiul d'). AdEH ;EoÃ:i
Cj oa d.Z;:ilcob:~c side i.'=hailt; was dekf,ri'#':ined by 1.1iC;
Pt`esirt`s:c of Ã1hoi;'1effi4<ieT#E t,,roLFp ..:s;or<`..ti
-d;.i'. i' 4,to.1` to +Ã` ~3iM~Lliõ~.~; g#'(r~.ly, 3s well to the t.,e~ 1 - ~i~,.ct`z c;';.'t, t}) ~~'~A ; il ; , ; . 3 3 ~?F ~3 ;~ tt131"l. ~~ ~?`{~ ~'r.~. ._ ~.~ ¾ .Va>h ati Ile Fi 'NITVIR spectsurn at ~33. l0N3.44 (m. 'H, OOH;)q ~a:}d 4.48-4,53 Ãs~
The coqx`ly1'11i., L.,?i>`'~.3 mg) wii;a dissolved in 50 n1T dxt
Ila3iÃj`+..'d:}
c~` Titl4.= '! ` .~.k 2?:T:e ~.,e ~ : $~it q i}\7i5qV ~ .f.2iiq t~1..:1r~.}~nw+ was a/= at )~?t24~24~ti:=\~ ,+S 1 tS2S}-y } ~(of._~i.~ y21 S:
n.i4~~ ~.~Z43.tiZ,~f~}5 l2. t VK 1l1`y~[:~a. f~ .2_Y~:~= times.
hE fla was P[ien pt ssaiz ud tE? 60 psi ~viffi hydrogen <iaid shaken for 24 hours. ~ 1 0 icaii.lan I}:1.~'`i:tum !-v}s lKiiS:r.t> ti.:}bus.:gh C3,=. itr`:= i:1.iii3 thS;i fi3tei Qako we:}shut:: or id v?0' i-n%.=
t~3~:?~3.~L;FE~I~nv}i~~bz3L. ~~~z~s~ st;;vet:~:;i 33'to'~' t?lf:i3. i,4.~;
Egr.~tir~i ti~"4='1~:lt: ~i~'~.i~~ ~~I,l ,~3t3. ,~'.3wr
`qac3s3EÃtt aE} v}`.'. Coniplf'.ET.'~ deprotection was d4$3rr21i1#1od by uhc absenoo of the bcÃiI4''l vcac:;_Ãis y sup pcak~ in the H NMIZ. sp"Ã.rLtm at 4.~84;5s (s,
xa.~`iY' le ~Z2 ~Y~~fbx?'S.y31c <~L3Er FLllaL=ti~~i~u1EleLa ~~"(Eli 4~zt~e?1 41~~ ttf f3ic`~..'~1'l3.-UZ? E ip;"t3li3::l}Tle q + `~- !r .~4.~,= `'ti. f. ~,}
A C,.:A'bz#xylzc, 1Cad d#.ri]lfizoi} copolymer ?,i?lCf(.1eSSi.11ct;iC`,ic s:,JE #11.?Ã t? ~w C3 tf ~,~ d.t3x.i?I? z ?) f't?f3i'+'i.Vzds $iyÃ?:hi.sÃ:r=acd using th,4 fibilo:tim?js
Wi':f;i ]3 s {?ir?~ ~13='>..LiF iW x'z`lf:i 1Ã3o3tf+~s?.',t'izvdr ester DOW,_.X} "+(+F~t~wX3 (`- henf}': ff]i.M=rl.tC'. ( 10 mL, ^31i'.~. and :ldapi c
I'Ãii?1) we,C, adided W owtai3,,~ (I Oix?.E.:). f3?I-#.em.lxtuif', wai i~.'t.ftix4d ,t?t' 4 h<)uÃS A 3 00 iTl.,; aI': the CaudÃ: product Wa:i pui'ifii:d, via Sific.'s: chromatE},..',iaphy to viL1d s clear, colorless lÃf;u1d
CH-COGH)Y 5.~)9 N 2:1-1, :(ThC;`f+~), "..:.':ii 30 tBu. 51-1V ~~rom<-btic;.
F+)r st.z.`1.c acid f'its:J;Ff.+ ~ "-(+].of-~, 5 r~If3:xL3 ^,='i3 Sdi:? Ãx t. : t<'';"iJd.s>t1;'e'.c'} le4:i;n<'.d1fJ?= acid i13t?.,?t bi 3?Ii'1 ester q0.184 & E,, 18 Ã?'mnz:}l7, p+3]`A : :~~h.'oLY ; ,:.`E~,t?~.~x's ` z~.~`3w= Lt3 ?: i e~?kt7zs i i.1)z~~~ i1-5 .~`'.{? 1umoi, 22 1'?3c?l % s. i?~ T3t;~ siv :3 DZ ~~ : t3. 1_=%'3 003) 3n;Ii3C?l), and DMAI? (0.032 g, 0.216 rTlf`a'.ml} were dl ty()l'v'ed, tI`
iI?L~I. ~1.?~` ;]:.;,a:ii?.i'~ 4'w ~.~ s:k'37~:i.~ at ~~ a '~i~Ã` IS h. The `l..~w! ~~.,$o>c;s~ ii:'?:`~'~~': Tirlemont
"L.vap\?roWfa, r3 Ã~~,: prCiZfu{::ZSiI~'"+. (.ki,S.st?iv~'<dIn {dit.=i loÃarneithai:t' (10 n:i. and cf3:d rnoÃhr.rod. T}if: -~c}li'cra was decanic;zl and subsequently dÃ'i.tx1 by ez:vwpt+m.zon, (83`J';.,
_yie:.lkt). .ldd:ti:ii of v.,~~.c carboxyl:,: acid side Ã:has.n ~~~as, detenm.;~~d bv ÃIae -p>osuc~:~ of tll.> ?~z?iÃ:cÃi k~,;4roupi .4A=it:~ peaks iii the 11-1 NMR; pLci.:m-n a: ÃF6 (s; x f1hCH:~),
rtti.++~ # lg ~?4'r ! tf3J.3 h[.:~~i:iTe.fJ[.` {E[ sd 2-:?I.U- ,`, `3 F:= f ;sk;,=t,sE~f<i3xtz';
1f'w.` ,,'opi. df'.7't?" (NO .T]g) was dissolved la, 50 md, Thy, aC i? trrt"~?~?l `, lc?Ã t: Ã?~.~?z.~ a
ParÃ' bo.t ~~ , w. I p : fl~~: ~. ~ (50 Ã? g' 35<~(~C3~~)2.'~_: f.fi(. t?3g) were ~ s+~ ~ a i3~3.~.;if .}.or.. ti, t~ts>.
iC3~t:t1(?I~ T .: .~"\..z.iC~t`'~fF~,. ~.z'11IS:~#.lt"`a~'= '4~'i?4 4'v'~e::~Ã:i~Isxat`s.ta~~~. and ~~1i .'~~ v 'd : ~.xq'Ã~ (Δti ~'.i_~ .3. Ca e
T;?~ .: ~-k ~;EeÃi ~~~~s..~.i~.e~~ [tJ 60 psi ~.~~iY1i, ~~~yc~r~~g~:.~i <~::~. sI~~~G:t:? f~~r ~.~ hours. I~ ~:~:~ dt<]ct?Lr?'4 r.i#x ;.t::If was a7ft-Qt`ill Ã~}T<?"iti''~? Celite and i'iiC filteF' cake i4' thx t 51-1 ??`ti._ c?`.ii:!'1I0'E:x.t1?Lt?ai:4,,:e. The ac7:v..t?w1 were theixa c;via..~F.>l: TLd to vit;d ?`liL- atn<Ãl ::#oiy,l?;.:'
(\F~.<?~?~#. <~ ~ t'.'w rt t~~,ixslot~: did:~~-~~t~.Ã?~tst}to. <.~.te:~~ti#:~z:t:~ `~ ;' ~~-~~. >~bs~:a~c~' of ~.~:s. .:}~~:x fxs`
pffrÃ~.actin;; group pca,, m ft3 1-.1 -N.N.-I.R. spec:.drum at 5.06 tw, 21H,
PhCfl-,j, '7.A# ;-7 ? 3 z#::, t3ao>3?wt3:c,
axs?n~} e L # 4'f~~L11?lc mSv ~ v4~ ~~ Ã~?it}~ c3i~~? t 1Ã< s f1 r L to)T~~x
- atz i hj'`a # i ?..di.t}a3an^2';JnC' and $'__G:.<;pri3-'s'h.fC1ll:3C.t{ snC: <.; t:=i}'mb3ileta
W1th ii_#S# ~# mfit}:?> (to a L4?~i.l.l of 10,0 1I3:`f?ol) 1I? i.~ 10 I L soi:?lc.A. flask t?E":t .I.1tieq(?eT.Al v 5 t <3<.u,atcv <nd R1?sxxitad with N t}.1TÃ:i: fi.12?Cs. Meanwhile, E;~c ctaÃaly:;t 6,5 Ãx a_:..
0.02 #,n-mo3y ratio .;: 500) is eve.i'4iuatut: in a :?ina31 flask foi- 1,30 mit.t-t.tr,s. ffie ::<ch;<,nk flask is p&rÃ.~..x:ly sub-~~iea-gcbl in a Lbr.rmostatted. oi1 path, prc:u,; ,ed to <40 C.
Ti?..Li\.a.':e (400 i:s added to the itIÃwli`i4?s+ ;;;1'3tt e.hi., TI1??2tlae 13;ti tcd via to thi.: ?-~.f?:1?i~? _ 1^ i < bt.lm5.~ ~Ctt' 48 l?o#.1r5, i`ciTlÃ?ve\i '~.i~'m?# f?[:4ii a?.f`.Ã> 4 =i?3i':d .}_Y ri}t``i:i
I4. ~~l.t. 24iii::~.,+ 1:0111peratur . 'IY'ie pc?ly^'?-lcA is dissolved in di~~~loromcfl=tm,e (10 n:_I.) and p;,.cipiÃated ir,
wid i~54.,=ltllv\JnL is d1:Wa};1edLi}[d f~SYl.}A Vl~~ by .ti l?c f's;suffing pt>.T:i7:t.?` :`.nF3s a v1`cC3ll", Ol.l or white sol,d prcõ_.px$.a\c C3ii;p:."'1d3.:?e. on the t 21'bl?:?att! cit.nwn: of :.1`` L= vpC?lyn?c?.
r?" \r-''f a-..r ~.r''~J i '~:/- ~~`~ ~.r ~ ~~.'~~
T3i r yj, Zc1P1';`:t3ti4 ,~~ i~:.Ea ~ 4n.LL.L3'C; :3A~3> .:< ,t t~= ~'3 `+ c ~:.C3J2L T Ã`s ~ .f~t3~ IÃ, 50 niL dr, a F`arr b: i;le, I t)"N, 1'&{~~' #,50 m~,~ <~.~.~~ 20% 13t1' ~.)k ~ ;# ;
9 nag) i?i'e ad>; ed i(`? 3_ht: SL>ludi3Ã.: ThL ..4.e.ctfon .11l:Ã?b(,Ã,tri: t e'` .2ciÃ,_.tt an: p;1. tged 46ta3 hydfo.;.`,~,~'.I3 dl,cE i;:311QS. The flask is pÃ"v,~;St#x12L'.d to 60 p,,,3 ~oi`ltffi hyd:'L~gen. and 1hi:\c:1 fb.` ?4 f3L3um Ã'w`.ait:i3z1.3nlazE:J';.e ÃS filtGt.`L:'i.ht?'agd3 Coliwe and the fiRf:i &Ka r:.~s-hÃ.'f,` v,.its`z 50
Tf w sc?z 4 (:Tlts are evaporated to yà 'L'yci the final polymer.
F`S.aIT3 p]:~o 15 PoNf\t4adÃf. .3L13l t}lli3n ~~a?~~~11rt à C z #. e:f3"3 c~~
"""'____.&__.._.. ... .- -_, .._"____=_ _________ ________-.. - ..-. . . Se
S FFF ~
lvcct (? 1.~'..3i3, ~teaF,w zsdld
D'~IA1' w-~. dÃ~,Lolv<:d in t:)Ã~ i-t3_I_.d y DCC. is added to, the rctic;ti,>n and i3 white prf'.i.;Ãi)1.<.EtL i.i}rms, The .II`xl.{twe>s fit1m-d wZr 24' i3mu3`S 3'+:ZZ?r3i 1M^, t.aitperi3.tuf'~~ unda 3':iii,;i,4?;:n. The precipitate compound is
F:st3.,..to3.a by filtration and ti-ic fiffictt:i': a?ila.L#3t1"atod, ra,`1,c +`.'.Ã3}`Is".eI3tS;attJd j-3i3~at.; is dIsso~~a! ed;#i a~,~ ~eA43lti`fllc'~~3.1#1 and pat:i',1;ÃSf`cat~.'-d 33 mRfluuat3l (25) ;rli.), _11"#.aw= ;iL?lbea:t is decanted tind . 3i34c:{ Ã ci`.tlv, dried by a:~ Ex, c mn 1L ...t F< `31`1G 1t F`I of F';C S?t3x l Ctlnec?zllaÃ>s' 11 LJA
N`1c:"o~,O4ÃF "1d i
B.Gc:b.4.tZ..b ab 3 p Si:Z' D.L. -Ia(..,~.Id k:,-LC3g, - kiy4{..;Ãd C ( I a~.~GA~ 3,<'E1~."+c{EtC.b..... ? ac;= a153dwht:eIi of paLl;t:Z2d . "I'hZ fahnita,.1.oi1 ttS.;ll_E-x.qu...4 l.iso:d to create P;.X}A
`_1C:=l'opii_u4.~4~~`s We2'e modified fI'o,Si Ediild3d. & ,^~lbo:i't`` 3t; `.3?d Wang `. :ii (1..:<3lul:ts #?i. ':~'?.,
At>v:. PC>, mw=f` Sd.. 15':6: 412?i}01Y tVai?.g s:" a.2's,, Chuo. l3hw~m BOz = ` Tok?ro,,
4. F 93:3,. ,> Ã'`}96) and ::.#.#.Uz,C'=kk a ifmaer in C3R C;12i.uf;stÃ71> teti1ll11qi7G, First, 0.5 g Z? [ fi..~ 25 ,-11.=GA `~AbSi3d?..b:e Pi,E ya1'iZ',?" .:i-#ti'mao-ioi1:3l, B=#.1'I3lit:ghaTli.
Al:1bi1iI?>l) ts1blf:tE (thi: yc,'L.=...n:co.i' i.llc vat.i4? of l<lcfic acid to glycolic acid t1kt> S..owtaf' the i`~.tea:*C".) were d?gsz?lvW1>, 4..li.`i_:
<11ihlfiF"s.33.,#t :hx....t, (k?i~,~.~.,t.via Aldr1t:.=1). St. L'C?li-ds, MO) i.s:ent; a vortexing dovi: L=, Afic . :t w, <vas co:-npIote g dissolved, 50 m~~ of paclitaxel ffax( .> MP Biomec,ic:.i1
Irvine, 0011btYai ~) ;?rvt=iÃYt~~~y sol'Libi.i:.etc in - 100 t.~i of zlinio _fiy . s:#:lfi?a:du f DMS O. . :dac:t'
flatF i.?kizi... .Nlt t. Z4 a:s e:sided and fud`diei `a=3.~Ã"texod. M fl`}. = fi1?fiI(,..tif3~n <?, x>:i?"tI.}i~~ PI,1 T.:~
beads only DMSO wa:: added. The st?lW.tm? :icis Pie;L'C.d i3't 10 ml t?f ~~>a dly-vz:=1yl illoolol
Fai f,iL.:i...it. (Fi4i i..r) and T`:?.Ertl.:C~.`G: it}i' 15 I'i?lt?wtes (or u`oi,icatcd using a probe fip CDn.catoq~ and Sfit`.cd ;tvL7?i# rhit, {the infc:E1p.Alt1cl^'.;s ws;;rti, i:=illlei,Ecx ilnd washed Ãhmt. :.fliS.s it:. 50 nA. L.>:td.is.#l,led:dt`,:,'i'r?niZed water. Following washing, Eilf'
IYOs~hÃ;'1.zOd 4 ftcc:?c st#:ed,; <and stored c3; 20''C ti) insure the qth.?il1.Ãy oflIaclit;xta. Fh4 e:,Ã::tipS..i`::{iÃ;n'.
5 cfft.,ii':.i L y z.?;' ta:r?;?l by lie i?i#c.iY?pw.t?L;le:i was Ã:tieterm#ncd to bÃ, 74~.5 4% by f IPLC
Niini>pF1.itis le5 Y.?V:.`#.`C3 prepared i-#s?.1?.v~ t3.I1.`aE?difiG'~,'tit}n of a m;il_ie32`#1;l41oa pt?ly?'.?xcicJ...:t.iot3 :ill:i;;t}1,.\ ; :-;.'?'Ã(?u;iiy Iep<3TIi',L~.~ (L%171tilE',vi*,..i el t:it Mlzici'i;F`~..1tk4..3cu 32..5?2.y
(AIBN), a free tadiia; initiator, wenk .
Lii-s:ii,AZT..ta in xd.?1&C?w~~d by #"f:I~'A~#if`t'i:#l of th`~:~:ik, oon¾.viil. t'owFY' cv>_iSC3nat.loa` Ã.i?itii ii vi,.ic Ã:i:, . ?i:t#lf4 õ4~iil iÃ;~.~:=Ca, to'i:?.cli'~\'',3~'. ~~lb3t S7b'~ ~ ~. ?,i? .~#F:3iEi1Ã?~:'; ~~ ~a=I~
A 3150t:ix--`ri.i]yimi:$hyl meth.ic?`y-lt!te, 0.: :? Iiig ttfpc ciit'clxe: and
3~~~~t?=<'ET ~Z~~ :i?.?i~`.`?iL ,1 (.AIBN), a 'i'Le i"cadlv:;ll initiator, 5.rei e
EtchC?ws:d by :"L.=Inl?vy?a of f:ie sÃ?l'S`=L'nft via `.repair:}' evaporation i123c3i a Z isco i.`a,".i?i~~t Lit"C,', rex?,.;aned. Tht.s.'IBtii,t.s i.7ixtuIc ~,viIS t11Ã;tZ FI3ixi.`d 3iii.i`#. %i it3l{.fili?tr, of soti`>.v?:1 dodecyl 5..#ffato, a in 10 1-111M pl-I 8 13111i43sp:1ate btaMr. .. _}3Ii: miXE-ut"ie, watt :hitõ`.,?i sZf.tlccttÃ.d eÃ`z hour ~I si?.S.%Ã1'L.Er pulses with a 2 second x ?th 30, W of power, "C?#.`i`.='It.t'4w tilt m a#.iein iii s:i?x?. and .i.:Elt4'4 Tug T}1L~
Solve11t to uS`ipsi#";.1 ;:o:
tdaÃ..s!"s.`rreCi` oil bath and 4t1l-rE'.l at 65
C $i#.i' 2' hi}s.ns to an#tie .te i.3e ~iGU^f~i2~#s tip p1?ly7:?lei?zaldt)n.
The <:'.~''14lt1ng li3'#~i~ p~1T"tFt.~,S.:~ were ~~a~,:i3 i~#:il~~l.~'1~ Fgx.i?.i~ j~ 5 ~3 ~~ { ~ phosphate }'bffi"r 4?4 s 1" two days tE? it.nZ?ve L'<<3Q5s ;~t%!'fiat:tant md SÃ$~ts.
1" k ml~i IL S, Syi#Ã 3. sik of Nia7lc)T} zs iii 1 , Ui#. pitmo 3p<<FÃ rÃl 1ec3.s Z>:14,.,?>Tvk:d #F. by ie#?'F.ov.il +`?~~the soavea; via `.:,?tary
QvS,p<?>atx<)>:t:laÃÃ:.1. :isa.u;=t..i?tUT<.MItUAaf,od. A~terxiativelyY~~~~~;~
dioxa;~yhFsc .ith; I Fsiei'aaf;rJ-Iate, wid ~.~. 25 ttag of pailitaxel was dissolved {..?::hzi37"s?nif .ih?_Fnw', f.3llC3wed by ?`~.Mn<)vFti of tx:d::
Solv4=F-1t via aoial`~,` suvaFp+?`.`FIt.om until a vISGi}L$` mI <:`i31'i, f.'::n7i1.if2Ã.=d, I i3-i:s viscous od was tiii::7. mixed w=illh a :'s+,Axi.itFt?..7. +Fi,sod:ZurFi dit.Jdt:cy.i -ndfiac, fl;.c s:~sa~.~fllze.ilg suÃ"iat~=~F:kAlt; z-n 20 anr4'`F
Fy~~~1cF14 ~~# 1>i1~3 bEaffcT'. ~~.~#Fy F.'!"1#x`i:r:`. was tih+.u. Si7n:c+..-t.;i`': foI" 3 0 31#31 Sputt:S L~iffi a 2 s i{ei+.y-; w`_F 30 W of pw oet f<?f'.i;si>g
I a} E.1c m1i:::8t}3.1k#t3n ;l;t. [il;:3wil.Fg t110 solvent to t.'?a# ba;.3k .'vaA}[3.eAte. - ,?D: r14=t=1g ;,".:.3#1;...a.\#k:;n, o`iiF'y and I VFny]2-pynol4dG}nc wesrc added to tiF.f: 'L:rnF:.Fi4Fo. .- g
LC.. flina3
E3? '.1'2 i.3m ..CF 2, 1#t~'~, ri:sped#.vi:l?R%; 111.i 's _F4 thi..n eapo`iõdu; light fi',.im "ca arc l;:Tinp operating at 300 W for .~=' F::i`_lz i~~.IF< b;:tt,g yfÃi`E'od e -LF?"~:?E `ly.r .:iii.Slag pi} ;'nnel"#.{iiE~Ãi.si:. Following !!?i?.~3~rt?~~'?IG~Fr`cati,.+#1. .hc ;,1;#'t1;1c3 ;=:'`s.'=3`R:..'.
Elite =<< L\~o":"f;~ to'2f~.i', =C~:'~liv'~';L''~~ c`~fi':1st 5 f7e 4l
b,,ffor s?5 <.i two d%iyaS to remove C;Ncoss- "-LF#fac1~Prtt aÃ;t salts. }>t+1pix~ ;it3si,~tC`~~ii g, 1.2 num!3 wid bei-izoyI peroxide (21,6 m& 0,011 triol.) _:vc=c dissolved n dry :~~lueric
(1{3 "ni...). The Ja:ik:'. as 4?t= U- l::Itl .d da`:iC. I"G'fifll"d w7.th. n1t"f;gE:nAhii'. tha1e5 tv .: 4i23t4\e'e o Yip ~?6 .'#, r.^.~~li' #.?3iY turc `<1':3S t:S 17. Se l-rS'd at 70 c'C R}? 14 .3(? r . The 4.`a r t 1'1t d w; J v,}1;S # i3 ~b\e .eiZ~iG.~ v CLi.~~f.'~b !.ttF:~ :rf.f'..a~~.{~ iii.CL~~F=~.i:~l was ~i~1::s~~l~1~L~~F. :~1 C~~F._``l ,_ ~`5 7~ F ,):-~F~~iL.?
õ ..`~'"ili;F~ #\..~~ +#. ~.+2 ~?i ~ l.::f., i". L:C`, ftJ i L3ltr.~ ~ ~ ` 3~ iii.: :i'~I~, ~~'. v 4~ L.i.~~. .F t a. `F.~.\. `;:..~3 `Ea ry `+'c3~:=Ea.aa.. < .~i~= .via ~ .:i`s. solid t.,.i,
filix.A:tt.#. T;te p.E'i?t7ui:t wa.. obÃai.3.ie,d as a whÃtf.' powder at 36Na.:iopa.,: dF: l: s :3 G=r'.< prop ared by first d.t~sol`.ring the pf?` i n.,x;:, ('53.; A?-tg) :n i 1a-:C;.:
l .5: 3.7.{L) a1.2d dissolving sodiLary( d\1dl+c1l s(.alCaCe (50 nY,~,;,) ii).i1lf~..~~t\.Ã.wzF~.Eid water (1() J.iÃ.~').
AltC.Ã"?`;.zil.=vZly, :~%aopi3..t..clb`:t w4ae prepared b' dIssC)a-vÃ1': j he pt Z''ilea (50 nng) and pad:wxt, (0.: n-,~g) it: CYHI(.1. = ~~ .t? ~.r~_:~ ~~~ad rAissol~vii-iw; odiu:".n d;&.=S`~. sulfate (50 a.z~;:;b :a? d6w2 .I ed water (110 I,1L.). ri'i#:: organic 4i3'~utPon was t1<,'?e#; <3ddc, to the t2qFLo>~s 'szr,wfbcti:.Bne, 4L?l.WE1:>tl and fft.s I":i3:iAwav 43La.a SSi;l:iwziied at 30 W of power f[fi 5 Ã:llwu`?os w produce `:T1c +::.a~i.Ãr~'io:t5.. The Ã"3Ã.:Y~uÃ4 w-a.5 stirred wl31le opm to t1c ab31ouj?h'.3v overnight to evap{?A.3le
Hh5,,, '.:3.>;e"^'s Dialysis a il2"'-v'~Ã''iar.~ ~~' Lett' if.l i' JikS.i'1r~ ri 3.> of>%:.~~i.> . t ~e r ~~i'i.: ,=,. using ~ a ~:~ _ ~:"A~ ~.=~....i. ffw`sb>
Eaw ti? E.>3:.oi='. . Xce:?4 :Si:1.F"ffiL:Ulti:t; ''`+ian4"ip37#.acf.e.s, dl2epaI"d Ll:i2ng t32s ` ux.o. rl\.: iat? 1t+;a~ swe 1 afi. pl, ., <
l~~ Se ~ ~'%3~3 ! 3t5'1I ?f ~~t~SE,~~1~d'o:' x~~.t~t1~ L<~I~7 ~~c1~tZ GFs e F 3r~~~ :~ ~~rat',s
Eacas?
i]3~t lac3:t 4,y : i:i~I~~43~'i3 ;Et3T1~ }~Tlr4l': t~c3Fi~:~$ M '~w:'~'4 used for
Po t.`'(h~4Z~rZ?~.~=' ~{l}~-:b',i?? A;
ht'' de;.ivi of p6...nitirexed. The f. bne<?iion tet;.hlliqI1o4 used to create z.hi i#tiJt;t:o' i? .13 {?ln. $:.. wziti;s fi:iz%ulSiC?n, *:i;4"ll'Ã1iquC'. I`Ma. U of 20.80 j:3;: >Z { l~r`i~ ~3;~:
S ~' ~ ~.~`a~ C 4 ~~~~.+. z?: ~..<~~'~ ~::~s~3.~:~~.Ã~ ~. zt~~'~?]~~~.=~~~~~.~ c~is~c?l.`ed in -~ md_ d.cti;orÃ)meÃs;an:
Aldrzi>1"i. SÃ. LoudsY MOi using a ;v~ilextng deviac. A>.er th~po.yn::e: was
d.Ã.s,oi :?cd" 50 :ing of pt'Ã?zctA'cxod pxs~viZ?7.fly s7ltIbilà z':?=d ]i, 0r91% ~`~t'~'aK.. .4::;~ .aude: <1F-fd to.llÃtVi::? I.Fi tte f::1bi$ci3t.Ã.f332 C?foi332t2`oi' pi',?l"V~a~~~-dxoxy glvreb,'.>'.5F ci3.:ebi' nc.#:tecf3-<s..
C=F1pi<?iaGrY}314,'.) b,~~:.1d.' o31l'`d 0.9r'C I-N:iCI wt14 ai~dQst, Th:~ solution Was 2?l,,ic:rd ],t 1'.~ afx3 of 5% poly`'viF:'y. alcohol :[?ÃfiaC.tua (f'i~ihea) and voaie-,F;:d 16i I
S.Fn.nl'a~~`i~'.?(ot so:;.iL=cif.C='.:.i uwl,,ga p?F:b>vbil? 3w"Ãi:=aÃot') and sti;3ed The f:"liFw.i'opK3iicle.s v-c~t`o ct?flQcÃid and. -w<zsE'?N`i> Ãrll~:,:~ ~im~.s in 50 n1i ,Ã di.q:led:`de,z?Di~ed water, Following thie
TiiF::.zopw.Fx1.,Ile5
L',Grt: ;.J`i3~.3~2?1~.Ã:fed ifP'4`.`.o1..+.' i>E'.1G[=! :wwStt:3iE:its, al "20` C t[.? 3Ã;.S[#:Ito whÃJ s:: pmKit o ;.3s;.;LZOiI`e?i.ciL _X,_$t~1 3:<? ~ ~ il~?I~L ~~~ Ã L3~ ~~t3~ ~~i~'t~~t3.'{~': ~,}tKt=::G`a~?~
Lr=1~~t3 ~_l~iõ L<? :a'L:cf 3n~3~c~i."~t1 i~3 _~`_______,.__. _...... -------------~ .. , __"~...._~ .- __ -_~_-__-_ _ .~
~artldes 1`rth;..FI.1E3T4"4L1~'~~.._r ag
- - - ----------
5~4:1~;~#'.=?~rL=C):Il. iFC.?~ J-~`i3i~?C??S~~:i' a~'~3d (0.005 g 19.5 Ã1#.awl)~ p4?i
(1.5 g, -9.6 x3ltrliA., 22 .i`IFi?l % uEt~'bt3naÃÃ.;}. }~: y~ao`i~.yli"r1t`.~,>.~ ~.~"~..) .'~=a i y ~"~ s~_f ~b~~..t;) ::~. Ã'(
i7 i7.6_ wu; ~~3(Ã~.4~3... ? d}, 0.26 ~~) ~.
F ), fE }' aa~sir\ ,~. a;~ C~ ~i,i fl.i k"4 . f pa =~~~.M.:or 1l. `5 hC~ti.~~`'s. ~1yvht. a D~-`~~7 'ar'i,:~.a i.~tCt 2 i ` ; ~~ >L~~ };ii,~:S inv "~ .:.. -..._ s4~i ~~i i'+.,. ` ~=~ ~i:~ ~,~.:.fC.=~'int'.
+:.1t3:pib:Ea1t:.d (q!1?nifti3ti`v`` yi;ld): The t.,`:i'3:si~ae product 6xdc2s -;fed,b4i;`,..:i:d 1I"# ~~~LIM, pun~~~+.C:te
E1swa, ~y~fz ~ t 1'1 ~ a"} n?d t r t3 T1 iAa~?~f'i1~7}~ ~ }: i1:3i~ f flIE3xIf'F` :1.. =v'l~"IE~~ ~,::)f:'Ioi=, f?5E.~i ~a a~ ~:
o-.o9L 48 how"; tt~? L"ns:b:o, all residual unbound Za3ro w4:s, Ã't:alos'C-d,
C.Z_:ma:i33 i?C`rllnd i:op{+ST'IrWI'.~-~w-fi9::lL"'4 wU"`T'e prLpairt'i.t by
z apoÃ.atlt?an :':ac~~aod. Br~~ fil} a l ;~~ gof copo`y>n..:waa dts..ohcd 1.1'1112,0 inl.,
The S'[Ziutxt)n Wi:s', pourC:d into amit:du':`Ciof 200-m.. deionized water 0,5;C +E>'v SDS. ``~~1~.'. unui;iiZ'/n was stirred tC?I 5 minutes bE ;oro being yLn,.lioGft~ ~~ s ~:;3> 30 ;~1#~~i:~~:C;S, vkt7.~. z~~.Pi<.~.i.~" dialyzed a~3r 3.~?a~,.if?~.ixTi3.i=~" ~4x. , ;;~.f3Lti'Cit~~ ~.:by ' ? ~ ~ `~ tÃ. remove tile SDS,
111'.' :3i3.nt5pi1lfic.t?= ko:.k 4i?i.`ai7iei (5 7Ilcg+_i7? l.) was d7laES:xa to a fini3l ..Z?.`. i'=L;'3'tt, i3.tIf.~#F T3f' 0.0 1 i'i?;y z, with :~C'=lsii7. ;31'~~= I?t<=Ci ~iYl'a (Di.llbeccta s
Modified t aa?e*v M.'d1vi?l), A549 hllman hw ng cuE,.,I.<':'~.?~l.a cells (.,Ã"$C'i`xi? TY1..~x CultÃar =~Z~~i ~~.C?T~._: ~t~c~ i.~~, ~, VA ) Lr .m4; pif3 i:'..d Z3i3w a 96 v4f:,R piaf:`a. . .tfi i.3. dC`.T141t5` of 5,000 Ã;Gft.:i.64 `,'"'.il and Fnt~.,.'.ub<.3:4ud t?'t`:=31.Iwx?E, or until ~ = Z ~# 3f '~:=i>k~~l yuv.<a acl." ( i~~~~i,:# i5:~?(..#.~ .~+ . i': ~~~~.. ~.=~25: a r rib:~~iuJ.~~ from "o:F:MwL.." vf a1 i.4:~.i3.. i=~'::dG....6 :'L:pls. .a'+
w1d=': 1003.#l_ of 0:01 TI`at' ;l"z.~,. IlaalopanIt:.Ile 5oliit#t3n auii, thv colts w+'.f;` stibset.,.E..zafl}'
iÃ.t l.l'e`?c#.~~.:~ ~1'F~i? ~.~i~ ~?LI?~it.~:~:~ ~C?i= An fti:.i~"S> f~t~a~: 1ci11f3A`3~;~1~'i~.:u :~~iF~E~.~.t3`i~.,l~.'~r`i:'- .,.::i dw3::lSr3'wf;:,
L.=L?~a ~bi~:i.'~ '~~,,~~~=t'~. i~1:'`C f~ i;~~~sC"~:.: s2E~.:i ~t~f.~a ~..s:>. ~a~~~ ~i3~ t:~: eI'C::i'4: 3 a,~~'(.; lf).:A1(4'4hf3te: , via a FII,"4 alil4'a..
>'xaIa:pl*, 22: Ff?s3idl' 1t 'm E1~ N>iV(nt aÃi4 4id Lt~a~l3~it;~ S ~? ~ y 7?~~t34~{3 N<#no25f3I .1S l4~
nac à umo~? :'. ert' p3e~.'<~~od by 6tÃ'3 emulSIoI'?=`si?l4 eÃlt: ev.spE3raf?y>F. ;IZf,fft,?t;, fir1+.Ctl'r p?i y(tiii;wic acid was dissolved in 2() 11=11,
25 dissolved 1Ã.:: lm=0>?1l~ ~~idalE?!'oEnothat~c containing ePtl1o: I or 10 wt % i.`?aa.'l.ttExwl pw.i w6ght tff pC?iyJ33S n Th`~'. ht)lutiC?#? S3 His poured iliti:3 a mt?'itL1TC'. of 200 1na., deionized wavr i,.txat<tIT:1lig ;v.+`6 SDS. Ti1C?c-a:1ul3ioiI1'S~yas 1,0""5 m.+.nuti-".`s bu:~3Y`4 "l.o.iTz#.?. nninutes, and xina.lly dialyzed for apprs?xun ..:,
Nanoparticle ESj2itilf.illlg In Az #` B-Ll2 Not Nt..Ea ?" d CY+}#
A S Ctl..n of ~.. ~. #~ ;at43t3z#~.Zi ~. r ~Ãil~;; C from i#l~>.:~... ¾;~ y ##? ~:?~. vf' '.} u;~~ v ~i.'Z ~c::#-~:3. a..>~i.:##3'~~7~~ ~~5 t.~. v ~#` t# 4,
oa ~.. 37 pC. TIw ~.~1umCltt'i' of the pa;tiz:lt,s ~~ <1w .hL'.:l IÃ:t.z'sÃ:"s'C'.'d a"
regular i:i:-nc iIA ,t.rval:i .:,yni? dvt#i,,a3'ili; 11,0pt it:Tafti':FIn:; (DLS), showing ht?w the pa.,A.#.dos ncr4~<>c":-~~~ d .11 ' S q} za5 ~+a~1 J.z> 373 to ' ?+r vat each + : `. 3 {~~ tJ ~~~ 5~= ,a'}~ ~F ~ 4 !. Li j kt Sr~~~'r y y.: ~~ L. ! ~i..= {.~ ljv? ~S{4...=, D.,~~~~L'~~~Z::~I.L \=' a iii.F.' 4 ~ r`Svd.t. s ro 5 5"L'. 1Ct3T Ai4 b,t'~..i;.~~;~ Particle 4L4i:llla. S^g x ; '~'Ã1~":t,. I + v 1i#ii Ir La:{~~:1 't *1~:~'~.=C', to near
I Lt#';?.?Ã, arYara:.=;t.#' ?-vas i?~'~se? i'+'d bsctr Fi r 9'3. 1.n addalzz?.3., t:a3e rci:<#:~e of fic,c.2,4:iF1#~~?[ 1'<<cl4 L; bzC:t'vcd #zSii?.- UV MVi,, 5pectro4co;?L s:t <:
292 also indit'.:Yt##1g iepri2tect:+J+3 of the posv23:('r ti#d4': ~,grcZl.p4 (s,C. Fig. `:.?),
a.iCse :`?at"t.c>.e. are u3:'fi~d for controlled rf;,lca5e. r3pphcciti:3t?s _.S 1v..;I ;.~s foiC ~ : ~ in ~ the ~ o Z > c t;'co. 4 .,t ~, y of ?i'c t.~,p~a~.ax~#~. ~;;3~3~1CaÃ.#i?i.õ~ #:~3 '`~l#~.~~ ~aA~. #1.~;F~.. ~~SL' lie vC?~~1a~_~. :~#..:~~ li,t..#i~.t;~~?., U;i:s`z;use tdii. Siza,Vc> Oi"tassue in!O Whsch xbaw~ pol"~ms'rs i?:'L. ttiji.L=ti:d.
F"x1mA 4, Nz3no-mirt1ClL ilnd SLv-dil1 J el`i)mA SLFfx` 4mYo~;
2 ro psi, .t} this ..=f?i:~~lC?$oa?E3 pv +3 v- vc S ~ described i .cv ~ e anti 4~5~?~i:3 .~x4,~ 1:'e`t. 11L'S.~ ~.3..~ as s':~s~?=>,~ by .etc.~~: 4<.
f;~..flt3+.;k et tX:,; .Joumal of the Chel:1Ti;tia ~'i#f Fdy. 4433-4 ~ 19:96
20, Slui:ol- uran SG ( I .<'XXI) g. 3.46 mmcl' and CN.2Ahyd)`#t...W (12 Y.V.tAv, 1.2 gqC`.2 }3.2õi1ioSY were dissolved til
Z?;riil.ikne(5 ZiS.) L.a.wl.. ww\..~\~W~i. ~:..`.
S_ .~I' 15 ra+3l'zrs. Then iv;l;o. (K<S M) k=vc,s 2Tld#:d, and Jki#a#`3 :aa. 65 (-,' ~' .I.`: :..+::)iltitl?w-:a
>E?I :aai:?thLr .,'J .C?l3zs :aÃ'li", tl?oS1 at ':'L`.'td3m ie1nporrata.e3'e i?1Cm#.gat. 3hi mixture :'i 3s extF'.i]i_wd with he:S.akf.cs i 7 .3!.L X 3,1 .,.d the combined hi'Ya:le:> w..>..#'c..ti.its vL eI'o tz?e#] -washed I M."
MO.. i: (15 ??1L X 33) iLI?Y.Ã. dic1E5nÃ:::4=d water (15 I31L), xbfl(ti,tml by d3"?,A#1N tFi'{ Y~'hc
Si?li'C:lÃt :vc3 < ionl3v+ d is$Ã?,: 1`a?ti#..~' ' e=b'%lp9:3?"at1'ri#av and tbt_= Ãt.`.aT:ai1Tn a?;Y `~.'13`I'#.pf:}u:`1d was dried #?#:dz:3 i"#ig-1? v< ct3aa.i#?. Fhe product was E?.:sta#.ned as :~ c4L.u oil
N.?>nibptl3:xS:ics z%,'e-i`.'. Ã>?3'aF?3#'Ld fir<4m d1s.`.' resut'Ã..ÃI'3g p,"?dt#.C=t by Ãia#:;ht?:`s dL.`tit.J ,}3c=Ã.l lioa"eÃz1. As:Ã3aap3e ?..?~ ~~oo nit-ni pci~~~:1dvS was Cifl1:Ãted i31 0. 1 NI
ICa anf3 mua1.1i ,.;Ã.Ytet.E at 25 'i_',
The :f.?ci#,acÃL:":`,? flt.I% p saft?::=:Eez,3 was thi.=n,.E"i]ea5u:Ãi.d at 1`t g?.:#laT.' t.,Tl..c int'a:a.,;.'v:a.lS {.SÃ:I.i.~ dyndmzc l~`x=?t ``+~'<3t.~.'.#'a~. co t.~Y~'{:E.~ iõ ~'+~' 3;xii~~.~.} iY 1 particles ~c~.~.i~.~~:tD ~ ~ ~ t >Ã~ i='`" over ' t ~~2l5~i~ (Fig. ~~ ~,.~ .. 'S: or e~'t'p h.~~'~.e ~G~~~wt.,v .~"... 1"'lg. 12, h.:ow:> .a?m 43t::a PIJ S>f aboL3.0a the particle size f?a9t3? about 200 I?ta"? Ã:L?
about 1600 ?'.Ti> t?t'a'T flX L:to;%il'S`v' t'#.{, f&d:3w 24 hs;)urs, whereas
M. pl'I of about 3.0s li`ae panÃ::=1c size is stc3blL etvcr the si$II.~. ##1't?:L`: pcIEC?&
E5T ~?i:i?,i?~ >~`~:. ~ ~ C2~~iÃ4<~~.~C?~a Ctr s.7:Ãa?~r~L i.~Z=i.# i~.R
--....... = _________ _~_____~~.~. ........~
wi:l'#:'. 4:.'t:+r: t?I?t#3 glass by dt.p##41;.1ng a pL7lSttei'# iota.ÃÃ.at??> ct3;t7.a3r7si.'d (`f tat? 1E:d;vW .#A osrpi.?ly?'?#C..a" #i'.i5.:l.?.d.ll?g baÃi. #a[?t hin3tZ:d e:t) p33l,r~(sLea-ri:<i aC`.d ~=i~Ã ~?~?f a~E ~=i? ,s t`=apÃ"}?jeiLtsyrw). dissolved i37. E`s.ti':3hytaaFi?fI:1:a`::i.:?. or tC=3lÃ..i,,.7.a;.'=, wMn"ii: ta Ã:.3ÃL;C3yy3 ilip'<. ?.?i:= sobvcut was removed by 5la?w i'.','~:poza.tit.$32 overnight i3?:.` dti ri placed under #=LdooW :`,#'(;ss1. rc for 24 hours.
"'Un niaÃion of ~1Iti 1av.;seed Pa, F _#~;
}y}fyai:iicc?rit_'. ;:a#....d ucÃI'~ f}:lik~<` fac ~ >3~?t~?~ifCaCp~at'~
I~iT?l~ Z~ Le'ci #.d;'2c:"ixl b[:"f-~,3"'r,.+=..`in a%Ãd3 A po(5(lÃsG:fit.'-i>t?-gli aol1i solution w a., Cipi?s1t~-'"I :3iltl; gl<#.44 using a `.iT.aerC?Sbl'Ãtl {i. Io fZ`Ifll sfihn, A pt?l5tt',b:I4= q ~ si,'~l:Ã 3 j lt7 ' ' ~~*~..rt.;, r~ to:~ ~-,..:;3.3#aix~.w L.tz =^i:i3~1~F~s`~~.~C:Ã1f:,'i.~:Ã~,%z~~l.~E.33'Ãi.#~"#i:ii~~.= ~#E.~ .,.f~i
`ri;:~~?l,.c:ask:ÃE3) film FÃ.Si~ÃiF? a Ãz?1S:=ri3`s5~=a'ta t>G~ to
Eyt'I]~ a `~.~.z;Ã?i.: ,s.~=~?i", i3
?:3t?l`r`(s`LC.,aazC: T3i.a41 i ei:t?~~~~tÃ.i=1~~~4r,^r;-S=i:~7I~?~Ã:li ~t?f3~ +, fihm a.:s#:li.? a .I?.LrosL if`g:: $t. .:U.E-I:i? -all11:E.E, = lft{`m
Em3m pai 2 _DevE? :C)n of Pt}l`rm:1 FYl#i4 on a ti=2iF f t <'
~e~-i~:a~-:~:. ~~~?a,. `l_'.~:.~t~,r . crr tit~~~~.~;.t.~i by ~ui~tÃ:~; ~Ã::~~~a~>~~ac,.~ I .~.~{}Tz a:.;~~;~11:..sici :~~ ~~a~ z~:~i~'x1~-~.<3l S:i)p:l~`F~'l%',E 1TES,'3~?~ but not i.itl:k#ted to "}.33l5ÃsLC;iL?`iv :i. 1d Uc11:bE?n,x:E.e Eco >
<.::3p`>olii4:,t(`P~S'=:#, dissolved in d3chl"Ã}rw`E"s[~than`s'., tetT'c`=Il"lydr4.3i.uIi:T3i or $i 6F:~I1`.:`=Y. usÃng a ynagc, Ihe Zb<.E:3= :I'eI11oS'i'.'.d ar Slow Lvc:poit:tzE?n 83vC:1n5ghi and f.h;:f3 plcicQG', ndet the<F~.~L k:%~ ~~'i e"es-~.C: di.):x ~N hl+urs,
~att~ SEL 7i ai o pi^kr"ht_>on 13if# P33I41`na F#it;l`>
- .....:.::._a-_ . _. _ . .. , w ______,.~,~ ........ .........
iag, loxided polyfla4ric, ~~~~~~~~~ ~~~~~~~e. cast or ,;Ira4e<l.>ziic# gla55 by dozo4Ãiing a. yry loy~. r< , ova k' tri-1<~n 1l'~=(x
I .~i3~~.r of ~ 1~[:3'~.~-.c3 i(: :lf.A i:[!~`~?1.1:i1Li'. C.i.= Y, z _tp3#~C~~ 1 ~~a. ,~ ~_ .7. Tyr G::3~ la ~ and us! õg a iYiicl'o` vniTage or c3i:;TosCl dei ive, T'1~= sÃ;#h e:z.,. :L =;:s
E'%.,T,os'ed by slow 1~.vs~pors3fion overnight aFtd Ghei3 pl:~~.~,~.`J, ti.ideE ?'<;ilticed pressure fo,. 24 h$:3 -ors.
E maiiv i 29 12Cs3M3~~`ÃtsTl ant` Patti.`n3fi> L ()flvdn3x ca Iotb. L a'i IF`
Pov'EnL F1hns a3i.Il ,~ lft.~S~ ~ "` ~, p`y : ~'l~.n'; i'~~.Inc gj#~sS >.. ~ :3.~sl~~k~ i:l {v.; .~.= ~:6.i ~Y~E.e :i~~'l+a . . .
?:t3 i'rop#:'a1lia or 1r.iL"r 1sy...iie:;it by dt.pi?4iÃi#lg a p()lyme?.' tiORIl-is?#. of PolL(4t:.c.ifi.: acid t':a .;bi3I1=:ite ci;..c-C(`tAsro Iad.n;.) }?rtchlC3romethcÃnc..1nd i.? :>
cot,Eroli,,.d -n:a:eu>!.'r to t`.Imm '"~+a.tto;ilS suF:<l3 as Stiip`ws :_ITW ta#4s. The solvent Y` wi, rt`fzlt.Seti by s-lS.;i' QvapoI<::`t1.1 i>:vG.Yn?gN c'si7d #1he.~ ~~act-d iittd['i i"sa:ducQ: pFes:~uIL` ti,#Ã`24 hcDt;.t';. 113.14 1-u,::`tl3#,?z3 i a 3:.#.k,y be L;Sod w>fl1 T]?mn:= than E?t-IC P(`.lyn1a s1~z.?~"':3ltaawi3iI`;sl}%.
Exwnpl1 30'. Rilsr?4c 43f 0?-I-IyLt~xaa3'it#thtidnfri 1T3
_ r 4 = r~':NiS:::":~t?. or..
An ~`,S;<3 paZ~~3~l1L. ,;#.I.3-~34 ~6 ~',.e Q<.s:: onto glass a'kv i~~. 7C#`~.1~i1~r.t. <` ~'#tzlE3'.T~. i:{)RxA7T18W f?f a3<,33y`c'r¾'#:l.~I acE[;3ie) (5 f?Ia',hloro5.31effi.-.Ike (50 aL)s a72d 10--
i3` (100, t-`g)9 usiYig a I 3icrotiv=~ungt`:=. The so:LC%n_ was :'
Tn(?t.''.d by ^^.alfL'`% s~.' z3p.?::.et#:.sn :?voI' liight and flaoa] plat.~=d :radial r4dt3i'.ed pb'c.Sslirf' l-z?r '24 h#3a,s. An initial bL2#'si was :`. i'Δti.' fli¾., ..,"e 1: two Ãac34s, .Tc<C:.aaiIlg <3t a <3.tt of aK)o[I.i 5 p`;.'da`:'.
f3r\.gov.io).aded poi\=rSni.2` films wek-e6(}so Ci<sC }ri.ff:o gY...a.`.s by dilpA}4`tin\ \; p:#3`imeA;
Si.?l::udt;F: E.o>;-x> $a.Soc, of ,.`t}:y,(wtE.lnic CFa ~?<?.i¾i.i 4c, ~ f;CsF.~~<3~ ~ÃC? 3'~ (.5 mg)
(50 i.fL). 3d paGI 1,.::Lxe:`z (100 .#g); using a microti).i.i?ga.?: fPhe solvent was i41:a#c~Q.i, by slow i: i aPife 23.~.~;)Tl "7 .or n`=?h,ft and Ik?Q3i placed tiÃil.t'Ã ro;Fur`ed prL:s`,"rL.u LSor 24 .i.~O....:>. i`Ew: resulting ,.7lx7iS 5,3:,ri: hoi"i]iitses?ot#:. ~.d opaqljc,'+vÃtb :yi:Z.?d adh.`: cÃ'?G.a`.~ to dhe g..'zl~~ su.?,,,`.Ã"i3.3o.
The fit.ti?s ri:ha5.`d rwxi?l over ~
of I i r o.348 l[ax fl Ã3m. vI4tG`k?"ic <Ã i{F
Dt..i;?~Ãi;aded pi~lyEY3or fibus were cast onto w?lc{sw by depositing a p:tll'
o~x~~?r;sol.? ~.f'~,~~<lz~(~tca~~:~. :a~:i~: (5 ,(50 "0 it ), i3:3t~3 (1~~0 ties) , using <31zl,LT'?SyI.nge. Tb:S si?lL'Cw, 1Y as t:i?':<3v(d, by slow o4'`lpora=ttci?2i (a)4'G; night iFÃ:?t'?tiZ.en piaC;<'=d under redz:wed_ p.c;~s"ii..c fb:-'.w' 4 f~f3urs: A 5lÃgak r.~~~l.i~ ~~~Ã"St was ht::'I~`a over ~~?~'. ?`EI'+~. t~#`~?
CiIZ's IC:~u'sl`:g wt ?Ãi:#tf t?e 1343 3i 3 occurred 43vf.'I:4t least 30 days ciE ., l'.:C `b z 4 cE3Y?`t3.<l::3f- Ec?le
15 "t ~ltL~'nnl?`Z g ? lbf:' ~ ~:? 3 films r~ ,~a tl~~Ã~~c.r i:~i >~:. rt, cast if:t ttc. ~ ~,1
`3+1ls.li?t..t. ,. 3>u;,Z?.? comprised of pi3 4(stf;13I'.Ã4 .={It'~~[J?:i1~G 4f3-bcr i c:~:?#i?~cE~ ~s?Ãi~ ~ ~~ '..3:~:~1. ?..,hlomF.ieffi:;Ãef' ('?i p.L), c?ndpaL,lftiaxt,=l (100 l.E s~. i,$siTÃg a ? t?lcxoi t E :i3 g?:.`. I'T':e st?.l~'e#':t
W<.,s N.ML+; u'.:d by sltw evaporation (wt:2' t71gh:: w`Ãd th#3i1 placed under t'eC$ll.ed prÃ,s~,f2rc tf:or 24 r3~'r"L~FS. a':his'. 1`11t.);; weI'e, h(}1F'#'3u:2?.i?i15 i?. .3Ca izpFzq#1e ?s`:'#ii gi?<;d U.f?.Tw<:'4=i?.>e ti? fb.;:: 20 <;`.iss s:tbsar:Ãt.:=. :The :iAnis t0casid ia:x{.at ws-cr time.
aJx{~.3~pjl~> ~ Rx;~eaye o 104_Iy'AmNaPtfy 1~ ctrl arorA.
D.-L1g^lt?a.#.E>C:d polyA.nt.i .:Ã.lkT?s w:I'C, cast Fsl.tt} h~li3ss by ~e1?E?~i3'~1#.y~ `c~. p 3.:5'?'?A..I JF?l"t:i:1.3:~"~ 25 Q[falpni`.,sed of poly(hydroxy -;S'GcrL.'l 4~:.?~>dÃt~~4 Gth ,: L.i~} C3~
>~a-=?~~>Ã?;d>a3?o (:)0 pL); and IN?j'`dt`t7Ns?a?"1ptE:3t:ho4Ã.1 00 ig), `ydLi~^ Ã Ãx=~C?4~?'Ãi,;`~=. i' ;o,ivei?t 1v<>q removed by slow avg1po?"at.of? over ;?zgj1'C and > >2i i.?i:>od 1f: F a #~.',c;L?ct.':d jptos5`si3'L for '24 ho1rS> AI?.i.dfti3l burst was se.Ie ;3vG;Ã' tbv first day. Ã`t,.,iowdig at a Ãi.lti= E3~~4
F3bz?i1tl8 l:Ã#.=`ta<Ar', Ct`.,3.#3:'`i.itl.1S T4'Ees,ÃaC' i?Ã;e-l..1#Ted over 'ekt I :a:ii )?} &yS, bt.?gi 3=lÃ?-<lt a 1:"t.itl:= to less than I ;.tG.N+c~3t' at aoliF' -%VLLk<i 30 i3Ã 3 #iif day and ~lo~~ ly decreasing
Y R : In Prt= Lt Turaor Cytoxicity wich iFc~ i' :;L L
Pt?`4(StLt3FFt aLTiE GxtFt~3Flaf~t` 4f) # ~ i `F1~xx# >i3~t,~~i~ t{2 ~
Lewiw Ã. fF~~_ Cucinoinz.~ (LLC) ceEl~ were washed wiÃx1 st:::r.fÃ: ph.i,,q)h..Ftc buEkn-ed s"~?m4 (aIn'=~~S) szsd tr~j3sinIz's-':f. The cells were tn"1.'C=ki counted u`.aingi? b,,. C_#W:C;f+ ool.`ef..tt::F" t3nd 3<3 S.4`~'i~?~ ]t t. 1~ `~ is<tall plates. ~.'i:,~l i t4 t,~ c; {li,<'.i`3'ai<s :C ::iF.F{.. Y then iFC,\3`i` .~.~.., A`. :~~3 .i.'F"!~ Se:#`~s~~~F ::3iL..t tn~3~1\ LZ... i:TGl or.~~ ~ t: ~\L ~.:GF}..= ~.~w treated qYt i it`:l i~- ?, = +}qT= t~3z . ..~4L~n~~.ra.x~-l"~ ~ 1:~.F1ti3~."~3'~ .~.t,.,es `r# 1i) lik'+ to]K :,Fa:;:
3?f..iFu:~cl^.``yf.Fin.aed ne3.1oputlt..les (I % Paclffi.aAel) fo: ez ~.to e da SperFod. A r~a3sF.J?vÃ. 4.t}nr:ri.'s''^. ci`.+nl't1.FnL.d IF134 <.3r the ;,a.l.Fa3e LoI]Sf:=TAFi.kt;.;3n of i'M pFo\c'.dvZ'a ao# t;.L:#.Fwd 5.:03:`, 1vv-h,~'+l`~.'. a 34:"gafive i:=o:Liftsl kwked r' BS, At :hG U<1vipleÃIF,?i. of t,|fF.. assay he cells Ly'4."G .,?~=Ã ~?F[~ i~ zv ith 5 "0 ~ :;r o i x x , 1, 11 i . Fo l~~~ ~I u i.~ =I'et:az <-3I iLj m Bro na ;d e (-N -tIT, S ' g=n zF) d'=~~~I v e ca i n 11 B S at "', "C .ba3" :3i?l:fr,.>. - l7'L: Fx3i;=d3.a w: 4 then Asp.F4.atG;d and 1,00 of DMSO was ..{dfaf:d Ã#-> each w:..l.F¾, 11hC =?i,:Ã'L''.<.`'s were then E3i3vedc7f. a s+3'ikal3,~~.~ det='ic5~=. 10F-nÃf?t`s:C.s t...3d Ã`.i4 Fra.cells >#..n;~:~d pÃfp.;4y ~.i>~Ã"s'=`~~>~~"?~~IIF~M ~ :Ã~~ the n+.n2?*-:e':] Twj..v1;_Fblo, :TF t11t; Z%s'ell fritted.: ?lati:s wi.n. ptui:t`.d wi an ELISA reader LJ3-ict scanned at a w%FvC:rt:=r?lgt}x o1 5. :.t #i#.: .
1 J!\ `w.} SY ={ C 1+-\ w~=yÃt: t3]'~~fx3 i:via.~ \: to values ~~`;?~3'~ F~. `i 1';t; ~.i'Ti~+~. ] C2, year1.:.#~<~ K~ t". ~ t .~ ~z;~ 4Fi. ~'tit] r :'~~3~~,r~=~~,]õ~~.i: ~'~,:1~::~ T~:~11~3[=i''I. .
cvÃua:i:;:3SecFiv was ob:iQõ"v'%a,d L;'?tl3 g17-: t 1TZp#i4! nanoparticles (a:* a Col-rt i1L whereas aFSn.. i. to.. '~.. J C~ ~ e[y ~ ~ [ ` 1'Y J ¾5~~1 ~~i :~~ Ã~~ ~~C 4 tls?C~
Exi~~~,,o.4 34 Czf ---- ..a:..- - ---=--__~ _ - _ ~ _, _ _ _ .-__ --------- -------- 20 1:101A(lau;i?v zlffil2Ãi Ly sÃoa1F'Ic) t~l"~:4rti3l fl#~Ff ~F E~~~ "tc#-
~s~~ah...i~,i.Fi~~'.d ~~i7l~~'f`:l[:F- .i.ea7,i ~4'+~::F'3~.. cast onto \,:.`.~~1s+ by ~ e~..t-:':~a~1 }~ ~.~`~?`~.'F`'31.T :]?~.+i.It=
f.omp:'i~'+cil of pst Y E.(Ic3 #:r:c' l.fy-#7sti . 2)iFlII]Ftii". or
(50 LF ~ .~= and ('100 t 4;t, : s; n43 c.i
Thw +?~Jb{ AND was rem'c3vcd ~.by'CSlow ev<3PC`>Ic3110# O:''i`,t 11g1-a and Ã:^t..ii placed 25 1F1..de1 :<.duceL. 3:'c4_.1Fre ;<);i' 24 h{1u3":'i. An ]IkFtI:'r1.l b`iFr.:i: was soC n. over tliF:, first di3v.;
1uC over at least 49 day-,, beginniFs.g al i.~nilie of 1"3 gh/day ud slowly S..tecroasing to aL=....L. :3~'++an I ug1RLa'vr tFE. xc3cF.r -w..cks :: Lc l'.Ãg. 6). F:IG. 6 sÃiows tbF.t increasing t1he h;dr<~pbiob3; ;Ãy of the po:yui:v.r
C~~,t.3~~3:~G release 157om Ãhi' petlyn.lt a's. Intl:i.FT1ed#.atc .F'elCilqc lTrofle:. .4: fluoS4.vhi7wn. bC: 30 obtained by F:32>.F#:g or bli el dI1.gThe a olZd~.'1L=:'s:
à ?aat # iyzÃ.Iol ( to a~1t321i3$~ 4i? .itoiig) i.111P4rÃLudi3.Em S:r# 4
D#u.Fa;-Ti>a4MC,:d po.ymS.:r i1311:1, ivi::rL''. C.Bcl:st ,3F.tC;pL.'.? #c:3:#'tiiu#ii by dr.,3o5,.t n`.~~, a PL#[ v#I?i::` sC)Ei#t3C3?F C?T3`FÃ?~~tn~ of pt?ly(4t+:.i.}:l'Fc T3i:id and ~ ., . s - . . v =, ichli3'Ã'o#F?i..tb:3#i~-r, i'S? ~d.), T3f:Ls (100 ixx. ~ ~ a t t t.
L.%3a17 7~[.~~r:L~.lz? ;.F,_, L# JF;.::; .i 1as1~=~' 35~ #.,..t.
x The si?rv,=a was ''LF~~i.i~~~~=Ã3 by slow e Lii~?C?r;31~i?Ã~ overnight and
Cis di ~3~ Ft=ti=C~ iF7 dea Itai ~'Cr p "i'=ssun, w ' ~~.<`~- >3lii:#:F'~. t~3:? ._iiit?i l tri.ftF'st was seen over illa`.'. ~'#r~.. day, .FL+;t3~~ ~~ `~TF 'y; ' ~ to'. of about 10' #r.4 i biy. CE3n3.F. #m# ru.ie<34 <?i G ili`.Fei d over at lec1, ?. 40 days, bed,aF.et?F~a4: lk :~ rate of 3 :.Ie+i Fv :ihn'* 3y C'F':'=vai.:a~.~'`+inÃ.? to less than I F.itx`l~e.F~, a.t .fÃ?L1Ã''~~j~i.=~'is (s~Ã. Fik.: 7),
Ex:i.-pp1e?6. Ce1l Culture and Ct1 Assays
M>,.;ar.t?Ã;lc`a ~'~I 6 Ca?lt1 6 (hC:xTI#.1FT lEF,.:; i,:?#'i=>.?'is3rn'c#):
A549 ~ ~#F#a ~F7 lung c<#.Fti:zT.iÃ?: c#)ti -rnd LLC (#?luf'.,.1C L5'.~v#s Lung Carcinoma)
Z~~C;"'S., d..+.;1:bi.~#.tt=:d #.~ 'C. 5,.:~~~??? w .:}F MEM ÃwA,h 10`. ra .eÃt~l bovi.itn soraFm (FBS) ;s:id M;) essential anitÃ>;:3 aõid-"i. - <
PnP.~iicz. Ws.s ~:,;1ca,t`. ;gi:" L?I.,a,.2" Z'.'L'.For :l-ti eC. ?~ayi,
WhC.:n '#FoE. Lah1.RF'C;.d, all cell ?IS:`seb x ..:e#'s... stzb:l'i:C> 3rf
IN-1 I {Ãi efinti. i:?okia~a al. -"'O'tY s WiÃb 501,1r. FB& 401% JUIM 1 aFAd 1:0% :-Paneth.,y} . u13bxiel~
(D~~SO)>F,. i . . 1 .. . i x and = x ~ aiF ~Y' ~ Z, \ Y~ t t ~. lines were ~iF~~~siz~,Xed fIUI~ An cm ~~cFt( ~ i;a.~: ~~:~.ÃaC=~a
F.xli.to ~ : ;~'~~ ~?;<at'S i:#.nd ci?Ã'At,..C.wF..fit.aF~iC;I` of 30(10 C:elN per T=3'C'll, All cell
II#.aE.s we.t'i% c#.2lti.1.Fa:(3 10#.' z:i Yt3oi."#od of at least three days .?ez#L?. e b6t?g feStL=d in cell '`~~~kE?l1fi:F"eat#on a:ss:Tys-
2kJ Tumor (. ei,iw w'L."ro washed with, <\, ti%? 4 i Ã~ ph},`7`p-h.Z r. `'- bal-TGiC'd.. ti. i # so(TIa': kY) and 4Z ,)43n:z+ ET:.. TaFt. cells wC::F'C~ tbuÃ3 C:<?l.#.FIted I.::ilTI~' .F
Coulter C.<#LIF.t:<':=#' i~,.#d pH':iEtE:Ci ?,.00+1
"1 ?:.` `?r~ 5st ~t~.::^. ~ (;sells ti~~~:. ~: 50.r',all ;.t'~~:'~:,~ ~?~tGF'1
Inc ;:.~a.t ~ ,.Ã.i.s_z~ ~_~ ~~ _ 4~'.#
pi!z"=fitÃ?x. , i::7nlIL) or pfai;l?la:1'l loaded azFerÃ.p,.inFC.xC<:: the a>c,'.)::`i &Ey. A posr9.`.vÃ. cLsx33-.t.'o. %':f;nt23aIFi,+Ca 1.0% F!,-',S or til`.'~ sz3.I3"lf' concentration of F.B:"i t).,o}dCd fo> i.et .#.'.:~ Ck.is, >~ ifflÃ: a ?FC".'atiSc i:o#tty`C)t lacked Fi}SS. At 4=t.te~Vfli:fiof2 of ..ee c1~say, the cells wz<-re.,M:;ubG.t:ed wi}ll 50 41 of 1 x Thiazolv( B1ix Tdr;i.f...Fus?'i
BF:;Ã,i-ldc (MTT.
S a ii7.<a) d?.,ti.3is'E:d FP, PB :r :Ft 3 7~. .+;#i two ht?1Frs. ~~'ht: mccl?tl Xi=i{S ~h +.F, iaSp F`"E.F,wd a...id 100 kt ~ of DNISO wits ad:dod to i.zxs:;b Y{ N~~. The pra[e. ~&=QF=c thicn. placed on dt~V:CC 1-<3r tt? 711.1,11utes amt the WcHs Ã:;~#rneÃ~ purple, cc?rrew~.~~.~ridxng witi fria: aur.Abe.,;; 3t ,iabl.e b.iiewv#~l The plates wdirC: placed on a:?, :_:F..;ISA Tec#-dc.. `ii..
LrS.:ui`.3ed a. a i. wvt C F1 g h of 570 Iazn. J 1te absi7ti;c' V:.3.eC.iG:F were "tof#elalfr.i..d to a lk:.2ii.svw?
Ã.E3#`.ihe? Z?fJ:` .i'#e~'? ccIls. ':t1c dt:3se ikfpC1el1'~c},.Hei at bi''?'#.cia 50#t3 s.JfeF.;.s are a.th~Es, or i_,D50, was (ai1c. #lani i~ to be 3C$wCei1 I = Ek Ã;<4 i23I:, : ~ ppm'Li:Y.zCklzif:~=ly 1 ':~,:;~~L~ ~3~.i*:..i.;2Ni:1 i<?c:Zet:=~?
3 . .^s > to "s~l'.~`YIi.= ;~~~. = similar `,i~?al+~::l.uRlot G<r t \
I?LL.>nt:~~.ffiiÃ":s .,in 4'r~`^, i1~4.Ul.S~i~33~ ;~ e: :;t:l;
a 15iz ttc Y^tin - tt?~.< ~=~'~ ~. a R =~.~=Ãry of t.1 ltaS.~ 'C
i,or :7.i~?i .,r..t'E3.~'#.ist ~~~=<~ . : ~ ~?, ~:or.~i..;~ a~ were
three >Ã.:tao; ci..x llaes, Le=wÃ'~a" LonS: Carcinoma (LLC),
NlehunGimi1..>,ld {.'a:z+3 (14iFlaili?
C ;Y.C.er) \.Q:3 l1nE.':i We3'e plated a. 3,000 cells/well `ead-kd whe:i7: ostcabe1Shei3. :Neft..:S3d .`,?1 iTac-df:tl. p<ai`_I?taxo3. Sikil`.5..' ,k.Ii1lt#.ni''i:; wC<i`c miafllata?'.t.~iod with f.p::#.Ã :i.E go`t\ ti3 ;4Lw`z"ti (`Cr"'.Ãm) wht;na`u t?thwõb WC..1'e scS'illlm, s;aI'vGd. (ÃloI3wg7o}Z Ãt3t.x3 cEa4turLS4. Rii. ,xf`s f.cl".
E31mw3' C:`l ; m-sl.-f<.t.;:iflon, was asSessei1. via MTT cÃ.i7t3i4's.i`i.
Data was X?hoEtt;C3 bv f`.tix.3.1ilir.ext_ii.?f3 w, 1}}c pt?s.ef?rc: xa*.z,.i.i7ti w3t1Vi;.
Con'E?l i:ultua`es, as O~'t3 :lÃ0 100?e i~~lubitlod?, respectively. 15 1 Y1 C) n;~'. m a. reliably l.nhib ,tS gTowd7 of .1c I.M melanoma, .i#?d Ct.#.l :a6 WmE)I'. <:~..`l i.i#i`\'.> 3T.
p.t}lffZ'.Ã'.h`.io;:Ãw~ I.:ll* data wa-, C?btai.i3eis. 1:1s1I`tgmioC~i.i's.`t eC?f.ta1r3:Ã`g I fs':at. i'BS, tposxfivC'.=
Ct. , i - `> ~ t cow.., Ear' Jikn' ~ i .e~:~ic~ of :?.I.ksi:~i "r.~#.C3?1 were +~ to ;ii t¾,4' the i~ a Ãu~ 1-: on tumor ~ow*h. J. Ã,Ãmor cells were pl.itc.tat. 3000 ,,.o11s;';i e>. mad l?osiÃi, ~~ aTlÃci ztpa
C.'Y.0- i w.. ;`'ze i P= af '~ r a > r+ i used [Initi An, J j ~~t.=..
I t>,;4ti,z ii=~ ~~.,?~z.:l~~ i3{?~~ cultures ~~'~.ii T1<k ~.l >. 1 z~ z:'~Ej
gww th .iÃhI;?il{<,n. F: sg)ec$13'~ ly z: wus found tll:a~ the addlfit?I7 ol zix~~tC#tii~ `c t.~Yf#?}4' results .i.`a i#.;.?:l>ivÃt?z: equal to PLiclit:axeS ~~~.~IaGeÃ"Et?tll1oÃ;s 0
L ~'>>s ~~ia i?"'i.,4Gn+,:~= ;5f se.luÃ7~:t ricl1 J11ed1<`x, lT3h.`bb#t1oil i1f tutnto:" r;#':iswt1i'it':A'' i?.C}r. ~?T=uti4~?'2t
)i=2tli'+,.onit-mS$~1/]V].`-r~~~ HiZ:~l.l?~?A2}.,{1Ax'4~.~1L1A~~ ~~\? ~.L1.?$, 4\~'S.~\iS.i ?. };!F'i'~vfw~~~.2~:>~ t ~~4=1~ .t.=t]L:~.L+~,3 i.i_Iad s`i'.t,,Uh in :a23 effective Tc? Ã;e~:~.Ã~.?.mi. Vine kcnÃ..tics of fic tiÃ~?tÃwtuaÃc?r :-e~pmÃ4e ~1 ~:t:~=c: by p3T.:t.it<xm..l Al<.:Ã:~ded 3?3 cI'i vpu: ..C`.J .Ãi%tx +., ,a4s%i w .R?A' a potential Ini"J. effect" of dill>_ :iLlek:ofiN a cell p3.3l1Aeicaldon a,,wsay i:=o#.il,%i'7i?gPaC.l.1tc:x~.~l li}ildcd msa;=IC?p:3T'tit.les and DN;`^O E:,'iklst.',?l? 3c, I#a.C.id:spe.#tt..l.Fe:s .isÃ:t?.g the `s11el.ai3i?InL..i cell lIt?L: w.i.. Itx,,~i f<?r fivt consecutive days Ev#~t~:. a plate ,Ã\ to>. < ~ .1 ilJsi:t ~. =Xi~:la > ~~ )#. ~Ã~ days } ~~~ 2 ~` ~a4'lÃtK.x~:l . { ~S.) =i~d,~Ã~'~~.w! wY?zF ~w~-. ~=~'"~ analysis V'~
&nd worf: :;d0ed Ã'il 5tri'urn rich modia -a{,d individually on tziFiatar coIl-; of the smi.?e pl,:Ftc, 'l`~-le rz:stFfts domorlstrate a dozt:w dopu~~deni : t~~i~?~~:<3 ~ .=:at:~: i1.: ad.F'flilffs:;:Nik?F.~ of s`cFds:a:Ye b-LÃt little t.fil"fl~FL;i1ei ti? ?:i3h?b4ii'sa; ft?...
vim dose on {s av 2 ~ s, i.iw {.1 3. {.~Ã1~..; .5. l~'f..~.9~~~ ~ ~'` j 3tt colia.~~~rm thl:{. ;Ft2-~+l1~,[i,5:4l ! >,i.~~v.rY"r~:{~~l~~o~ ~ ~Ã..-.
Cle:` iii}ixbià aÃ.unci~~=~ wr.3l;,vÃr3 qu>.ckly With littlc diffcronce .ir.
1Ãi..T1<3I C;=yipf} =aFÃ'1',. This is ctSÃ1S.sttv11t with u iT13:Ã11L3.i:;:Fe rL'a#:'.:3se +Ff C~ Llg i? ld 1:W21"s.3`i~'t bui?'St 3~ 'R '.~ic~.#~+G ~ic~ii3Cl~~ ~.+ pH:ci3~tC+. ~~,LYC1.sl~
3imopii.Fric,~-5 YvVle cI"C'.a{t'C?ct as ds:1st:.r`sbi:<:E.eÃ"C'.?Il wI:li tb?4 add::tÃE?s3 i?:~ Y.? t?F4Zt% i;3` t .:L;o#'t.4ci.:.lt N+,7n-;init3.~l QEL .[Ing c:1.F5cof A"t^+ff ce.as were \S...Ltd:',tÃ. onto a 96 Zot u:l p.c:te (20t..#00 oi,.[N Fvt:>laf and H3E.LFbaed o~(:t`:tight ~.¾~ `7, 'C .3iJi~3 5`1+) c::::bo.ii. (sioxidv, F`a`o mLd1;i wt3:~ th+.;: 3oÃ'ncnk:d ftt:[]1 rho W<`.HN .F11i? :'t phiced 'FZ`iF:h c. b'xFs_ti..ad. St:Il,:';; -ollÃI3o.n u4s?tlaini ÃgflE..(?i"Z:=Sc`1.'33~ niÃnC]p`c3rtÃt:lex at a ok7E:i.'~~'2trFft.<2{a of 0 5. 3 oa 5 IC43-;1tti3ls not S.tÃ`~tai.Ã17nff li's.3l1C7pr3 }1des 13'~C,Ãe also poI'for13iod. Afti'. at YY 'C tFÃi d 5% ~.b.3,;?~~~ dioxide ~.~~{~ 0.5j1 , 2, or 4 i~~s:}.F`~^, t~#::or{ (iv {:{.`; and the cells wcà :t .L :43'Ei:, weL~~lfffei'i.C3 >~Fl~Ã~~3~:'tkFlia
F.via.F;.~y4t:#.~ with 100 #<~.
`~ritaF#. X ..OWI{ in 0:.~.3. M sodfL3nn h 1tzri>l.Ãdo. Mfouhua1Ã1 , thC Qs.l;
sz.i m~.'~:~ ~c :+t,*,. ~~~ -.,.1FonW,,Fv+~~??4npth 470 x3iit,i'.nnd4Sao3{'Sts;C2i F?Ã.~. 5 18 nI..3 `ai3i>
20 cof~'.T3i,`-.F.{;:P.g it? a standard i:=taI L o g:ivi;. the concentration t:& I3~{1~:~)3{Ã:E C~:. ahs'
Thc cells iiC3~F w[a ;.F~%F~ c$y:?IS upi.3.k^v over fim~= il%3d.'L'1`";tll decreased z? m'..1~,~.?=-lrtlc_Fe i,oncoitr Foot;. .:i the buffm
I-tal.F=o 25 Ceii aiiie (MSrl`O-211 1-1) is fniaub~,k:t>ia f _1" C' with NAR:M
(w.Lt"i 10% f4sa..ba?-v::3c s4roÃ'11 (FBS), I% ossc.t7.t.tal a?nd 3c? :>cI&,
w.th ',. ~(giutami-n_G (Per-i, Strep), F-3.2 HAM (ixi:h 10'.:n .fiBS a.Fi f~ .~,.~:~) and LN,11.:~:~ (~~~It:~ t~~"k3S ;~~~~~. 1% en/St.ep) Ã;ne:al~F rim,,pczs:.ve ;~ wiffi, ~lo~;i~i~ i.b.'1..Eli`;w=s C>.#:3o[; ovC,'.:`yr' .b!=oC' :]<3ys, 4d,%hc::i1IlC?t cultured, iFit a,N.ls#nF:uni tr Nn.. :i:oT.~F: i>`Ã 30 R'.t+W: .ÃAE.. fF:?g Ãi.odha at -80, 'C (wi1}? 40% RIFMI aF{d H)t, daF.w.hyl s.31f}_~xiz:e.
(DMSO)) Col.. 3ir{eta W3:.ro t{ypsa{'{1.: od f1C}na 15 cm plt3te:a and `'~.`.t'ded FI,ei1 9{`.F 3x<t.~: pl;Ãi.us of z000 c6h, per wL.l1.. All cÃ:ll were cu:tn;red tor a II>L~nod of at least lti,Ge &,ys bdfibrk bviag Iest,;>f; in oe1l pr,_ali#eration. aSsavl-".
-c ~ zf.i~~L.F'Ii:.3i.t;at I#i ~`?iFt3 '~'~L `~~~~SE?Ã~~af.3ÃF?Y1 :~F1 I2C5I F `c.al #i I itilh ~.e'i#~t Elf ~i.s `~t~`?r`
0:11, Tv>,.rth washed with sterile pht.Ysplhatz:hFiffired San rio t.PBSt and t.yps#,Fized:
r11':ic cells were thC.`:Ã: colÃ#i:.C.`l~ ,asiÃlg a ('C.iF:Fti.Ã' i;t)IJ33_te#.` :aF3d plated 3,000 L;el;:5 wc-fl #$, 96 > ~, p:ÃF SLs. (,;~~ls :Vs.RIE.. ,c = \d ''.3~ i..L1T .. a ;;Y~~t t13i= = 24f3 ~` ~'Y',~."., i, ? Sci ~.?4:t3~., ~` =~' 4~:x~:~i~~'`.~'~:~:c.Ãz ~?'i.t3 :4.,4:ted,
con ..E.ti}õ~~(hy#.F'+.rxy #..3ycerol 4i$i~3t3t?s3~~'Ell 2,L:Ã#~sEl3~z~~~6s'iswi #F-i#cri3p,1;:ldE:s t3-r VwnIL;;Ãi3xed
C?a`LF` ik `~EeI3z ~z: ~ ~ a , i, dzoxy ,1,lyF:~:,Ã'm?l ~.:~li~.tlc.~`:~ iÃ~ s:-~::?~?tC?~~~~C?,7t~=l x?F~;Y'f3~`ci`. ~~~~.i~~i ~a?~' ~I~,:~i iFay:
A po':rtus~ cQ-F3.'#ol #;<(?#:wI1?e:a IFBS iliGhe S3FTF:te 4mFcC #ixai:o.Elof FBS p.i+v1:i:#.d >sji" r;:l."zitÃ:.d + aw;ls. whiiv a TTF+. f' <I.t:vC: [:537-ft3'(3l lacked FBS, r=i.Lilie of ,..$k a.is>iF3.y ti-3e cells w~~rc IÃ:cWbaÃed with 50 xd of I x ..('h:azoI y: B1ue I ctrzrzo:;ui::F from.i: o tP?F+:F) d ?S,.o, h'S.d IFz ~I B S at 3:"C Ios";t1x' o b <`,Flip's. The
F.T]..dzC: w ;:ts ili F-ià w:j,ckit:d c3=3d a0 0 al #~A DNI'. +O ~; a1 ,`=,ld{t.W to oc.C=f# w03, I'T1e ni<1lti:.h were thie31 p,.,.,S..f. a ;?Ti .à shaking ds.Z 7:-:L'
x i#ru;~'. and ~~ ~d >l=: s t.~...~;xest ~. . 1le, =ps3t~~ ~iaG to ~tY ~c tlf,.:,.~ ~. :~3~? ?~ ~..,. ~~"~~.y , ~ i#~li. ~c'' Ã~a~~ , =+ ~ : F >~, ~ :~.:~1 1~t'~. ~#~-F~:. s;
1? lE#i~.i t.~Ã1i~Ã"ii~ #-~# ski,:' ~, ~..~z. .~'a.L'. ~7l:i:~S.:~i 3<'e.tÃ. 3l:~F ~~.~ f3x-F an ~..~.,.~ Sti 3`5:`i~~t # <LiI s~ <~v1F?. ~ i3.~ a
Wavf.'.l''~`.~Ã':g~1-F of 5 .'f? nam. .rh4 absi11`~.since 4'alf#,cs were i;:Ã}c*~t,nahzs.,d to values fi:t?#.:; a k1"ls:3wa'# nc~r~~~s~:~ of at: ~~>.?c~~ ce1l~. 1'lie cioGL of per.~ietrea~~~ at: :ih#c;-F 5~~~; of cells <f,~~::~:Ãl1~.~a
LD50, dete'f7Fa'#?'ÃeZ> to bi.' ~.~a1~~'eGt1 0.1-1;0 pgrnl:. A~~3~3 i3'.IÃ;#~{:Ux1 .? ~~.i#.3 <x ?f1f,},f?Fkt! pY'..na+..rY'e:fi"? :L?:FdC.'~d ili.vÃ'o~.?ti:rt`acli.s1well or -_.100 ;,22i 0"opFÃn t.;l exo.'h:f.r,`.3zbr of l: .le're nv+..6.'stiarv to EdnIc :t. pt.'..al%L.#'Q.YLd concentrations and ::elt CiC:i#:F:}2,
cFp7 oxLec?1`?fi_tzeL; tF fFtsT?? l lhns3;. tFn T:t3.f} .Iwr#3tv Cell P~'i?lifa::.rat#on .r~~~,tw;
3'i.`.Vint.T ffli~F1s a:(?i1i:iFI111:1`; 10- 3`, ydY't?X\%t`_=:.IYt"#.ptof.hGci:1", vva:...` cast s,2``itz? wlfo4 by ..f.'.pi;'Ma1I`g a P(5>'+`:TFer bi3lu ..Fw? S,'.oll?p:lsEd of poIy(:i':ec#.Ie 3Lim1 LarbtZF?sti . #;.C? ;k 5:-2?.p.i?l.3Litti,Ã.') Z"= mg3 $,50 ,.Alvf and ' i~00 J:i:;;)
Films we"I.'`v= l:?tpt}F>+.'d t}? *Ulttl<'si`.ia3let f:UIV,`o- radiation ovem3g}Ft :?r1F?A to 57+i.?.:g plc3.C:=ed F#?Fi? 12. õ'-w`:. plates containing 3,000 Lewis
LF`tbg F_;.FFc#.ni.3#2#3 (L3....;....) cells 3s.. '~ tLa z~~ ~, ~ `x:s Y a ~'x ..~. incubated 4 for . ~FiÃ:ay e:t~~4~FÃ`~:
= ,~~~;, z_~~iÃ~t ~il~~F: a~ ~~F~, -
h.sx.. (Fig. }) i`rLF'#i3iiti eFlow then i1.:asc'F.yvd fi3i viability
F:E:dnIF1F.H ~E~.`~.r~ T :of,::i?.h or },3:F'~?tC3Ã:#.?x5. Both ix~~~su:-c: prov:ded c+~~ecfiive imbibition of t.un:or {.=c.'1 prolifer.a:aon out to ~5 days a#3:~ 1-b:c ,.mt..i#.du4zw= xpf`3:.im pefli+:)d co#a:inued to effts:nv4ly k:3l., t:mi51 Leth, as late ~.~s, Day 30, B-t cE;#. Ar ctrisi3n,, exposure Ão films L<'3wa.1#eiFlg lit? dz wt,.',
ZuI.~t3:.3di,d .:bna 3 <.t31dea ':TAQ, s4allfe exposure i;t?iid?1#C)n<i lpp. tlef:ltc:d I:FiJ {,.ytoir`jxic d'fcc.s (tit(~ Fag. ; Ll"1a~ 3)These Fu4i.1l1s
#n{ii.~:SaaS.=thai;,`ur pol-YiiIei filf:ls cw:tliinit':g 10-=
4~f e.:=:n=i~,k :si.?,. w>:7.1a# ci.li;r for as long as Ãhi'ity days.
E"'l,it; 9 t. ~i2 .crrz ,' rrT{r T#.i#F s)T ~...N-tE~xiL~rt4' 3i~~.~~c.14.a~~t~'.r.e ~(r~~G~.. ~~~li,i?.3i.to'~.,.Gas;n; --- ------,~-.-
a"t. ` tualoi` z: tZH{ a'..i~.f~;~ i,, ~'~~~3i'tÃ,t: ~_,~_.~.. ~~ and 1~.~...~~4rr .., ~ .> :. ,~t~.~+-;c-x4~D0 ?: =. ; #.tab Y' tkw:i rn caI and..~~ 3~ (I ~, -16); anus offichoma (~~~~~Ilan NA STC3-21I l. 1 '1), b-r,:a~~ (b u1-n an M (" F") ] l-m Y.n,m,
v4f'1pha:fea3. Ee3..:L.s1#nt:E (LMS05) t, ano5:r:i wer.: i=:uttur453 at 37
C./ 5% {O' ti. the aRpri;pr,.i`=.'C:=
ink.adia supp;anuria.~ w-it;~ 10% I"e tl Bovine Ser~~in (FBS) and 1% 4;4th L-;;fi~ta;,nine, with Ãhe c=e,~-it:oil. ot TVIEN"l ;sic(fia wf~icli. a:.of#ta'..invicta I i~ssi:Ãlxlaj all:ino s?c1dt^; and I I~it~'IrIA.: of bswi:'i`,' xeis'.:#fi.Y. 11..:wEi ..,~Jf :ezrt 'i"....
scc.ded at of IMOi) ; L:_.C. B 16; AJ,49MST~ 21 1114, NC'-1+460.), S.S`;?:: {NIM ) or 10,000 (UN4S05) col1s wJ1 i#-itl) {)6-wel1. aysmy plates -i.n, f?.<I~~:A w ;.s:ab,tsta Oic appt:;pr.atc it:.ntir etr.: ,iEattng dc=n4.ity. Cells ,~'c,rc;' :,'o-cul"utcd fffit 7, days wiffi, paNliixt.SeEst7au~::.,a4 w;.Wd,{1nd;?aded :+-i]'ii=thyi ,~`^().4.;{3-t1 .iTT['t.F~4)xypl: 4i3vi }-i =3 dFZ>?<a#.e-5 i l :1l0$h,li metha+'. -plate il,iÃtt?paificze:, ffalbI'1L:~2itioi:i, dS,.xit,-:1'1bf..d t3b:#b=c',t. ~'~-4.fuZi'the 1ncubc~tiE3r, pLaI?_?d9
~t= z.~ ~ .~~4r.. ~.by ; ~ xfer viability :~.=~""1 :.~~~~~~'~~. .~~:~ Ã':LLC, t .~=. ~ Ã~~~. ~~.W.u~..~~.agw of'v~ia~~le cells using a P.. Sltftit. Co::i3'}to (culture cC?3?t.ial]ÃIbg no n.x.iCxs1.A:tt+..Te4;) to, rep.a.` .#..:i3.t if.i 0 'u i&, 1.6 4bo Js ;hw m;.c< for LLC and 17 Shows fc7r cxpt;i'l#:ls:nts.?3'1d ÃndÃE.ate thzit pa..^=fitM.xtJl~lCIaCEtad, butnot cell proliferation ior several dt-t_te-reait cancer jitter at a caÃ;.'cw=nÃ#'aÃÃonh as low l R+ mw<r#?;L of A]~rA} t~#t A 1 Ei.a l3 32 ~IUaE 4 ((:={371ti1I!`:iig:ippr(.)xk.m<3tf'ly 100 Fig n.3..: of .E'<S:lv``aila;<~l, LAJ.Isf'.:te1 witb, the IC.~(e of }?'. .<a peiL.=aft.tixt'l,+. 1`SG. IS :~bL?ws the antacid:a`:icor activity o.C pat:l.iti~xei l.,t<3dC:=d ?1<1:3opc3l..ciC': w"#ta7 LLC' cells in vft1`L?P =(all(:s[; i"#..sLalt: ;F:ld1c;3:te tA :1t. l3 #: po:STI i:?'`.^`.
~i..; c s e~i~e s(A e that c : ~ =,.l .i#$~ I an :~# ~ ~:.-i:c ` - `. can r to'v`>i v.`l,.<. F
C <xc, ~,='."i3'~,:.3 ~.t3t?l_C.~x'~#i` :~N?~. zi ~' :#l"
VrLfncVrr.ryell>>fo. .5uhta nt:ktp].+.t,to\!s of S.ti)..te, Ai*iy~a w`:bV3:4=!~'4 }2{~yi#K.}.i\fit3Wt.unden43s.= offfic"
x xq>j 4 L3. Ql..ad]ti:E3gfitif3i1 of ml4,d'C) ET k.....- ? ii
To ;L? ~'~ 5 '~~~<l~'L'. iÃal i"53~3iEi'~;i: =~1 `rkt:<icz3d71eltt to 1 lung it silii, p%di`d c 1 cs s:v~=: suEpLiIdi<.Ã. iii. Afimi?i3.i4 .:'vF-1 27 or water e1.11t~i f'=aci3 5t?(utl~alt was pad3dWd C;i?tt? thio Ff3..Vdc 7i#i.us4 R1# gs. h< t`.1e:<,3i..fingo,Y r=~e' t y~.._õ j ~= ~ ~'~.a :'x pleural ~~irdC~e ~iit cta'i~'+:' d.ltf r~t3:i~?C> ~t+,.r15.3+.~:~ ii:~i~ the percent of i3't~f#~:..i.,~F diavi`{:3;3~#.itlt\ vl., 4 T3i.Δti.i'mx#le.d a.:#81.id..; a 'L`.+o.ilftfi,;; i:i.;vinier. Ati(;r a one bol3..:' exposure tt5 PBS ~v$'ttiT?.w ilii' ?iAng, thL' 4up.'t"Ãaa';aÃ`z? ~'~Ss; rL'??dt?vi'd and cou.`itud foI' adhvs[',nt m:cropartdc:es; wC'.rc tht> t.fug;Ay fi?Esed tC? avoid cS)L1naT.:7gadRdE'.4d3'#"1 to f17i'a.
A73.3..e dc]t:~,.S..i flh4Yz lud.1,w, a:w i.?L` i.stmt ,?i:P ?ruz<.rt?pa1"t.z.,Se- : dhoT.'#.'t?g to lui1`~ WaN ou,11d by 'cd`<aaoi;g tho d'd?.FÃ:i~.~4:'1 of .n'icri?parE3.Jle:*
I rG`.G,..:iF'=d to .:he s3F,~e:i'~.lsZ$I.3.~1t. It was rdEfi.f~ that t}iGd'i; is a nnl#i;h .:1gl;.u pe7`4c.7t aft:ai..a3mon`~ 89.9 1 0) of :';?3.i1'r~,:,pa.tFcles loaded in .PlLii't3:71c NF12;
Y:.~,r.x3:t "vk#t..i tl:?w a? ~{?f`~1~ .Gtt; gel .
i?` ` ` "~~~.~ if. :3 : (28.3 " 2~~~~. .a ~ ]a '~S'~'7~.` ?`~~ to.?~o4L,~,.tkie.11.n:nti ~~t ~;t di.3,,~ 3 ~~''~3'~.s..:" }..S"``n'.l'~i'.5. ~ ~ f'z ~~(:i, in is tto-it#.5t#i::ally >;t,t?;#,`#m?i I ' 4051 and indicates that ?..dfl'iS..:ii\'e:, such as NT>.27 g~.`l o_tn tÃssuo, Such as :tili<} ttss.,:.
=___==___ _._ , .... ...~.... ........~A ......... ~~___~__
( j(750,000) were .~~~ Y \ t
H Carcinoma cells (fF~~.S.,1 Vb:~~1+d wafla os v, ibmm.[51D a . - . `. ii']iz~~~ ~':.:to:-3`a.~:Ãt~.~.~;l lf~?.<~.~~~c. ~ ~x~iGr,~p~i~Ãi~.le.s _<~i~ac:dt<~:~c~?c~sl,~ ~:~-. ~.:~7e`~~,f~ ~~~l~ce. It is
=itell i.;>aa:ei7.#.\ItL'`'d that this ;%tmi}r iit3Se I'C'sl\ilts :d1 a4bcE'slGdnct71:#:i tumor i.s:3dE3.1e. .v1$?7.II` 1 20 week wrt.l? Ã'::lpdd w;;'i?wah. requiring 4;~L%'#fii;e, witit7ed3 2- 33 wecks, tit t1'3e t3.ne following ir?,s.cfioii it 3r1i3'+ R)wid tt14tt t?aMor size Wck5 slgi7d#tcF. ,i;aly dc'~.~.'e._.sex? in ..Eni.:r?<.hs Ymo;vii :~:.
LXX colihand vs. iirLi. s..el5;2.oI3e. AE: c3.t.ai:cC;;
l`kiit~li}.;~ ~=~.'=?y~.IIi,:~.~ 3.8 0-9 `~.[`3s sx'`i~~dt~bis ~.1:~:.3 i~
y ~ r ~ =. ~ ~ -\ 1 \.,.. -} ~; ~ 1'~ - ..: '~ ~ l i~ by p 'S l (l t3w.t ld..~? z..a ,+sx.#,:~.a~3 ~..1~.. (tt} d~iZ.~L~ j i~~ i~zli~t~ ~ .~~- ~
I i3~1:~ (Day > : ~. i_ .05).
25 'I'~~c naajo..ty of PIT_tA-pac::.oxen loaded micropanicl:e treaml animals developed minimal ?<.vrdei'icc. f.5f :tm.aod or gyC?wrh. Nc; toxicity ffioi:f ni. fE,'d. 'flhlts> the data suggests that locally df;li ; t,Ã {.G ohe1;,isiht.T~:ipy via d'I3T::ri3piSl3'<,Tks Uan, deter ~~:Ã.'= gowa and i ie:i.`~ab?1sha:i2C;1:t of 1i.mg ca3"+ ..i):< .d'..; :Jx ' e :oI:i".z. us3C . taz`i;=aiis I~dC~t Gi. C3f twmor b3`T3pSiit?EtAtii?f?,
30 Fc33Fd'dca .t.'C2 i)-11.ciEbpk1.i'taGi't':4 were 1 5 ~.i.:n in d.1cEI:iC.te:`;, t:#,i?(?th, and 3aQk pu.io'~ity aiw~~'stix4 that they will ;Y1r3i11t{32Ã': i? di:li3t# x'G`l~' l l?d3 5i3s3r fa;?=.LL? ii=aF <:i~4 a ~??~?y ~+~.iÃ~;.~a tJS.
tFII;f:', If 1,. ..>itF3'?r'e1t4~ti tP?;i~. 4UI.?ci t?-liF?t?r~:.d4~il I s:;~'i'~ia~:s .:1 ti3e 5-10 zl?z .~~.?ii:l: :S stEl:x<1.tC:d to be abF.gi. a .` .i?.icF`l}paitxc" {:s per cell, .{z,l a" c{.Y_It *jwÃ;t:ià ; K aF~~ nF of ':oiz...:tt; ueUs a:Id tÃ:..?#.~'.i?:ii..i .iel:AE:Ã~Ci, z'FiÃ~.i+3w343.1tt:i;::5
CCC.',F'F"#t51:i;~~..cit4~ 1~~]itl a C~C`,~~'. of 1i~~t: f.33#.ffiÃ3?;i mF+.:i'z_Jp(I.dÃl :le,`~s i't?.iii'pictL'I <` inhibits gÃ'mvth iunf4 iS1a.?l.;ii3;.11ent C?fÃ'FfffFt?a Ã."cflk 71'1"a3I Ã&a;at3.on ta;s.zyS ..;,id z,r^;
Si'tJ i`?jixdEf.a:^ hc3ve iiz>o d`4'i.i3{3I?strai+'.d that the GC?iltaC?l
PLGA #.F-F1La{3'hSc rtFi ii <?iv. IFI.'~~:`~i and ti ifft{ywFt a k 4:Ã =.; vr, tumor 3?Fi.3wth.
E;Sis~~1 TaS ~, ~~.`~.na? TL1IF.zÃ)7 ~' q~7{?i7s4 C?f F3II?E3`ifAl'tl L~`r if#ZSS~ ~clt?t# ~i3ij t# le 1k ~`E f I# t3 --_ -- --- ------------ - ~--~-~---- ~------ -- -...___ .........,...
I.t`.I- fe..f'fii<:t`,S` of eftG:ÃTFf?t>1eF'G1py^lC?:id>õd F3imoptinJLles f`>Es,n Exea..7Fple 3~ were ~~valz.a"'vd i,: WÃ.l1-{~~tablistled sabcutaneou4 Lumox models. lot.s::. 11..C or hurn;:t:#
NIS''lO-2 _ 11-1, 0-atta::ET CeiÃ. 1:i-nek wore impiaiiz-<:d ii~~~i (,57BL6;~Y a-espt.s.:Ã:ivelT.'.
S?.lsi?e}'1sF{?f?:", were with {ai11.m l?i? af.d iFiu:3i?p._;::.AÃ.:`?L:s#iaii? tho s:. w#t7Ã. .imans.:3tt i lfs.`.*iFes of the bc-.ck C3: :,?,i(:i:: 13t?ih
A3:t.". ` ,h"`2:5 Ã.:It`r `, Z,~ ti,?'i?$.~ ~?c'~~. :Ek,a.,?Sil;
UFd sli:?w" # 2.5 I.33L'F`53f4'7 i3 p.mr':'.d) 'llC?se~'_, of aiiÃ?oÃ:+e$z'tzLlE.\ `e .`L.ic e'4s.Tuiarik-'& A"ziii:'#EFh,
??jected W?~:,i: i,a.`#?i?r cczh-, a.ont,?.n PBS's, tt3f?-if?T tv7fli
Iz.$E:I:.ficial dE-xie;, Ei;.e,.f?...z.,ed f::3I,cttc,:ni3i
Tumor Ã3~ lc?~iÃ~:~.~~ 3:~?1`. f.;#.ill{:~~l.F,url {;:~~1?~i~~~'1!:.~~}t71asI~f~C:_~ I:~G1nC:p3rirt~K Bae:i k4,'.{ i:~`}z. ~i:~ controls. .r$:'`ir~
was m;3nt:i.;I'4d :?ÃtrL'i.#..lkly, and i:1.F-#.lfTlais wC:I`Ã; 1h ~:*.i.Il.>r~,h` r(.'clchcd 2 cm if? >. zÃ.:, As 2#ikmti.. aitf''.~d C#i.
B bM3da :he high ilml I.{.~w doses oia pai: i.iiaxt`u`.E^3.63<ldE:<i fid8.cbiE3llz$l ?c.#1+3~3,.1`FL1~4 ,ikll#.~7?~ted w;:?'FÃ.FT gt'i~tt'fft 1n flf?ii'e (~.3 = }4?OS`?Y), and were F"?3i#if ?Ilt)"e 6FlCc`i2b e iF.:.?in even the pi3+,..,,ta?k.a:.l-lot:fdi:`,d b3.It Sat?Y?-'t x;?.inSF%e Ã'z:li;ligp..1.fiG=les. Thi`=se d'c`#.t;.; i.rctiTev dk.311.s`s.S;tA:3ts;~ that the v3t3 tu.?1C?r Ã..ffs'r.=t;> of
Piichiw".0-1Ã3:#-d6;;d a{F# :zi~???t:a niFlli?;?{arlit.,:i:;j s~..i:? }:ss t ii.;'~? t#'aa=a3s:t;.tes to ~{k~7?~ ;,; iG1 F~FÃ3 7~x ~#F ~#r~i t' <r #?1r`~~`# ii', F s~ (.<,
EC 1m3lu' 4i5' Ad7t;~,,.T Fl..7i ~a~' of St1beti~c~l7es.3bis ~~l~lyIF3k F #fT3? n`.zi..#tsF e~zs f 3 ~~
i~.*,:: r+ "t ~ .'~:{-l > .~~.',.~ ~.i~a " 3Ã:"# '~ aà 2..,i3 2 :,lz 1'": ~ ~~.i-71'~t1. G2L i.C,t:~ f ?i iyE- ~ ci71+`..~`~Fi`, i~i~.~`y# F } :F 'at t'K`z] ~ .cl:`l t\ ;~``~'`~; ~.:;r evaluated using i.Ã. Sub i,.3t.x:1{.[,ia:s ti]n14,?I` n?C}Q'.Ql, After lni~uobitsn . ..t ,..;~e..~r#aa.; ~..~:? + .Bi.<:E?
il?#.~;i.'~ ~~C?a. \iaÃ~Z C:.i<z :F.J.d :?k:i~#'? EiF:i the back of the
F'I?.f e.::i(wTaw prC ;:pod li, a ha s..FFon. .`al;. i#?:.s;:{3:i z?: i,.:'`s :'.nz made bc:.weGn thC shoulders :iFe J.t#G :. 17.0
d.li#'+'wA i.F;.ir. sY:tr, L?sz?c.'t @ed with ti pii3.d''C?f sterilized tweezers t(? :t7.c3..'3."w a s.l.i`z.=t.#i>..,Fed.at,E.:1
I?o2'kF:t. A }.4:ct;' of Gif#'ffI Ãzed" ptl ZiZ?s.:' fi I len dn{:d i.'+$? a ps'.'E1~--iirda:.iy2e strip (i?,S x 08 cm) wft~s inserted into the st1bÃ.:i..4a#?{:=Ãstts pC3e.ket with Fhu drug-loaded sÃdt, Ã,Ffthe fiII>? }`,lnod ijpward .i.,nv:FrfYs ii-ic ,L,,d to-ie IF.cisif?n was closed with 54) sutuFos. Nfi,x went 110-nit~~red Linz.~i futiv recÃ~~ven-A from anesthe5ia., given :wut.~gegic~ and w..:~0 housed un a SPF specific pAFl:-lorren 'guiudl4: "LFnirna.E facility. Two1}:zFYs worti adF.(.fwCid healing KZs>,t: f4fi?ai 750,000 I~at~ilJt= LLC tL~iTlit# s~o=ll `~"'T f~7~:`w` i~ C3 s17 = ~..:Fitixy i?:3 ti':q) of t}ic 1mp1ara:~C'~ fi`f-t3 'i'#,, a 27-guage n4i'.dlL,
TF:.~i:si`i ;~i2::'inc'~F5 iF';t3.F1tt33'~iF 3~~'s`.'t;3s~~' ~3=[3~~. z.EF#iY.:Fl;~ ii~~.T~.z"#.tChec].I3Fz:f. Fl.tFT:i3õi?x'i 2 a=f`? ff. 4 .{e. Funr39.i,F` .,1o~`rtb. didn<3t occur oL\w:c,p \?` ap{.3I` moA :.flh":ts >.Cs<difod w.Fi.,1 30bllw L~ ~": ~ {5~~'~:i}i1~~?`~E~~;1~"=41~ (10 1-icPT) ÃI~' any of ffiÃ?:
C>.%p..:'Ãmon,.:i` m..u (:`s'i.o #` :-3g. 14).
Th:h is #.x ci37?t.a#.sa ~.t~~ the tlli7:31?Y g7"owti3 ihF3t ocC"L.rn':_l directly on the 1..:11oi$ZieiE pC3l4':x#tF fflam IF': over 7 -5;#:t3 of th:, aIa?lIl'c3ls tested. .. .,a:aU
(,"~'T ,.ofE cli~d polymer alli11s did develop Lt#:I~..ois w.Fiii delayed fbt,E)'Z:-up bF> theso EFF3n+3i"s w4.:Ti. &Iwc t`ti .iF ti.le p,F FphC.#"=y of the pocket :iF,~d away ffim~.i the filiFl it, ei'; is>.i` Fig. I.'~?).
Fddit#t?:i tt:" '.b,. delay iF:: tumor appearance, Ihh.`'~s'C; F.i:Fl.F::t3TJ
W'L``,i `t. sFtx;i-1FfiCi.1.nt.,i. , iF..iS.l.,eF' in .#"I,e (p ~~, 5K ui~Sx:':'i312~, ~s:1c`3.it) `t i 14~ :~ Ã-~: f> 3 "f~1ti; Y-l 5.~` Ã~-(~~ 3 films st;>i=`~..I.L~:~ .Fig:~~~ t =C?t ~ ;C.~~~.YÃ.at.\ ÃA : Str y, l:l y"~ ~ 3`;La 13 Wnt)r i-r1Z3d~.'l.
?`3r > ~ ' ?: N..3~ {.~.. ~'lbF.`' . x 4 In ti4'}`xt?~.~Ft~ Ht¾t2:~a~gI1~~~ tl~F~t~ 1'~`~.s:~'~.ca i) ~. S~~.~?w~' Ã ~~'ti1~t~=~> <~
PC`i.i'F:?#c: fihnS were subcutaneously <,.inplaF'::ied ;3'.'3 fltr:i.= bi1& of finFc~:=
3~ or ~ rc ~. ~ . .~~3` under %IFFt.~:;:F':t:.~3i3 as described ~`~Os~.1:1. `~t_c3li E:E1i cis :;sMe~;~~a[~ i:.3L~~fvC;E#.i?E,.:I: that ccci~~~.to `. ~~ s{'II'l lt :~s~:d i~t~lyin:F -~ilfa?~, u>~1.~?a~3ec~ ~t~1yF~icr iii.Ã~s or s~~<2>3a . t, cFy ~xI~c.~ pockets ivi.re ~"',=['Ã:pwFF'('.(3 btJ.t Flt) film wi$.>i I3'F'1pliu]3.C'C.. 1~ll #.F-4. iJFt`.a3i were closed 1i Tta? 5-0 ;tut-u. ~,'. Th+`..# L`, was i1o t=,:4.Fduii.:t:'. t)f w)EFnf.Si drõlul;.L;cx`.t.,~. early or lt3 w (::[l) to s t.iq:;> :n u:iF.tF#':al's mat received lC?.:3ded or un:oi.:.dGd .iii.IT7s.
In adE..#ti~`f] ~.'1`~.`F"e wi'e~ Iz(? 25 dF.~".zL''re.Fai.:e ;r, 5"`."yfh`'I'f2%: or <L'ouF-id <r`,o3pC<i3:1:3.F2ci; ami3Ã:gc#.Flx"."11;3.l;s witi] r~'.Fhns 4CtÃ':sCIs s,.F.#nn,
Exc]ini~~~ ~~ Lote:il Dii1tF R<xe<zse of `>F 3eFxl.anc43us Pt7`ynFc 1`lffiF ~
#~` ii? ~a il drug .~.lft~.;ii1 of ~ .3Ek~~,: ti,<?C~:=tz ' p:sl.,,:F`F3:=:w i'~Fti(:. ~g~. SEI.~i;=.l~i~'~~E~~~~' IT,1~"~~i3~1~:~ .x~ . 30 `Fi1m5 :'~~ 1'41,0 ;.x.Fs ex< ~~~ned. PolyFner fitrns were subcutaneously
Fn .??.Am..z`. on traceback tsf C57BL/6 F1>iL'.5: LIFFfseT.':7;IleSt.ti.3eSF3:35 dest-t7bed abt')iCl. At weekly ;,nteF r w:s implilntx3bon of t..ie.'; fllms, 4h,: s+.:rrt?uT1dL$'1g tissues Weis ?1a2"vf:swLa. Tthe:L' #.3:~`~3.w;:r ?it..;':0 t:,::3:: in a filsi>iozl 's: w<? r ur+3_"+:I tA34 fi';FII and s`s?q,,il:i7(1a`.ily SC gpli;I1.tt:d cl. 3::-rITri d#4taFlcÃ. .'i aY2 ..sYO 3`i \>m t.i Lb 2. k i d 2Sq thus pro} h 4.i F. L Atf i~ saw fo[Si.J sc ts`me1 i F.at }ra}} oi:ts i.iii 1.f!_i r LicT)Ca.~ Ad
S_F1acefiYSn:. awriv fi.-L>na the dI33-3i;i3ded fit.E#n. ThC.> concentration lf',, the w:?.I~ d1ilt<'.=d at tzi4~ tea.`ik1;#s dusiafiLes was dheI% fx3+e:}i Iss[1o se FInL'..=Ilt L.#:?i:-Lg 1 aPF_:C for t1hC:. ti,?ct:Ãc i~I3i.:,; of fl `~"LL4~. The k'.`t"i:ldIt;$1t of drug t.(3nm;2tr$i:=.#o!? Y-v1i:h1#> z. 2 cia'. t.iamnacF of
Y' > t Y '~+'Yr~,T = + ~{,Y the :,La:~~.~.~ ~i3"t~~<~ film , ;<~~e tlaplotted to L..~Ã~~blisf~ t?~~. ci~=ti~~ r.L,lL,xs.~ ~.r~~c.~ :~~.z~ ug, <31st?,l?utim': zia;.o '.hi:= surrounding tissues in }'s'exo.
1.:K.'t1mpIti. 4~-.~: _ t#.ML?3= Roc1:#1'?''moL Model of ~#3'Ã3L ~~~i z~4=~
Lfti L~II'i~3 R>.5~cfi%~~,'+13
J'J)o svqppt`cs.,_~joji of twnor rey.urronie, by drug..toarJc.d nar,op.;r:iclz, an_~~ dlru~,:,_
loitded pol:.mgI fiims bit'C', also being examined a SsiF'#.g a well
L..s;..3~.`ll:.4wd .>t. 14ve,`r tE.J,ET:Ti>a:
to fA~4~ <~it~r( S1> ~'`~ > mZ?C3i:i (Qcr.Ci:3? ., .ai, A-n#aTho#'ai` Surg 80.1046'?i., 2005). ~?g1.,
Fl:ct; c3,1~=L: :a:.
tuA`.1oi' model w,.l..t,'w:=d if`: Iv7SiLLi1plC3 4,13, 750,000 Ã:Ã.1{ti' z_C.la`.s 4x'ac titier..:'..=tsi and i?flowl.ΔYl to T ~p..e tumor wi3_ti 4,kC`3;'iL~lftL'..Aa y #"e:iZ:ctt+i fl1_I'mijL a LO i,'.Ii1 #n~~:is.L?i3 p;...allyl ti, tits,'- tu711i3rand ght``. enuTc: ttu21o, is removed and ¾}.''o-s; Fn4isiC3I1+.?z`.sefa in control a$1in#:i.iks. Uffli..laded. or drug-loaded tlr.znopartli:le4 C)>
Po:ymer fi.tTis xl"S; applied
C).bÃL3 the I#...zl:,:i' bed Ltd L tip ~ ~ i.illE=#l~r#~ animals and the skin #:EaLis,<31.: `, :hiF2]_.3.a..y ?..Io,,wd.
Aniu-mada arc a..sL.sm1 b.wockIy.fL>> ele#ice of recu::-ent tumor gamwill v;lAi ,..h our pil:z~ st.aL.#Qw h3! e di.=mof']s ratei, occurs aggressively in i_431ArC3l animals "h.#t do nit i`ew.t.'~fW s~ru4,..}k,i,.sdod or P#.Zayme.#' fi9:mls.
Exs_Lit7olu 50 +TFi IniFÃxJI1t~33#Ec7l '4~L sL~a}1~ niL)i~i~^ ~`~~~i# i # with _ ________` :......... ._.---__T~
Pt3.vx~tax4''3"Loa'`l~F'4S.i Nl.
t ~' 3.h: abia~+` ~ i'~ r ~,at #,A#~L~~ ~ c) v>`~ ;3r~~.fed ?s #~L$s~t{3~ rfiUle :i to > ~ ` ii . ~.~.iii,=ii~ the Cr#'ow"i, ..r ?,{'..~,
ca;IbS :lE t.i%o wilhii? 01"#e >.3iil'i3pe7'xii>I#.cal ii.lv7td' has altso bot'.II us 11`", <l I~~i..3'lI1t~: mo{.Ftii~of vi''olle'3iiabiished :!~i vivo t{.i,L,~$ nno~ ~?.#r~: : f=` t
Tht'.fai:ca5.mivati SL1rK,. 1:32.117 9-88. 2006). Cultured
Y1iL:=sC,tuiG~~io#;.>i3u#.1:L`:: <;+,.il`~5 million M:? ,YO 21 11 ~'t .AY; :::o-iJ:tjGt .:d witl? '"a,.3a%=,tdtmt.l $ngc dLd ftiF3a.oR"'Eal a`cini)pc3rfi.cli?S 6u1a3L?.Y ce.l5 alone in P13S L?. tEiT:I3r with identical dt5:,4:, of loaded i1L3nf..nia.aZnz,# (1)t>z}--
xpa1?sÃl+ a z3ai?opbl#fit res ;ie.i1'ed <i i i?iitif?li for ttl..Tit?iig
QF~ic>ty %1,,ml IIFmf?pafticle it>x-jL'#.Ã'~~~ t-s;~~-s~:~::~i z~ ~:I >=.
1e 51: ~EMf?fFAÃ.~3s
L~-by \?l~.._l;3aftW }.IoffkiFc. fi.'f:.%.L=.F were cast otiiS..J gSLi4Js by ~epL?sal.[ Zt.f .~i poL;,`iIiV't r;+oluhi\}I~
comprised ,?i'pUl,1(stC,.ik':.C ~u~~Ji??227~f` `dJ t. t ~~?C?~fl~~C?~<L~ i ?'#? ~~ C~; 4~~,~?,,:>Ã1?M:.1:.Ã1~= L ?~3 pt)~i:#CT Ã~.v~~4Ca (100 ~#g). t25EIru a llaliriivY"Ãrx~t
O. ~ a`.1+,: .`9ok-Qr.. 4u ?C. ~i'~ ('SÃ. by il.t3w ev<$p<1:;Ãii3. over n7,+.,,ht, i1Ã'id then placed
Llnde;'.rL`ducei.,?xC.~s:".uI~fo.. 24 x:<3ua^s.
Prior ii;r. i'{Ti23Ela:g, the Fll`l1s wf?t'e, ci3:3l:i:d t4>tl7 7 lIi-n of
At3lPd. The ;.3hms e4 erc #:;=?.aaged is'^~?iYt` .1'#;,Δti .mi.11'... 01wi"o>? microscopy. f-T1e Starfal=C:s of the flim i3.ppearQd 4`.zE~oEYkh atsi `~oi'o1:i5 w,l~i fibrous-like i3'?ictm+Ni3:tu?'ff.'. As s}.lowt-}.iv'3 Fig,
S. cri.yS-:?Cddoal Ãnl":s;es tsEso revealed a D0,11--POri3US il-Aerial With Csfii;isÃent :hÃckiiusies thanol:ag oW. dl.. l,:agxh of 15 Examplo 52,~~
IZzr scanning electron microscope SENP :n.,,a~.img were prop4~rec by w li Ãir~g a smpte o~~`3' undSpa-mlicles, .s? a C:tni..eI:?,Ã.Tat.Ãor, :Jf U5 `Ã"'ig':alL waih dojE3Ã?iFed"11 wW.'e;a, A 10 ul. pd.?rt#i.Ã: of the d1h:Ã.Ld-sar-apl rvil5 tht:n. placed iSF:: a Clown ai?E.n.ÃI3:an "s-Au"Z fl'#e sa3?'fpies were coated 4<.t}? 15 Ãiza# 1 to,~~!' of
Au~"Pt. Sc7r?lpli.:-, we1'.i.. ;:hF:i3 1 .3. 'L;~'di i~.Ã~a a Zeiss ~?~,~P3.
>~~f E.3C:d'ii.ltz~? t`i lth.{t,:;:3: of ~l ~ r The image in ?. I ~i d~34'k~~s pz;.F.~i,:of'\ fe<3'1'l''a abmi .C? ;'.~~Ã,=.` microns SZT Ã:3G= pmt;:i L4S e3etwC;ei1 5 :3:[ld 20 `zI1lC:3.`i3ns.
N5T; Cf}x3t<3~~ ~i?.z} e~'~~~1~t1~`LÃ1c:?~
p;3>y-ÃI?er films Weri`.- ust i#;at~> ~5:x~3:+t1".~.~~~ .~~#Ã~ the contact c3:~7~rlt~ ;S~~~i';.s~:~~# ~'AI~~'i
W.Ã.'_e deÃei-mined i3.,,ÃEa4~ '3 Lentil.t .9.,:3'.t.?;iv
Ef;Ã~..7L?:.~~LÃ.1.~'`. ~.~:E.#ll~t.c.'~~. ranged .~:~4F#i:i 75 1J.:~~t'.
i`or i ;iai?`P.ti=, `hc i ol'1Ã<1vb aF~,oõ1Ã' of p4.?~.y4`v'to.~1i'i4~ acid 4 Ã"~~i31~i~tt.n. ::.;3 C C.a,4Ft~?c:LÃixe~~ i t3'ill
I i SK "Ã,aiw t:'Z?z3tt:C:t aiigiw~ of grl<.s':i is about 35r .
_--- --~ --------- --------- --------- ------__
Th a':?-:ial trt.t:n.'s#.F.iol:?s' of ead? Po:,``,dl??Cr were mi.:i`bsu1't:Ã.3 iÃSIL?<or t iftZ.ra'..' ..1a. 4t,aiin.S.ng i=~low il2t"tI'N. P?lymii5 Q{ mpt?st'd of <: ca(?rf?Aai tt?tli- <?ird beEl'!Zli??ti~v a1'~~c{~` tzI ~:Ã?rbz?maie m[3nC)i.ne.iS we.nm formed v.11th t1`si:.= Sfi.~,lli,;wÃng carbonate mole
Iflc,ctFiTI? _. 0,05. 0. 0.20,
V".of ~ ~ v 0,401, r).J~( 4.1,.LL t of )s\t Yi itf zo1 ksi !c}=~+~ y~cj\~k.i `q*~i.~s l. '} 41,c {<i~'4ta }[ C~~)={~ 'y .,i .) ~= t~~A E to.l #. `~yF ()q ~
s~,,.' Sly. 1.00. Y~{-'fliixy~ ¾ LV-4FS~~Z-:2.Cl.C y~k:t?.f}.~~~ `~i.l'~'~ l-
>~"ejtlliw;~;oÃ;i~rt~I<?~.i..'~=> lc.ia`FG:~~. {~S"?~3I;;1 2! ~s~ti 50'sC
Usa:a?E#iL. and f3T..ha a,.i1x741l,s'Y:7cx ~1,~...4= a.Ttt?IphoI:I's.
0`rilER EMBODIME NTSS
It. is to i?e ui?:day>t #oif thF:twh.i>``.e the nvt:nt1o#` has .zi;m dest.Pibei. j.. ~. Lcl.l.t_:t?D.
E'e'i:':T t:xt; dci:ffliEt> theri.~C-yf, til-hf! lz?IF=gt?iS-1g descttpI"it?ta is 1`:w: ded to iflustriite and Il ~. If.:.,~?: L1>?~. ~iC~~:?~~t~ of tz?a, i>?~~'~s`I,let.?Ã?~~, ~tr~Yli:~'? Ã~ <~:;tin.t; by LiAc scope of dFo qlpeTtded
Cla:if;s. OÃ:#i;rt#*pect", 'wdvw%ts, and mi3d.ific'c?t7.oriS c#.int;will.i?.E? flIke swpe of :lw 1olIt?zvir?g claims.