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1. WO2007140483 - FILMS AND PARTICLES

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[ EN ]

FILMS AND PARTICLES

CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Application Serial No. 60/809,334, filed on May 31, 2006, and U.S. Provisional Application Serial No. 6O/S44J22, filed on September 13, 2006, which are both incorporated herein by reference in their entirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH
This invention was made wit.1i Government support under U.S. Army Cooperative agreement Mo. DAMD- 17-02-2-0006. The Government has certain rights in. the in vention.

FIELD OF THE INVENTION
Provided herein are compounds and processes to prepare polymer based films, particles, gels, and related compositions, and processes for delivery of agents,

BACKGROUND OF THE INVEN TION
Medicine traditionally utilizes pharmacologic agents or surgical interventions for the treatment of disease. Specific targeting or localization of pharmacologic or biological agents to desired organs and tissues is a complex challenge. For example, cancer is a leading cause of death for both men and women in the United States (Jernal et *//., CA Cancer J . Clin., 56: ! 06-130, 2006). Current methods of cancer treatment include chemotherapy, radiation treatment, and surgical resection. As evidenced by high rates of cancer recurrence and low survival treatments of conditions such as cancer often remain relatively ineffective.
Other diseases and conditions which utilize drug deliver}1 technologies include immunological applications, pain control wound healing, infectious disease, transplants, and the development of vaccines. Potential drug candidates often present solubility, toxicity, and pharmacokinetic considerations. Thus, there is a widespread need for targeted and sustained delivery of therapeutic agents.

Certain polyesters, polycarbonates, and poϊyamides are biodegradable polymers with low toxicity and degradation properties. Such polymers include poly(ε-eaproiaeione.k poly(p-<1ioxanone), poly{trimethyiene carbonate), polyf amino acids), and most notably poly(glycolic add) and poly(Iactie aeid}(see, e.g., Agrawal of «/„
Biomaierials, 13:176-182, 1992; Attawia et aL, J. Biomed Mater. Res,, 29:1233-140, 1995; Heller et aL Adv. Drug Deliv. Rev., 54: 10154039, 2002; Miiier and Williams, Siomateήals, 8:129-137, 1987; and Athanasiou eϊ a!.. Arthroscopy, i4:?26-?37, 1998). These polymers are used in a variety of applications including the delivery of therapeutic agents. However, physical properties of the aforementioned polymers are often limited by monomer selection, polymerization techniques, and post -polymerization
modifications. Properties of interest include thermal transition temperatures, bulk strength, flexibility, elasticity, degradation, crystallinity, and hydrophobic* ty. When polymers are utilized tor in vivo applications, the physical properties of the materia] affect host response. Hence, a need exists for polymers and delivery systems with desired characteristics that are effective for treatment of diseases and conditions.

SUMMARY OF lISE INVENTION
The invention is based, at least in part, on the discover)' that certain polymer films and particles can be utilized therapeutically and/or cosmetically. For example, many of the films and particles described herein can. be ased for the controlled, localized, and sustained delivery of various agents for treatment of diseases and conditions. Provided herein are compounds and processes to prepare polymer based films, particles, gels, and related compositions, and processes for deliver)' of agents. Provided herein are polymeric films ant! particles that deliver one or more agents, such as one or more therapeutic agents, to a local site, where the release of the one or more agents from die film or particle is initiated by a ρϊ-1 change. Also provided are biodegradable polymers.

hi one aspect, the invention features oligomers or polymers having a repeat unit represented by Formula XX;



In such, oligomers or polymers, Q is selected from among O, S, Se, or NH; G 555 selected from among fee following structures:



R^ is selected from among hydrogen, a straight or branched alky], cycloalkyK an.'!, olefin, siiyl, alkylsilyl, aryisilyl, alkyiaryl, arylaikyi, or tluorocarbon chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryi olefin, silyl, alkyisiiyl, arylsilyK alkyiaryl, aryiafkyl, or tluorocarboπ chain is optioαaϋy substituted internally or terminally by one or more hydroxyl, hyάroxyetlier, oarboxyl, carboxyester, carboxyarnide,. amino, mono- or di~ substituted amino, thiol, tliioester, sulfate, phosphate, phosphorate, or halogen substitucnts; Rj is selected from among hydrogen, roethoxy, etlioxy, amino, a straight or branched αlkyl, cycfoalkyl, aryl, olefin, siiyl; alkyisiiyl, aryisilyl, alkyiaryl, or arylaikyi chain of 1-10 carbons; R^, Rs, and R^ are each independently selected from among a straight or branched alky!, cycloalkyl, aryϊ, olefin, siiyl alkylsijyl, arylsilyl, aikylaryh or arylalkyl chain of 1 ~I0 carbons; and R-? and Rg are each .independently selected from among hydrogen, a straight or branched alky L cycloalkyi, aryl, olefin, aSkyl&ryl, or aryϊalkyi chain of 1-50 carbons, wherein each alkyl, cycloalkyl, aryl, olefin, alkylaryL or arylalkyl chain is optionally substituted internally or terminally by one or more hydroxy 1, hydrαxyether, carboxyl, carboxyester, carboxyamide, ami.no, mono- or di-suhstiiuteά amino, thiol, thioester, sulfate, phosphate, phosph.onate, or halogen subsiitueins,
In some embodiments, the oligomers or polymers are represented by Formula XX':


In suub eiTibodiments, n is an integer from 2-750, and each oligomeric or polymeric chain has a terminal group, the terminal goup being selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
hi another aspect, the invention features oligomers or polymers, or portions thereof, that are represented by Formula XXL XXlI, XXOI, XXIV1 XXV? XXVl, XXVH, XXVfIi, XXIX, XXX, XXXI, XXXO5 XXXlIS, XXXIV, XXXV, XXXVI or XXXViI;



hi such oligomers or polymers, or portions thereof. Q' is independently selected from among O, S, Se, or NH; G1', Gt', avid G^' are each independently selected from among the following structures:

Gt' and G?.' arc not the same; R;' is selected from among a straight or branched alky!, cydoalkyt aiyL, olefin, si!yl, alkylsily!, arylsilyi.aikylaryL arylalkyl, or fluorocarhoπ chain of 3-50 carbons, wherein each alky], cydoalkyl, aryl, olefin., silyt alkylsily!, arylsiiyl , alkylaryi arylalkyl or Ouorocarbon chain is optionally substituted internally or terminally by one or more hydroxy! hydroxyethωr, earhoxyl, carboxyester,
carboxyamide, amino, mono- or di-subsiituted amino, thiol thioester, sulfate, pbosphst€-phosphυnate, or halogen substituents; or Rj' is selected from among po!y(etby!ene glycol), po!y(elhylene oxide), poly(hydroxyacid)), a carbohydrate, a protein, a polypeptide, an ammo acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a. polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor; or R-. 'is selected from among a photocrosslinkabΪK or ionicaliy crossϋfikable group; Ri' is selected from among hydrogen, a straight or branched alkyl, cycloalkyl, aryl, olefin, silyl, alkylsilyl, arylsiiyl, alkylaryl arylalkyl, or fluorocarbon chain of 1 -50 carbons. Each alkyl. cyeloalkyl, aryl, olefin, silyl, alkylsilyl, arylsilyl aikylaryl, arylalkyl, or Ouorocarbon chain is optionally substituted internally or terminally by one or more hydroxy!, hydroxyether, earboxyl, cai-boxyester,
carboxyamide, amino, mono- or di-substituied amino, thiol, thioester. sαiiate, phosphate, phosphorate, or halogen substituents; x and y axe each independently selected from an integer of 2-750; a is selected from an integer of 1-25; b is selected from an integer of I-14; c is selected from an integer of 1-14; and each, polymeric terminal group is selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, metals, alkanes, alkenes and alkyncs.

in another aspect, the invention features oligomers or polymers, or portions thereof, represented bv Formula XXXVIIf:



In such oligomers or polymers, or portions thereof, Q' is independently selected from among O, S, Se, or NH;

Gf is selected from among
or Rj'; R1' is selected from among a straight or branched alky), cyeloalkyl, aryl, olefin., silyl, alkylsiiyl, arylsilyl αlkylaryl arylalkys, or fluorocarbon chain of 3-50 carbons, wherein each alkyt eycloaikyl, aryl. olefin, silyl, alkylsilyl, aryisϋyl, alkylaryl, aryialkyi or tiuorocarboα chain is optionally substituted internally or terminally by one or more hydroxy], hydroxyetliers carboxyl, carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substitiients: or R;: ϊs selected from among poiy(ethyiene glycol), poly(ethy!enc oxide), po!y(hydroxyacid)), a carbohydrate., a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or HKA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor; or Rj 'is selected fro.ni among a phofoerusslinkahie or icmicaHy ctossiinkabie group; x and y are each independently selected from an integer of 2-750; e is selected from an Integer of 1 -8; and each polymeric terminal group is selected from amorsg amines, thiols, amides, phosphates, sulphates, hydroxides, metals, alkanes, alkenes and alkynes.

In another aspect, the invention features oligomers or polymers having a repeat unit represented by Formula XX;



In such oligomers or polymers G includes a first group that is convertible to a second group different from the first group at a pH at or below about 6.0, such as below about 5.5, 5,0 or 4.5; Rz is selected torn among hydrogen, a straight or branched alkyl.
cycloalkyl aryi, olefin, silyl, alkylsϋyl, arylsilyl, alkylaryl arylaikyl, or iϊuorocarbot) chain of 1-50 earboas. Each aikyl, cycloalkyl aryi, olefin, silyl, alkylsilyi, aryisilyl, alkylaryl, arylalkyl or fluorocarbon chain is optionally substituted internally or terminally by one or more hydroxy! hydroxyether, carboxyl, carboxyester, carboxyamide, amino, mono- or di-suhstivuted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen subatstuents: and Q is selected from among O, S, Se, or NH.
In another aspect, the invention features particles having a first volume and .including an oligomer or polymer having a repeat unit represented by Formula XX;



XX
In such particles, CJ includes a first group that is convertible to a second group different from the first group at a pH at or below about 6,0, such as below about 5.5, 5.0, or 4.5; R-.; is selected from among hydrogen, a straight or branched alkyl. cycløaikyl, aryi, olefin, silyl, alkylsiiyi, arylsilyl, aϊkyϊaryl, arylalkyl, or iluorocarbon chain of i-SO carbons. Each alky!, cyeloalkyi, aryS, olefin, silyl alkylsilyi, aryisi!yl; alkylaiyl, arylalkyl, or tluoroc&vbϋϊϊ dvdn Is optionally substituted internally or terminally by one or more hydroxy], hydroxyether, carboxyl, carboxyester, carboxyarøide, amino, mono- or di- substituted ammo, thiol, thioester, sulfate, phosphate, phosphomrte. or halogen substituents; and Q is selected from among O5 S, Sc, or NH, When the particle is placed in an environment having a pH at or below about 6.0, the particle increases in volume from the -first volume to a second volume that is more than two times the first volume after equilibrium is established.
Polymeric films or particles can include any oligomer or polymer described herein, In some instances, the polymeric particles include a first volume at a first pil ami a second -volume at a second pH, different from the from the first pli. For example, the second volume is IX or more greater than the first volume when the second pH is lower than the first v^U such as 4X or more greater than the first volume when the second pH is lower than the first pH, or SX or more greater than the first volume when the second pH is lower than the first pH,
Any Him or particle can include a therapeutic agent. For example, the agent can be a biologically active agent comprising one or more of an anti-cancer agent, an anti-hiotic, an anti-neoplastic agent, an analgesic, an angiogenic, or an agent that promotes wound healing.
For example, the particles can be used fur applying to one or more of the following: (i) a surgical resection margin, (ii) within a treated or untreated tumor or cavity, (iii) a target site of disease away from a surgical margin, and (iv) a lymph node. The particles or films can have one or more layers.
The particles can have a diameter or less than 500 nanometers, such as less than. 250 nanometers or less than 100 nanometers. For example, the particles can have a diameter of between about 1 nm and 2 microns.
Any of the particles described herein, can be applied at a first site, such as a surgical margin, and then are carried by She body to a second site downstream of the first site, such as a lymph node. In such uses, Jt is desirable that the particles have a diameter of less than about 250 nanometers, such as less than !00 nanometers, or even less than 50 nanometers.
In another aspect, (he Invention features applying any film or particle described herein to a site using sutures, staples, and/or adhesives,
Ln. another aspect the invention features applying any film or particle described herein Io treat pain, or to alter healing, e.g., to avoid scar formation.
Unless specific definitions are provided, e.g., as indicated below, the
nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, biochemistry, synthetic organic chemistry, and .medicinal and pharmaceutical chemistry described hereia are those known in the art. in the event that there is a plurality of definitions for terms herein, those in this section prevail
As used herein, the abbreviations for any protective groups, amino acids, and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IU PAC-IUB Commission on Biochemical
Nomenclature, Biochem., \ 1 :942-944 (1972).
As used herein, use of the singular includes the plural unless specifically stated otherwise. As used herein, "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including'"' as well as other forms, such as "includes," and "included," is not limiting.
As used herein, the terms "treating" or 'treatment" encompass either or both responsive laid prophylaxis measures, e.g., designed to inhibit, slow or delay the onset of a symptom of a disease or disorder, achieve a full or partial reduction of a symptom or disease state, and/or to alleviate, ameliorate, lessen, or cure a disease or disorder and/or its symptoms.
As used herein, amelioration of the symptoms of a particular disorder fay administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing oi" progression, or shortening of duration, whether permanent or temporary, lasting or transient thai can be attributed to or associated with administration of the compound or composition.
As used herein, the term "subject" is a human or an animal typically a mammal such as a cow, horse, dog, eat, pig, sheep, monkey, or other laboratory or domesticated animal. As used herein, the term "patient" includes human and animal subjects,
As used herein, the term "carrier"' refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation, of certain organic compounds into cells or tissues.

As used herein, the term "pharmaceutical composition" refers to a dϊrøύcal compound or composition capable of inducing a desired therapeutic effect, in a subject. l.n certain embodiments, a pharmaceutical composition contains an active agent, which is the agent that induces the desired therapeutic effect. The pharmaceutical composition can contain a prodrug of the compounds provided herein. In certain embodiments, a pharmaceutical composition contains inactive ingredients, such as, for example, carriers and exciplents.
As used herein, the term 'therapeutically effective amount" refers to an amouru of a pharmaceutical composition sufficient to achieve a desired therapeutic effect.
As used, herein, the term "pharmaceutically acceptable" refers to a fbrniuiation of a ccHTi pound that does not significantly abrogate the biological activity, a
pharmacological activity and/or other properties of the compound when the fonmϋateά compound is administered to a subject. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a subject.
As used herein, pharmaceutically acceptable derivatives of a compound include, but axe not limited to, salts, esters, cnol ethers, enoϊ esters, acεtals, ketals, orihoesteτs, hemiacerais, hemiketals, acids, bases, solvates, hydrates, PEGyiatioa, or prodrugs thereof. Such derivatives cars be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced can be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine sails, sucb as but not limited to chjorϋproeaine, choline, N^'-diberøyl-eihyienediamine, ammonia, dieihanoi amine and other hydroxyalkylarnines, ethylenediamine, N-mεJhylglucaminc, procaine, N-benzyl-phenethylamins, l-para-chloro-benxyl-2~pyrroiidm- I '-ylrøethyi-benziϊϊiidazoie, diethylamine and other alkylamines, piperazine and
tiis{hydroxyτnethyi)-aminomethanc; alkali metal sails, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited Io barium, calcium and magnesium; transition metal salts, such, as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disødiuni phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to
hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malaies, tartrates, citrates, aseorbates, succinates, hutvraies, valerates and fυmarates. Pharmaceutically acceptable esters include, bat are not limited to, alkyl, aikenyl . aikynyl. aryl., heteroaryi, araikyi. heteroaralkyi , cycloaikyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinie acids, sulfonic acids, sulilme acids and boronic acids. Pharmaceutically acceptable enol others include, but are not limited to, derivatives of formula C=C(OfI) where R is hydrogen, alky], alkenyi, aikynyl, aryl, heteroaryi, aralkyl, heteroaralkyi, eyeioaOcyl, or heterocyclyl.
Pharmaceutically acceptable røol esters include, but are not limited to, derivatives of formula OC(QC(O)R) where R is hydrogen, alkyl, aikenyl, aikynyl, aryl, heteroaryi aralkyl heteroaralkyi, cycioaikyl, or heterocyeϊyL Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or I to about 100, or 1 to about 10, or one to about 2, 3, or 4, solvent or water molecules.
"Alkyl" refers to an aliphatic hydrocarbon group which can be straight or branched having 1 to about 60 carbon atoms in the chain, and which preferably have about 6 to about 50 carbons in the chain. "Lower alkyl" refers to mi alkyl group having I to about 8 carbon atoms. "Higher alkyl" refers to an alkyl group having about IQ to about 20 carbon atoms. The alkyl group can be optionally substituted with one or more alkyl group substituents which can be the same or different, where "alkyl group substituem" includes halo, amino, aryl, hydroxy, alkoxy, aryloxy, alkyloxy, alkyithio, srylihio, aralkyloxy, aralkylthio, carboxy, alkoxycarbonyl, oxo and cycioaikyl. There can "be optionally inserted along the alkyl chain one or more oxygen, silicon, sulfur, or
substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is lower alkyl. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. Exemplary alky! groups include methyl, ethyl. i-propyL n-butyl, t-butyl, a-pentyl, heptyl octyi, cSecyl, dodecyi, trlάeeyl, tetradecyl, pentadecyl and hexadecyl. Useful alkyl groups include branched or straight chain alky I groups of 6 to 50 carbon, and also include the lower alkyl groups of 1 to about 4 carbons and the higher alkyl groups of about 12 to about 16 carbons.
"Aikenyl" refers to an alkyl group containing at least one carbon-carbon double bond. The aikenyl group can be optionally substituted with one or more "alkyl group substituents." Exemplary alkenyi groups include vinyl aliyl, rt-pentenyl, decεnyl, dodeeenyl, .etradecadienyl, heptadec-8-eti-l-yl and heptadec-8J i-dien-i -yt
" AIkynyr refers to an aikyl group containing a carbon-carbon triple bond. The ajkyπyi group can. be optionally substituted with one or more "alkyl group substitueαts." Exemplary alkyrsyl groups include ethyπyi propargyt n-pentyuyl, deeyrsyl, and dodecyrsyl, useful alkynyl groups include the lower alkynyl groups.
"Cycloalky!" refers to a non-aromatic mono- or trmltieyclie ring system of about 4 to about 10 carbon atoms. The cycioalkyl group can be optionally partially unsaturated, The eyeioalkyl grcmp can be also optionally substituted with an aryl group substilυent, oxo and/or aikylene. Representative monocyclic cycloalky 1 rings include cydopentyl, cyciohexyi, and cyelohcptyL Usetul muliicyclic cycloalkyi rings include sdamantyl, octahydroπaphtbyl, decalin, camphor, cannphane, and αoradamantyi.
"Aryl" refers to an aromatic earboeyciϊe radical containing about 6 to about IO carbon atoms. The aryl group can be optionally substituted with one or more aryl group substituents, which can be the same or different, where "aryl group substifeeπt" includes alkyl, alkenyi, alkynyl, aryl, aralkyl, hydroxy, alkoxy;
aralkoxy, earboxy, aroyl halo, nitro, trihalomethyl, cyano, alfcoxycarbonyl, aryloxycarboπyl, araikoxycarhonyl acyloxy, acyiamino, aroyiamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, rylthio, alkyltliio, slkylene, and -NRR', where R and R' are each independently hydrogen, alkyi, aryl, and aralkyl. Exemplary aryl groups include substituted or unsubstitutsci phenyl and substituted or urssubstituted naphthyl.
"Acyl" refers Io an aikyl -CO— group, wherein alkyl is as previously described. Exemplary acyl groups comprise alkyl of I to about 30 carbon atoms. Exemplary acyl groups also include acetyl, propaπoyi, 2-methyϊρrøparioyl, butanoyl, and pahυitoyl.
"Aroyl" means an aryl-CO- group, wherein ary! is as previously described.

Exemplary aroyl groups include benzoyl and 1 - and 2-naphthoy!.
"Alkoxy'1 refers Io an a!ky]-O-- group, wherein alkyl is as previously described. Exemplary alkoxy groups include rneihøxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and beptoxy.
"Aryloxy" refers to an aryi-O— group, wherein the aryl group is as previously described. Exemplary arylαxy groups include phenoxy and naphthoxy.

"Alkylthio" refers to an alkyl-S— group, wherein alky! is as previously described. Exemplary alkylthio groups include ineUiylthio, ethylthio, i-propylthio, and heptylthiα
''Arylthio" refers to an aryi-S-- group, wherein the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
"Aralkyl" refers to an aryl-alkyl— group, wherein aryl and alky! are as previously described. Exemplary aralkyl groups include benzyl, phemietbyl, and naphthylmethy],

"Aralkyloxy" refers to an aralkyl-O-- group, wherein the aralkyl group is as previously described. An exemplary aralkyloxy group is benzyloxy,
"Aralkyl&io" refers to an aralkyl-S— group, wherein the aralkyl gxoυp is as previously described. An exemplary aralkyithio group is beπzyithio.
"Diaikykrmno" refers to an -NRR' group, wherein each of R and R( is independently an alkyl group as previously described. Exemplary aikylamino groups include ethyhnethylamlno, dimetliylamino, aad diethylamiso.
" Alkoxycarbonyl" refers to mx aiky1-O~-CO- group. Exemplary aikoxycarbonyl groups include methoxycarbonyl, eihoxycarbonyl, butyioxycafbonyt, and t-buiyioxycarboπyi.
"Aryloxycarbony!" refers to an aryl-O-CO-- group. Bxempiary aryioxycarbonyl groups include phεrtoxy- and naphthoxy-cai'bonyl.
"Aralkoxycarbonyl" refers to an atalkyl-O— CO— group. An exemplary aralkoxycarbcniyl group is benzyϊoxycarbonyi.
"CarbajEnoyl" refers to an H2N- CO-- group.
"Alkylcarbamoyl" refers to a R1RN-CG- group, wherein one of R and R.' is hydrogen and the other of R and R' is alky! as previously described.
"Dialkylcarbamoy!" refers to RrRN-CO-~ group, wherein each of R mid R' is independently alkyl as previously described.
"Acyicrxy" refers to an acyl-O- group, wherein acyi is as previously described,

"Acylamino" refers to an acyl-NH— group, wherein acyi is as previously described,
"Aroyiamhio" refers to an aroyl-NH— group, wherein aroyl is as previously described.

"Aikyiene" refers to a straight or branched bivalent aliphatic hydrocarbon group having from \ io about 30 carbon atoms. The alkylene group can be straight, branched. or cyclic. The alkyiene group can be also optionally unsaturated and/or substituted with one or more ' alkyl group substitυeπts." There can be optionally inserted along the alkyiene group one or more oxygen, sulphur, or substituted or unsubstituted nitrogen atoms, wherein the nitrogen subsiituent is alkyl as previously described. [Exemplary atkylene groups include methylene (--C \-h~), ethylene (-CHrCH2-), propylene (--(CHj)3 ~), cydohexyicne (-C6Hj0 --), -CH-CH -CfI-CH-, -CH-CH-CHr-, --{C'F?.)j){Cib)tn", wherein n is an integer from about 1 to about 50 and m is an imeger from 0 to about 50, -(CIb)n-N(R)-(CHj)1V1 -, wherein each of m and Ώ is independently an integer from 0 to about. SO and R is hydrogen or aikyL methylencdioxy (—0™ Cl-K-O-), and eihyi&πedfexy
An alkyiene group can have about 2 to ahmn 3 carbon atoms and can further have 6-50 carbons.
"HaIo'' or "halide" refers to fluoride, chloride, bromide, or iodide.
The term "agent" includes without limitation, medicaments, vitamins, mineral supplements, substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness, substances that affect the structure or function of the body, or prodrugs, which become biologically active or .more active alter they have been placed irs a predetermined physiological environment.
A "bioactive agent" refers to an agent that is capable of exerting a biological effect in vitro and/or in vivo, The biological effect can be therapeutic irs nature. As used herein, "bioacuvε agent" refers also to a substance that is used in connection with an application that is diagnostic in nature, such as in methods for diagnosing the presence or absence of a disease m a patient. The bioactive agents can be neutral or positively or negatively charged. Examples of suitable bioactive agents include pharmaceuticals and drugs, cells, gases and gaseous precursors (e.g., O2)., synthetic organic molecules, proteins, enzymes, growth factors, vitamins, steroids, polyanions, nucleosides, nucleotides, polynucleotides, and diagnostic agents, such as contrast agents for use in connection with n*agnεtic resonance imaging, ultrasound, positron emission
txansmαgraphy, computed tomography, or other imaging modality of a patient.

"Genetic material" refers generally to nucleotides and polynucleotides, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The genetic material can be made by synthetic chemical methodology known to one of ordinary skill in the art, or by the use of recombinant technology, or by a combination of the two. The DNA and RNA can optionally comprise unnatural nucleotides and can be single or double stranded.

"Genetic material" refers also to sense and anti-sense DNA and UNA, that is, a nucleotide sequence that is complementary to a specific sequence of nucleotides in DN. A and/or RNA.
The polymers provided herein can be utilized therapeutically and/or cosmetically, For example, the polymers in any form described herein can be used to promote healing and/or that inhibit disease by targeting drug delivery to local and regional areas. The polymers provided herein can also be used for a variety of applications including, but not limited to, production of micro- and nanoparticl.es, films, coatings, sutures, and orthopedic materials. Such materials can be used to repair an injured tissue, organ., bone, or genetic defect Other uses of the polymers provided herein include treatment of early, late, or previously treated malignancies, pretreatrnent of malignancies or other condition as a sensitizes' to augment therapy of another agent such as with radiation sensitizers, avoidance of iocoregional lymph node metastasis, augmentation of local wound healing and decrease m infection, manipulation, of structure and abnormal scar formation, and for the treatment of post-operative pain. In certain embodiments, the polymers provided herein axe used to treat cancer. For example, the polymers provided herein can be used to treat various malignancies, e,g., lung, colon, prostate, pancreas, or breast cancer. For example, when a film carrying one or more therapeutic agents is utilized to treat a cancer, it can be stapled, sutured and/or glued in place, e.g., with a eyanoacryiate resin.
The polymers provided herein can also be used to deliver any agent. The agent can be in any pharmaceutically acceptable form, including pharmaceutically acceptable sails, A large number of pharmaceutical agents are known in the ait and are amenable for use in the pharmaceutical compositions of fee polymeric materials described herein. Acceptable agents include, but are not limited to, chemotherapeutie agents, such as radiosensstizers, receptor inhibitors and agonists or other antineoplastic agents; immune modulators and bloaetive agents, such as cytokines, growth factors, or steroids with or without the co-incorporation of tumor or pathogen antigens to increase fee antineoplastic response as a means of vaccine development; local anesthetic agents; antibiotics; or nucleic acids as a means of local gene therapy.
Unless otherwise defined, e.g., as above, all technical and scientific terms -used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent
applications, patents, and other references mentioned herein are incorporated by reference hi their entirety, unless noted otherwise. In case of conflict, the present specification, including definitions, will control. In addition, ihe materials, methods, and examples are illustrative only and not intended to be limiting.
Where reference is made to a URL or other such identifier or address, it understood that such identifiers can change and particular information on the internet, can come and go, but equivalent information can be found by searching the internet.
Reference thereto evidences the availability and public dissemination of such
information.
Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of subjects.
Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., dectroporation, lipo lection). Reactions and purification techniques can be performed, e.g., using kits according to manufacturer's specifications or as commonly accomplished in ihe an or as described herein. The foregoing techniques and procedures generally are performed according to conventional methods well known in the art and as described in various general and more specific .references that are cited and discussed throughout the present specification, See e.g., Sambrook et «/., Molecular Cloning; A Laboratory Manual {Id eti., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y. (1989).
Other features and advantages of the invention will be apparent ii'om the ibflowirsg detailed description, and .from the claims.

BRIEF FIGURE DESCRIPTION
FlG. 1 is a bar graph showing the number of cells after treatment with 10-hydroxycamptαthεciii loaded Sims, control films without lO-hydroxycamptothecin, blank films, and lϋ-hydroxycampiothecin alone.
FIG. 2 is a bar graph showing the rmraher of cells after treatment with 10-hydroxycampiotheein loaded films, control films without 10-hydroxycamρtothecin, blank ilims, arsd IG-hydroxycamptotheein alone.
FIG. 3 is a bar graph show-ing the cytotoxicity of po!y(g!yccro!-co-caprolactone} rsanopaπides,
FRX 4 is a bar graph showing the cytotoxicity of pϋiy(glycerol-co-caprohctone) iianopartidcs with 10% pac3iiaxei.
FiCf, 5 is a bar graph showing the cytotoxicity ofpoly(g!yccro]-co-capro]acione} naτκ>particks with 1 % p&clitaxeL
FIG. 6 is a graph showing the release of 1 Q-hydroxyearapiothecin from polyOauric, myristic, pahn Uic. or stearic glycerol eatrbonate-co-caproiactone) films.
FΪG. ? is a graph showing 10-hydroxycaπφiothecin release from polyCsiearic glycerol carbonate-co-caprolactone) films on pericardium strips.
FIGS, 8A and SB are scanning electron micrographs oi" 10-hydroxycaniptotliecin-ioaded poly(stearic glycerol carbonate-co~ε-capro!actone) films; FiG. SA shows the surfece of the film (scale bar =:: 3 microns), and FlG, SB shows the film in cross-section (scale bar ™ 10 microns).
FlG. 9 is a graph showing particle swelling at various pHs.
FlG, 1C) is a graph showing the deproteclioii observed by absorbance using IJV/Vis spectroscopy at a wavelength of 292 nm.
FIG, 1 1 is a scanning electron microscope (SEM) image of πanoparticks.
FICs. 12 is a graph of the diameter of sugar derived mmospheres at various pHs, [1ICs. 13 is a bar graph showing tumor volume in response to chemotherapy-loaded πanopariides.
FiG. 14 is a bar graph showing tumor volume in response to subcutaneous polymer iϊim implantation.

FIG. 15 Ls a bar graph showing the percentage of turaor growth in response to loaded 10-HC PT and unloaded films.
FfG. 16 is a bar graph showing the anti-cancer activity of paclitaxei baded nanopartieles with LLC (king cancer) cells in vitro.
FIG. 17 is a bar graph showing the activity of paciitaxεl loaded iianoparticles with mesothelioma cells ia vitro,
FIG. 13 is a bar graph showing the anti-cancer activity of pacliiaxεl loaded naπαpartides with A459 human lung cancer cells in vitro.

DETAILED DESCRIPTION
Provided herein are compounds and processes to prepare polymer based films, particles, gels, and related compositions, and processes for delivering agents. The following describes the synthesis of monomer units and the polymerisation of those monomer units. Also provided is the synthesis of polymeric structures that incorporate therapeutic agents and methods of using such compositions to treat various diseases and disorders.
We will iϊrsi describe vinyl monomers that can be used in making the new polymers, as well as methods of synthesizing the monomers. We will then describe methods of preparing and using the polymers, "Then, we will describe the preparation of iiirns and particles, as well as the incorporation of agents into polymeric structures. Finally, we will discuss the applications of the polymers and polymer-agent
combinations.

A. Vinyl Monomer Units
As shown below, various vinyl monomer units are disclosed herein. These monomer units art- used to prepare polymers, as described in further detail below. V in; v monomer units include compounds of Formula 1, II, and Ui:

where each Q is independently selected from among O, S5 Se, or NH;
CL or G and Q together, are selected from among:


< or R:;
R5 is selected from among a straight or branched alky!, cycioalkyl, aryl, olefin, sih-1, alkylsilyL arylsilyl, alkylaryt aryMkyl, or fiυorocarbon chain of 3-50 carbons, wherein each alky L cycloalky], aryl, olefin, siiyl alky!si!yl5 arylsilyl, alkylaryl, aryialkyi, or rluorocarbon chain is optionally substituted internally or terminally by one or more hydroxy), hydroxyethεr, carboxyl, earboxyester, carboxyamide, amino, mono- or di-sαbstjtiued amino, thiol, tliioester, sulfate, phosphate, phosphonate, or halogen substitueϊUs; ov
R5 is selected from among poiyCethylene glycol), poiy{ ethylene oxide), poly(hydroxyacid)}, a carbohydrate, a protein, a polypeptide, aa amines acid, a nucleic acid, a nucleotide, a polynucleotide, any genetic material, such as a DNA or RNA segment, a lipid, a polysaccharide, an antibody, a pharmaceutical agent, or any epitope for a biological receptor; or
Rj is selected from among a photocrossliπkabte or kmically crosslinkable group; or
R; comprises a first group that "is convertible to a second group different from the IJrst group at a pH at or below about 6.0;
R-j is selected from among hydrogen, a straight or branched alkyl, cydoaLkyL aryϊ, olefin, silyi, aikyisilyl, arylsilyt alkylaryi aryialkyl or fluoroearbon chain of 1-50 carbons, wherein the alkyl, cycloaikyi, aryl, olefin, silyl, alk>-lsilyU arylsliyi, aikylaryi, arylalkyl or tluorocarfaoti chain is optionally substituted iπtenially or terrairsaliy by one or more hydroxy!, hydroxyether, carboxyl, carboxyesfer, carbo.xyaoiide> aπήno, mono- or di -substituted amino, thiol, thioester, sulfate, phosphate, phosphonate, or halogen substituents; and
R" % is selected from among a straight or branched alkyl, cycloaikyl, aryl, olefin, silyl, aikyisilyl aryjsilyi alkylaryl, arylalkyi, or flυorocarbon chain of 1-50 carbons, wherein the alkyl, eyeloalkyi, aryl, olefin, silyl, aikyisilyl, arylsiiyS, alkylarΛ-l arylalkyl, or fkiorocarbon chain is optionally substituted internally or terminally by one or more hydroxy!, hydroxyether, carboxyl, earboxyester, earboxyamide, amino, mono- or di-substituted amino, thiol, thiocstcr, sulfate, phosphate, phosphonate, or halogen substituenLs.
in certain embodiments, a compound of Formula Il is selected from among a compound shown below:





where R. ''S and G are independently selected as defined herein.
hi certain embodiments, the compound of Formula IHs a compound of Formula IV, where Q is oxygen. In certain embodiments, the compound of Formula ϊϊ is a compound of Formula V, where Q is sulfur, hi certain embodiments., the compound of Formula Il is a compound of Formula VS, where Q is Se. In certain embodiments, the compound of Formula II is a compound of Formula VO, where Q is NFL
In other embodiments, a compound of Formula HI is selected from among a compound Formula VI!!, IX, X, or Xl, as shown above. In certain embodiments, the compound of Formula 111 is a compound of Formula VIIf where Q is oxygen, in certain embodiments, ihe compound of Formula II! is a compound of Formula IX, where Q is sulfur. In certain embodiments, the compound of Formula 111 is a compound of Formula X, where Q is Se. in certain embodiments, the compound of Formula III is a compound of Formula XI, where Q is NH,
Sn other embodiments, a compound of Formula II. is selected from among a compound Formula XlI, XiLI, or XIV, as shown below;





where R"? and G are independently selected as defined herein,
In certain embodiments, the compound of Formula H is a compound of Formula XIL in certain embodiments, the compound of Formula Ii is a compound of Formula XML Irs certain embodiments, the compound of Formula II is a compound of Formula XlV.
A compound of Formula Hi can also be independently selected from among a compound of Formula XY, XVI, or XVU, as shown above.
In certain embodiments, each G group is selected from among a group shown beiow:



where each Q is independently selected from among O, S, Sc, or Nil;
R.; is selected from among hydrogen, methoxy, ethoxy, amino, a straight or branched alkyh cydoaikyi, aryl, olefin, silyl, alkylsilvl, aryisiivL alkylar>1, or aryialkyl δ chain of I - 10 carbons;
R4 and R5 are each independently selected from among a straight or branched aJkyl, cycloalkyl, aryl, olefin, silyL alkylsilyl, aryisiiyl, alkylaryl, or arvlalkyl chain of 1 - ! O carbons; and
R 7 is selected from among hydrogen, a straight or branched alky],
0 cydoaikyi, aryl, olefin, alkyϊaryl, or aryialkyl chain of 1-50 carbons, wherein the aikyi eydoalkyl, aryi, olefin, alkylaryl, or arylalkyl chain is optionally substituted internally or terminally by one or more hydroxy!, hyciroxyether. earboxyl, earboxyester, carboxyamide, amino, mono- or di- substituted amino, thiol thioester, sulfate, phosphate, phosphonate, or halogen siibstituents.
In certain embodiments, each G group is selected from among a group shown below:



where each Q, R4, and R5 are each independently selected as defined herein.
In certain embodiments, each G group is selected from among a group shown below:



where each Q, R-.:, R^, R,i, !I5, mid R? ai-e selected as defined herein;
R<, is selected from among a straight or branched aikyl cycioaikyl, aryl olefin, silyl, aikylsϋy!, arylsiiyi, alkyhiryl, or aryl aikyl chain of 1-10 carbons; and
Rg is selected from among hydrogen, a straight or branched aikyl, cycioaikyl, aryL olefin, alkykryl, or aryialky] chain of 1 -50 carbons, wherein the aikyl, cycioaikyl, aryl, olefin, alkykryi, ur aryklkyl chain is optionally substituted internally or terminally by one or more hydroxy!, bydroxyether, carboxyl, carboxyester, carboxyaitiide, amino, mono- or di-substitutcd amino, thiol, thioester, sulfate, phosphate, phosphoαate, or halogen subsiituents.
in certain embodiments, each C5 giOiip is selected from among a group shown below:



where esch Q, Ra, R4, and R? are indqiendentiy selected as defined herein.
In certain embodiments, R?. of Formula ϊ is selected from among hydrogen, Cj-CV; alkyl. cycioaikyl, alkyjcycloalkyl, ary!, ajid heteroaryl. Sn certain embodiments, R2 of Fomiϋia i is selected from among CrC2O alkyl, cydoaJkyl, ary L and heteroaryl. hi certain embodiments, the R? of Fonmiia I is selected from among any group shown beSovv:

In certain embodiments, RΪ of Formula ! is selected from among. t'VC-ao alkyK CJ-CJO haloaiky), heteroaiky!, cycioalkyl, alkylcycioalkyl, aryi. and heteroaryi, wherein the alkyi, lialoalkyt hsierøaikyl, cycloalkyl, aϊkylcycloalkyl, aryl, and beieroaryl axe optionally substituted, ϊn certain embodiments, Ih of Formula i is selected from among Cj-Cji! alky], whereiu die alkyl is optionally substituted with halo, OH, HHi, NH(Ci^)5 N(CIiOo, or ODOIl In certain embodiments, the R2 of Formula I is selected from among any group shown below;

B, Methods of Synthesizing Vinyl Monomer Units
As shown below, lhe vinyl monomer units described herein can, e.g., be synthesized by reacting a compound of Formula I' to provide a compound of Formula I;


"HLG"
where each Q, G, or Q and G together, and R? are independently selected as defined herein;
and LG is a leaving group such as Cl or Br.
in one embodiment, a compound of Formula .HQO, where Q and G are as defined herein, is dissolved in a solvent such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, diohloromcthane, 1,4-dioxane, tetrahydrolunm (THF), acetone, acetonitπle (MeCN), di∑υethylførrøainide (DMF), diinethyl sulfoxide, acetic acid, n-butanol, isopropanol, π-propanol, ethanol, methanol or water. In certain embodiments, a compound of Formula HQG is dissolved is THF. To this solution is added an acryloyl halidc, such as methaeryioyi chloride. In certain embodiments a base, such as a trialkyl amine (e.g. triethylamine), is added to the reaction mixture. The resulting product is a compound of Formula L
in another embodiment, a compound of Formula ! is prepared by reacting a compound of Formula HQG, where Q and G are defined as above, with an aery! anhydride, such as mcthacrylic anhydride, in the presence of a base, such as triethy! amine.

C. Methods of Polymerizing V'inyi Monomer Units
As shown below, a compound of Formula I can be polymerized to yield a compound of Formula XX:

where each Q, G5 or G and Q together, and R2 are independently selected as defined her«π>;
and n is an integer from 2-750; and
each polymeric terminal group is selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, alkenes, and alkynes.
Any method of vinyl polymerization known in the art can be used for this reaction. For example, a compound of Formula 1 can be reacted with a free-radical initiator. Free-radical initiators include halogen molecules, such as Cl^, azo compounds, such as 212>-azohis(2-methylpropu>nitriϊe) (AIBN), and organic peroxides, such as di-t-butylperoxide. The polymerization can also be induced by light and a phøtoinitiator.
in one embodiment, a compound of Formula 1 is dissolved in a solvent, such as hexarse, benzene, toluene, diethyl ether, chloroform, ethyl acetate, dichloromeΛane. i.4-dioxaae, tetrahydrofuraπ (TlW), acetone, acetonitrile (MeCN). diniethylfbrmamide (DMF), or dimethyl sulfoxide, and reacted with AIBN to yield a compound of Formula XX.
In certain embodiments, the polymer of Formula XX is hydrophobic and contains a pH sensitive group. G groups that are pR sensitive can be selected from among the groups described herein. As shown above, polymers of Formula XXi can be obtained by acid catalyzed hydrolysis from polymers of Formula XX, which contain a pH sensitive srouo. An v method of acid catalyzed hvdrolvsis known in the art can be used for this transformation. For example, the hydrolysis can be realized by immersing the polymer of Formula XX into a hydrochloric acid solution. The pH of the solution can be between 0,1 and 6.5, In other embodiments, the pϊ~i of the solution is between 1 and 5, For example, the pH can be bdow about 6.0, 5.5, 5,(1 4.5 or 4,0, IR certain embodiments, the pH around 4. In other embodiments, the pi I sensitive group can be removed under basic conditions and/or can be cleaved enzymatically.
As shown above, the hydrophilic polymer of Formula XXI can increase in size as compared to the hydrophobic polymer of Formula XX. The increased size (S5) can be between 1.5 and 20 or more times the original size (Si). hi certain embodiments, the change m size from Sf to Sj is between 2 and 20 times, e.g., between $ and IS5 5 and 10, 2 and 4, or 8 and 10 times, the original size,

E. Additional Vinyl Monomers, Polymerizations, and Hydrolysis Conditions
As shown below, a compound, e.g., compound 1, 2, 3, 4, S, 6, 7, 8, 9, 10, 1.1, 1.2, 13, 14, 15, or 16. i.s polymerized alone or in combination with another monomer, to form a polymer, e.g., compound Ia, 2a, 3a, 4a, 5a, 6a, 7a5 Sa, 9a, 10a, J Ia, 12a, LIa, I4&, 15a, or 16a. Any method of polymerization described herein can be used for this transformation. For example, compound ϊ, 2, 3, 4, 5, 6, 7, 8, 9, ID, 11. 12, 13, 14, 15, or 16 can be reacted with a free-radical initiator, such as 2,2'~azobis(2-methy3propionitrik} (AIBN). The resulting compound Ia, 2a, 3a, 4a, 5a, 6a, 7a, 8a, 9a. 10a, ϊ Ia, 12s, 13a, 14a, ISa5 or 16a is generally a hydrophobic polymer with a pH sensitive group. Any method of aeκ.1 catalyzed hydrolysis known in the art can be used to cleave the pH sensitive group, as described herein. Enzymatic hydrolysis alone, or in combination with an acidic or basic solution, can also be used to cleave the group. For example, compound hi, 2a, 3a, 4a, Sa, 6a, 7a, 8a, 9a, 10a, 11a, 12a, 13a, 14a, 15a, or 16s can be immersed in a hydrochloric acid solution. The resulting compound Ib, 2b, 3b, 4b, Sb, 6fo, 9b, IiJb, lib, 12b, 13b, 14b, 15b, or 16b is a hydrophilic polymer and can increase in size between 1.5 and 20 or more times the original size of compound Ia, 2a, 3a, 4a, Ss, 6a, 7a, 8a, 9a, 10a, Ma, 12a, 13a, 14a, ISa, or 16a, respectively. Fur example, compound-la, 2a, 3a. 4a, 5a, 6a, 7a, 8a, 9a, ΪOa, .1Ia, 12a, 13a, 14a, 15a, or 16a can be exposed to an acidic solution for various periods of time. Longer periods of exposure can lead to greater swelling. Alternative methods of achieving gi eater growth include raising the temperature and lowering the pit. The degree to which the particle swells can be reduced by adding difuiictiona! crossiinkers. Difunetioπal crossliiikers include di-acryiaie species and provide crossiinking between ployiner chains that further restrict the size of the particle upon expansion.
Compounds 1, 2, 3, and 4 individually are polymerized to form a polymer, e.g., compound Ia, 2a, 3a, and 4a, as shown below:



where each Q, n, R->, Rj, R?, arid imnbal group are independently selects*.! as defined herein.
Compounds 5 and 6 are individually polymerized to form a polymer, e.g., compound Sa and 6a, as shown below;



where each Q, n, R^., R4, Rs, and temiinal group are independently selected as defined herein.
Compound 7 and 8 arc individually polymerized to form a polymer, e.g., eoTupound Iz and Sa, as shown below:



where each Q. n, R2, R4, R5. and terminal group are independently selected as defined herein.
Compounds 9 ami 10 axe individually polymerized to form a polymer, e.g., compound 9a and I Oa, as shown below;



9a



where each Q, π, R>, R4, R5, and terminal group are independently selected as defined herein.
Compounds H and 12 are individually polymerized to form a polymer, e.g., compound .! In and 12a, as shown below:



where each Q, n, R-?, 1^4, Rs, Rt- and terminal group arc indspemkrstiy selected as defined heroin.
Compounds 13 aixi 14 are isidividualiv polymerized to fbππ a polymer, e.g., compound !3a mά f4a, as shown below:



where each Q, n, R-:., R^, R?;, and terminal group are independently selected as defined herein,
€ompoimils 15 and 16 are individually polymerized to form a polymer, e.g., compound 15a and 16a, as shown below:



iε 1Sa 16b
where each Q, n> R^, R3, R4, Rs, R1, Rg, and termma! group are independently selected as cleilned herein.

Fv Vinyl Horaopolymers aod Copolymers
Provided herein are homopolymers preparal by polymerizing a compound of Formula I. In some embodiments, compounds of Formula i can be co-polymerized with any vinyl monomer described herein or known in the art. For example, Compound I cm be co-polymerked with Compound 2, Compound 3 CM be co -polymerized with any vinyl monomer known m the ait, for example .methyl methaerylate.
in other embodimentsf any compounds of Formula I can be co-polymerized with any vinyl monomer described herein or knυvvn in the art to produce a random copolymer, a block copolymer, alternating copolymer, or a graft copolymer using any methods known in the art.
In additional embodiments, any compound of Formula I can be co-poiwicrized with any vinyl monomer described herein or known in the art to yield a linear, branched, star, or comb polymer, again, using any methods known in me art.
Any ratio of a single monomer relative to another monomer can be used to form a copolymer. Different ratios of monomer units impart different physical and ehermoai properties to the copolymer. Properties of interest include, but are not limited to, thermal transition temperature, bulk strength, crystaliiniiy, flexibility, elasticity, and
hydrophobicity. Thus, by varying monomer ratios, it is possible to afford a copolymer with desired characteristics. For example, introduction of a bulky hydrophobic side group will make the polymer more hydrophobic and reduce the rate of hydrolysis, o
G, Additional Polymers s«cfe as Polyesters, Polyethers, and Polycarbonates
The following polyesters, poiyethers, polyether-esters, polyamides, polycarbonates, mid polyamino acids can be prepared according to the description provided below. These polymers can be used to make the films, particles, gels, and related compositions 0 described herein, and can be used, e.g., to deliver various agents, e.g., bioacti ve agents,

As shown below, ihe chemical structures of various new polymers having Formulas XXL XXi!, XXf If, and XXiV;


where each Q! is independently selected from among O, S, Se, or NH;
G', G5', and G2 are each independently selected from among:


or Ri'; wherein G5-' and CJ2' are not the same;
R;' is selected from among a straight or branched aikyi cycbalkyl, aryl, olefin, sijyl, alkylsilylj aryisilyl, aikyJaryi, aryl alkyl or fluorocarbon chain of 3-50 carbons, wherein the alkyl. eydøalkyi aryl, olefin, siiyl, aikyisifyl, aryi siiyl, alkyiaryi arylalky! or ihiorocarhon chain is optionally substituted internally or terminally by one or more hydroxy!, hydroxyether, carboxyl. carboxyester, carboxyamide, amino, mono- or di-substituted amino, thiol, thioester, sulfate, phosphate, phosplionate, or halogen aubstituεnts; or
Rj' is selected from among poly(ethyiene glycol), poSy( ethylene oxide), poiy{hydroxyacid)). a carbohydrate, a protein, a polypeptide, an amino acid, a nucleic acid, a nucleotide, a polynucleotide, any DNA or RNA segment, a lipid, a
polysaccharide, an antibody, a pharmaceutical agent, or a«y epitope for a biological receptor; or
Rf' is selected from among a photocrosslinkable or ionically cross! inkablc group; or
R;' comprises a first group that is convertible to a second group different from the first group at a pϊ-l at or below about 6.0;
R->' is selected irons among hydrogen, a straight or branched alky!, eyeloalkyl, aryl olefin, siiy!, alkylsiiyl arylsilyl, alkyiaryl, arylalky!, or fluorocarbon chain of 1-50 carbons, wherein the alkyl, cydoalkyi, aryl, olefin, silyl, alkyisilyl, aryl siiyl, alkyiaryl, arylalkylj or iluorocarboα chain is optionally substituted iπtemaily or temiiπally by one or more hydroxy], hydroxyether, carboxyi, carboxyester, carboxyamide, amino, .mono- or di-substitiϊted amino, thiol, thioester, sulfate, phosphate, phosphorate, or halogen .substituents: x and y arc each independently selected from an Integer of 1-750; and
each polymeric terminal group h selected from among amines, thiols, amides, phosphates, sulphates, hydroxides, metals, alkalies, alkerses, and alkynes.
Also provided are compounds of Formula XXV and XXVI. as shown below;



where each Q\ C, s, y, and terminal group are independently selected as defined herein. Also provided arc compounds of Formula XXVIi XXVIII, XXIX, and XXX as shown below:



XXVΪO



where each Q\ G', R2', x, aid lei-iumai group are independently selected as defined herein: and
a is selected from an integer of 1-25.
Also provided are compounds of Formula XXXL XXXII, XXXl if, XXXIV. and XXXV, as shown below;



where each Qf. G', x, y. and teπniπaϊ group are iπdepeodently selected as defined; and b is selected from an integer of 1-14.
Also provided are compounds υf Formula XXXVI and XXXViI, as shown below:


where each Q'', G1,
x, y, and terminal group are independently selected as defined; and c is selected from an integer of 1-14.
In certain embodiments, the C of Formula XXi-XXXVH is selected from among any group shown below;



where each Q' and R5' are independently selected as defined herein.
In certain embodiments, each R1'. GΛ G2\ and G" group of any of Forniυla XXI-XXXVII is independently selected from among a group shown below:



h\ certain embodiments, each Rj', Gi'.G?', and G' group of any of Formula XXf XXXVH is independently selected from among a group shown below: In certain embodiments, each RV5 (V- Ga', and G' group of any of Forrnuia XXI-XXXVO b mdepsindeiitly selected from among a group as shown below:


where each Q- is independently selected from among CX S, Se, or NH.

in certain embodiments, each R;', G5', G2', and G' group of any of Formula XXI-XXXVIl is independently selected from among a group as shown below:


where each Q' is independently selected from among O, S, Se, or NH.
in certain embodiments, each R1 ', (V, G?\ and G' group of any of Formula XXl- XXXVO is independently selected from among a group as SIIOWB below;


where each Q' is independently selected from among O, S, Se, or NIL
In certain embodiments, each R5', Gj', G2', and Cr group of any of Formula XX! XXXVIi is independently selected from among a group as shown below;



where each Q' is hχ]epcrκienιly selected from among (X S, Se, or NH.
In certain embodiments, each Rs\ G;', G;>r; and G' group of any of Foπiiuia XX! XTXXVfI is independently selected from among a group aa shown below:

πelhyi
elhys
isopropy

^ . "v. '^ -'^, ^,
'V.'-'^ -'V... ""^v ' X^'N- 'V- 'V-'' V,

.-'\-'^^'
-X' Nv V -'-

" V^-'V^'-V

Mo
,'- ,Sk
-Me




bi'K-yv,

where each Q', Q\ x, y, and terminal group is independently selected as defined herein; and e is Si-lected from an integer of 2-8.
hi various embodiments, the compounds of Formula XXXVIIl can be a random copolymer, a block copolymer, alternating copolymer, or a graft copolymer.
In one embodiment, the compound of Formula XXXVlO is a compound of Formula XXXIX, as shown below:



where each Q', (]', x, y, and ievminaJ group are independently selected as defined herem. In certain embodiments, the compound of Formula XXXYOI is selected from among a compound of Formula XL, XLl, XLIL or XLIIL as shown below;



where each G', x, y. ami tεπrαnal group are independently selected as defined herein, hi certain εmbodinierste, a compound of Formula XXXVIII is selected from among a compound of Formula XL where Q' is oxygen. In certain embodiments, a compound of Formula XXXYIO is selected from among a compound of Formula XLI where Qf is sulfur. In certain embodiments, a compound of Formula XXXVf H Is seseeicd irom among a compound of Formula X LH, where Q' is Se, in certain embodiments, a compound of Formula XXXVIO is selected from among a compound of Formula XlJIL where Q' is NH.
In certain embodiments, the compound of Formula XXXVlII is selected from among a compound of. Formula XLlV, XLV, or XLVI, as shown below;





where each G!, x, y. and teπrUnal group are independently selected as defined herem,
In certain embodiments, a compound of Formula XXXViIi is selected from
among a compound of Formula XLiV, in certain embodiments, a compound of Formula 5 XXXVΪΠ is selected from among a compound of Formula XLV. In certain
embodiments, a compound of Formula XXXVlIl. is selected from among a compound of Formula XLVI.

TL Synthesis of Polymers of Formulas XXi - XLVI
10 Any method of polymerization can be used to produce the polymers of Formulas XX). - XLVi. For example, polymers of Formulas XXi-XL V] can be prepared by step- reaction polymerization, ring-opening polymerization, or by chain-reaction adduion polymerization. As shown below, a polymer of Formula XXXVIII can be prepared by ring-cφeϊimg polymerization of a lactone monomer and a carbonate monomer. The

I Fs product of this reaction is a polymer of Formula XXXVHI where Q1 is O, and C is
benzyl

where x, \\ e, and terminal group are independently selected as defined herein.
Any method of ring opening polymerization can be used for this reaction. For example, the ring opening polymerization may be induced by healing iliϋ reaction, in one embodiment, the reaction is catalyzed by a metal catalyst, such as Sn(OCi)2, The reaction can be performed neat, or in the presence of a solvent, such as toluene, dichloromeihanc, or diethyl ether. Any ratio of monomers can be used, for example, the ratio of carbonate ixionoraer to lactone .ncnomer can be I : i , 1:2, i :3, 1 :4, 1 :S, 1 :6, 1 :7S 1 ; S, 1 -9, or 1: 19,
Any ketone can be used for the polymerization shown above. As shown below, the lactone cars be a four, five, six, or seven membereii ring:



where x, y, e, and teπninal group are Independently selected as defined herein.
As shown above. Compound 17 is prepared by polymerizing a benxyloxy glycerol carbonate with oxetaϋ-2-onc;. Compound IH is prepared by polymerizing a bcnzyloxy glycerol carbonate with dihydrofuran-2(3H)-one. Compound 19 is prepared by polymerizing a benzyloxy glycerol carbonate with {eirahydro-2] f-pyτari-2-one.
Compound 20 is prepared by polymerizing a benzyloxy glycerol carbonate with oxepan-2-oτie.

L Chemical Moilifications of Polymers of Formulas XXI - XLVI
Polymers of Formulas XXI-XLVI, wherein G' is a protecting group, can be further modified to contain various side chains and pendant groups. For example, G' can be any protecting group known in the art, In some embodiments, G! is a benzyl ether or benzylideπe protecting group. Any method known m the art of adding a ^ide chain or pendant group to a polymer cars be used to modify the polymers of Formulas XXI-XLVL for example, a polymer of Formulas XXi - XLVΪ cm be modified to contain a side group selected from among a straight or branched alkyi, cycloalkyL aryl, olefin, siiyl, aikylsϋyl, aryLsilyJ, aikylaryl, arylaikyl or iluorocarbon chain of 3-50 carbons, wherein the aikyl, cycioalkyi aryt olefin, siiyl, aikylsilyϊ, arylsilyl, alkyϊaryl, arylaikyl or fluoroearbon cMm is optionally substituted infernally or terminally by one or more hydroxy!, hydfoxyetbcr, earboxyl, carboxyester, earboxyamide,, amino, mono- or di-sυbsiituted amino, thiol thioestεr, sulfate, phosphate, phosphorate, or halogen subsiituents.
Other sick chain groups can be seSccied from among pαiy(ethyiene glycol), poly{ ethylene oxide}, ρoly(hydroxyacid), a carbohytiraie, a protein, a polypeptide, an amino acid, a nuckic acid, a nucleotide, a polynucleotide, anv DKA or RNA seuτπeΩl a lipid, a polysaccharide, am antibody, a pharmaceutical agent, or any epitope for a biological receptor. Additionally, a functional side chain can be incorporated into a. polymer of any one of Formulas 'KXI-XLVl, such as a photocrossimkabk or ionicafly cross! i n kabl e gro u p.
One method of modifying a polymer of Formula XXXVIIl is shown below. The benzyl ether can be cleaved to afford a hydroxy! group. Any method of cleaving a benzyl ether known in the art can be used for this transformation. For example, the benzyl ether can be cleaved by catalytic hydrogenation. The resulting hydroxy! group can be reacted with reactaiits or reagents to produce the polymer of Formula XXXVI! I with a non-hydrogen G' group. Any method of reacting an alcohol known in the art caτi be used for this transformation .



In the compounds shown above s, y, e\ and the terminal group are independently selected as defined herein.

As shown beiow, the polymer of Formula XXXV1ΪI containing a hydroxy! muiεry ears be moduli αl to yield a polymer with various G' groups. For example, the alcohol can be reacted with a carboxyHc acid, such as stearic acid, oleic acid, or myπstk acid, In other embodiments, the alcohol is reacted with 6-bcnzyloxy-hexanoic acid, hexancciioic acid morsohenzyi ester, or imoc-6-amino-hexanαie acid. In various embodiments, the G' group is a carbonate, an ester, or an ether.



In the compounds shown above x, y, e, and the terniinal group are independently selected as defined herein; and g is selected from an integer of 1-25.
As shown below, a polymer containing a hydroxy! moiety can be modified to produce a polymer with various groups. For example, the alcohol can he reacted with a carboλyhc acid, such as stearic acid, oleic acid, or mytistic acid, in other embodiments, the alcohol is reacted with a bcnzyloxy-aikyl acid, a aikyl acid monoheπxyl ester, or a protected animo-aJkyi acid. The benzyloxy, mαnobenzy], and fhioe protecting groups can be removed by methods known in the art to produce at! alcohol, a carboxylic acid, or aπ amine, respectively.



!.n the corrs)K>unds shown above x, y, e, g> and the Icrminal group axe iiidepeadently selected as defined herein.

J. Methods of Forml»g Particles and Funis
Various types of films ami particles can be formal tium polymers ofFoπnuias XX-XLVI. As shown below, various types of films and particles, such as micro- or nanoparticks, can be made itom polynicrs of Formula XX and XXXVf II. Any of the polymeric lilms and panicles described herein can be made to incorporate bio&ctive, e.g.. therapeutic, agents within the polymer structure to produce a polyrner/agent complex. Any method known in ihe art can be used to form a polymer/agent complex from, the monomers and pυiyrners dcscribcπl herein.



In the compounds shown above, each Q1 Q:, G, G', t% R2, x, y, e, and terminal group are independently selected as de&ied herein.

Methods of Making Films
The polymers described herein can be used to produce fihns using techniques known in the art. For example, as shown above, a polymer of Formula XX or XXXVlII is dissolved in an organic solvent, e.g., dichloromethane, tetmhydrofuraπ, toluene, or an aqueous solution and deposited onto a solid surface, such as a glass surface. In certain embodiϊBcr:ts, the polymer is dissolved in a solvent along with an agent, sach as i 0-hydroxyeamptotl'secisi, and deposited onto a solid surface, such as a glass surface. The solvent is then allowed io evaporate to afford a polymeric film either at ambient temperature or pressure, or at elevated or reduced temperatures aud/or pressures. In certain embodiments, the polymer solution is deposited onto the solid surface using a syringe, e.g., a microsyringe. in oilier embodiments, the polymer solution is deposited onto the solid sorlace, e.g., glass, mica, polymer, collagen, pericardium, TEFLONCik metal, metal alloy, ceramic or an oxide, using a spraying device, such as an aerosol device. For example, films containing a polymer of Formula XX or XXXVIII can be formed by dissolving the polymer in an organic or aqueous solution, or a mixture of organic and aqueous solutions, and applying the solution to a surface.

in other embodiments, films containing a polymer of Formula XX or XXXVlH are formed by melting the polymer, 'The melted polymer can be applied to a solid surface, such as glass. In other embodiments, the polymer is applied to & solid surface and is then melted to form a polymeric film,
in certain embodiments, multi-layered films are prepared. For exanφk% a polymer is deposited onto a solid surface as described above to produce a film. A second polymeric solution is then deposited onto the first film. Polymer films of 1 , 2, 3, 4, 5, and 6, or more layers can be produced by this method, In other embodiments, each polymer film is produced from a polymer of Formula XX or XXXV 111, In another embodiment, 1 , 2, or 3 of the layers include a polymer of Formula XX or XXXVHL and either !, 2, or 3 other layers include a different polymer, such as polytiactic acid), poiyigiycohc acid), poly{iac-ie~eo-glycofic acid), polycaprolactonc, poly(triraeth!ene carbonate), polyester, polycarbonate, or polyamide.
The various layers or fillers can be selected to dissolve orbiodegrade at different rates to produce devices in which different agents are included in different layers and are released at different rates. For example, a first agent can be included in a first surface layer designed to provide a rapid release, e.g., within a few hours or days, and a second agent CM be included in a second layer designed to provide an extended release profile, e.g., 1 week, 2, 3, 4, 5 weeks, or even more. Alternatively, an other surface layer can be designed not to release any agent, but to m early delay release of agents in subsequent layers.
In c-sπain embodiments, a patterned polymer filrn is prepared by using a microprinter or a micro-syringe. For example, a microprinter or microsyringe can be used to deposit a solution containing a polymer of Formula XX or XXXVlH onto a solid surface, such as a glass surface. The microprinter or mkrosyringe deposits die solution in a controlled marmer to form patterns sυch as stripes and/or dots, 'flic solvent is removed by evaporation. This method ears be performed with more than one polymer simultaneously. A solution containing a polymer of Formula XX or XXXVlO and an agent such as 10~hydroxyeamptothecin, may he deposited onto a solid surface by this technique tυ a fiord a patterned agent containing film. Such patterned films can deliver agents to specific biological areas and tissues, aa determined by the specific pattern of agent loaded within a film.

The polymers described herein can be used to product; micro- or nanopartides using methods known m the art. For example, a water in oil emulsion technique is described by Edkmd and co-workers (see Edlund at aL, Adv. Polymer SeL 157:67-1 12, 2001 ; arsd Wang ei aL, Chem, Fharm. Bull,, (Tokyo) 44:1935, 1996). Briefly, a polymer is dissolved in dichioromethane using a vortexing device. !.π certain embodiments, the polymer is dissolved in dicbJorornethane along with an agent, such as paclitaxei. The solution is placed in a 5% polyvinyl alcohol surfactant and vortexed (or sonicated using a probe tip sonicator) and stirred for 16 hours to produce micropartides. The
niieroparήcles are collected and washed with distiileά/deionked water and lyophilized.
To produce isasioparticles, one can for example, use a minienmlsicn
polymerization method (see, e.g., Landfester et a!.n Maeromoleeules. 32:5222-8, 1999). Briefly, a monomer as described herein and a free-radical initiator (such as Ch, 2,2 ;-azobis{2-mclhyfpropionitriie) (AIBN), or di-t-bυtylperoxidc) are dissolved in a solvent, such as hexane, beαzene, toluene, diethyl ctlier, chloroiomi, ethyl acetate,
dieWoroniethaiie, 1,4-dioxane, tctr&liydrollsran (THF), acetone, acetonitriie (MeC'N), dimeihyifoπnaiiiide (DMF), or dimethyl sulfoxide. In certain embodiments, an agent, sudu as paclitaxei is also dissolved in the solvent. The solvent is removed via rotary evaporation uiUif a viscous mixture remains. The viscous mixture is mixed with a stabilizing surfactant, such as a solution of sodium dodecyl sulfate, m a buffer solution. This mixture is sonicated for 1 hour (I second pulses with a 2 second delay) \ύih 30 W of power, which forms die mimemuision and allows the solvent to evaporate. The mimemulsiøn is transferred into a temperature-controlled oil bath and stirred at 65 0C for 2 hours to initiate the free-radical polymerization. Optionally, the resulting polymeric smoospheres are dialyzed. e.g., against 5 raM pH 8 phosphate buffer, acdate buffer, bicarbonate buffer, or sodium citrate butler, e.g., over two days, to remove excess surfactant and salts.

Alternatively, nanoparticles can be produced by pbotoinitiation. For example, a monomer as described herein can be dissolved in a solvent, such as hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate, diehloromcthanε, 1 ,4-diαxane, tetrahydroiuran (THF), acetone, aeeiorritrite (MeCN), dimethylforrnam.de (DMF), or dimethyl sulfoxide. In certain embodiments, an agent, such as paelitaxeJ is also dissolved hi the solvent The solvent is removed via rotary evaporation until a viscous mixture remains. The viscous mixture is mixed with a stabilizing surfactant solution, such as sodium dodecyl sulfate, in a buffer solution. The mixture is then sonicated for 30 minutes ( 1 second pulses with a 2 second delay) with 30 W of power, forming the roiniernulsion and allowing the solvent to partially evaporate. Eosirs Y and I-vinyl-2-pyrrolidone are added to the emulsion. The mixture is then exposed to light from a source such a.s a mercury arc lamp while the solution is stirred vigorously. The resulting particles are stirred overnight while open to the air to allow any remaining solvent to evaporate. Optionally, the polymeric nanopartieles are then di&lyzed against a buffer solution to remove excess surfactant and salts.
Polymeric particles can also be prepared by a precipitation method. For example, a polymer of Formula XXXVIII is dissolved in a solvent, such as dichSoroπiethaπe, along with an agent, such, as pacliiaxel. The solution is added to an aqueuous surfactant solution, such as sodium dodecyi sulfate in water. The resulting mixture is sonicated to produce an emulsion. The mixture is stirred while open to ihe atmosphere to evaporate the excess solvent, such as dichoromethane. The resulting particles; are collected and optionally άiaiyzed using a membrane with a molecular weight cutoff to remove excess surfactant.
Irs some embodiments, the diameter of the particles formed is between t πtn and SO microns, e.g., between. LO ran and 1 micron, between SO rssi and I micron., between 100 nm and 500 nm, or between 1 and 50 microns.

Encapsulation^ of an. Ageist Within. Polymeric Particles
Any method known in the art for encapsulating an agent within a polymeric particle can be used to form a polymer/agent complex. For example, an oil emulsion technique is used to form paclitaxe! containing particles of Formula XX. A polymer of Formula XX can be dissolved in a solvent, such, as diehloromethane, in the presence of an agent, such as paelitaxet The polymer/paclitaxei solution is vortexed. A surfactant solution, such as 5% polyvinyl alcohol, is added to the pαiymer/paditaxel solution, and the resulting solution is vortexed for about 15 minutes followed by stirring for about KS hours. The resulting panicles are collected, washed with ϊvater, and lyophiiized In certain embodiments, the encapsulation efficiency of paelitaxei by the particles using ibis technique is between 30-99%. in another embodiment, the encapsulation efficiency of paclitaxc! by the particles using tnis technique is between 60-75%.

Agents that Can be Incorporated into Polymeric* Films and Particles
Any agent can be incorporated within the polymer films and particles described herein.. For example, a polymer film or particle described herein, can incorporate a pharmaceutical agent selected from among (1 } nonsteroidal anti-inflammatory drags (NSAIDs) analgesics, such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) opiate agonist analgesics, such as codeine, lentaπyl, hydromorphone. and morphine; (3) salicylate analgesics, such as aspirin (ASA) (enteric coated ASA); (4) Hi -blocker antihistamines, such as clemastine and terfenadme; (5) Ha - blocker antihistamines, such as cimetidirte, famotidine, iiizadine, and ranitidine; (6) anti-infective agents, such as mupirocin; C 7} antianaerobic auti-infectivcs, such as chloramphenicol and clindamycin; {8} antifungal antibiotic ami-infeetives, such as amphotericin b, clotrimazole,
fluconazole, and ketoeonazole; (9) macrolide antibiotic anti-infectives, such as azithromycin and erythromycin; { 10) miscellaneous beta-lactarn antibiotic arsti-hyfeciives, such as azireonam and iinipencrn; (W) penicillin antibiotic anti~ini"ecUves, such as nafeiUir! oxacillin, penicillin G, and penicillin V; { ! 2} quinolone antibiotic aiiti-infectives, siseh as ciprofloxacin and norfloxacin; {13} tetracycline antibiotic aπti-infεctives. such as doxyeycHne, minocycline, and tetracycline; (14) antituberculosis aπtimyeohaeteπa! aπti -infectives such as isoniazki (LNH), and rifampin; (15)
antiprotozoal anti-infcctives, such as aiovaqiionc and dapsone; (16) antimalarial antiprotozoal ami -infectives, such as chloroquine and pyrimethamine; ( 17) ami -retroviral anti-infectives, such as ritonavir and zidovudine; (18) antiviral anti-infective agents, such as acyclovir, ganciclovir, interferon alpha, and rimantadine; (19) alkylating antineoplastic agents, such as carbop Latin and cisplatiπ; (20) nitrosourea alkylating antineoplastic agents, such as caπnustiπc (BCNU); (21) antimetabolite antineoplastic agents, such as methotrexate; (22) pyrimidine analog antimetabolite antineoplastic agents, such as fluorouraci! (5-FU) and geradiabine; (23) hormonal antineoplastics, such as gosereliπ, leupmlkk. and tamoxifen; (24) natural antineoplastics, such as aldesleukin, interleukin-2. doeeiaxd, etoposkle (VP-) 6), interferon alpha, paclitaxel and tretinoin (ATRA); (25) antibiotic natural antineoplastics, such as bleomycin, dactinomycin, άauπorubiein, doxorubicin, and mitomycin; (26) vioca alkaloid natural antineoplastics, such as vinblastine and vincristine; (27) autonomic agents, such as nicotine; (28) anticholinergic autonomic agents, such as benztropine and trihexyphenidyl; (29) antimuscariπie anticholinergic autonomic agents, such as atropine and oxybuiynin; (30) ergot, alkaloid autonomic agents, such as bromocriptine; (31) cholinergic agonist
parasympathomimetics, such as pilocarpine; (32) choli nest erase uih.ibi.tor
parasympathomimetics, such as pyridostigmine; (33) alpha-blocker sympatholytics, such as prazosin; (34) beta-blocker sympatholytics, such as atenolol; (35) adrenergic agonist sympathomimetics, such as albuterol and dobutatnins; (36) cardiovascular agents, such as aspirin (ASA), piavix (Ciopidogrei bisulfate) etc; (37) beta-blocker antianginals, such as atenolol and propranolol; (38) calcάimi-chanπe! blocker antianginals, such as nifedipine and verapamil; (39) nitrate antianginals, such as isoxorbide dinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin; (41) class I anti-arrbsthmics, such as lidøeame, niex.ilct.inc, phenytoin, procainamide, and quiϊύάiπe; (42) class Il
antiarrhythmics, such as atenolol mεtoprolol, propranolol and timolol; (43) class III antiarrhythmics, such as amiodarorsc; (44) class IV antiarrhythmics, such as diltiazem and verapamil; (45) alpha-blocker antihypertensives, such as prazosin; (46) angiotensin-converting enxyme inhibitor (ACE inhibitor) antihypertensives, such as capt.opril and enalapnl; (47) beta blocker antihypertensives, such as atenolol, meloproioK nadolol, and propaiioioh (4S) cakium-channel blocker antib\pertcαsive agents, such as diϊtiazem and nifedipine; (49) central- acting adrenergic antihypertensives, such as clouidine and methyklopa; (50) diurectic antihypertensive agents, such ,as arailoride, farosernidc, 1iydrochioroth.iaz.ide (HCTZ), and spironolactone; (51 ) peripheral vasodilator
antihypertensives, such as hydralazine and minoxidil; (52) antilipernics, such as gemfibrozil mid probucol; (53) bib acid sequestrant antiliperπies, such as cholestyramine; {54} HMG-CoA reductase inhibitor andliperriics, such as lovastatin and pravastatin; (55) iπotropes, such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside
Iπotropes, such as digoxin; (57) thrombolytic agents or enzymes, such as Lilteplase (TPA), anistrepiase, streptokinase, and urokinase; (58) dermatologies! agents, such as colchicine, isotretinoin, methotrexate, minoxidil; tretinoin (ATRA); (59) dermatologieai
corticosteroid anti-inflammatory agents, such as betamethasone and dexamethasorse: (60} antifungal topical aaii infectives, such as amphotericin B, clotrimazole, .miconazole, and nystatin; (61 ) antiviral topical arHi-in.feet.ives. such as acyclovir; (62) topical
antineoplastics, such as ilυoro uracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosemidc; (65) potassium-sparing diuretics, such as triamterene; (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) uricosuric agents, such, as probenecid; (68) enzymes such as RNase and DNase; (69) immunosiipr«ssive agents, such as cyclosporine, steroids, methotrexate tacrolimus, sirolimus, rapamyein; (70) antiemetics, such as prochlorperazine; (71) salicylate gastrointestinal anti-inflammatory agents, such as sulfasalazine; (72) gastric acid-pump inhibitor anti-ulcer agents, such as omeprazole; (73) Fh -blocker anti-ulcer agents, such as eirrseiidine, famotidine, nizatidine, and ranitidine; (74) digest&nis, such as pancrcHpase; (75) prokmctic agents, such as erythromycin; (76) opiate agonist intra venous anesthetics such as tbnuuvyi; {77} hematopoietic antianemia agents, such as erythropoietin, filgrastim (G-CSF), and sargraπiostivn (GM-CSF); (7S) coagulation agents, such as antihemophilic factors I ~I0 (AHF 1 -10); (79) anticoagulants, such as warfarin, heparin, and argatroban: (80) growth receptor inhibitors, such as erlotinib and gefetinib; (S2) abortifacients, such as methotrexate; {83} antidiabetic agents, such as insulin; (84} oral contraceptives, such as estrogen and progestin; (85) progestin contraceptives, such as levonorgcstrel and norgestreh (86) estrogens such as conjugated estrogens, dlethyistiibestrol (DES), estrogen (estradiol, estrone, and estropipate); (87) fertility agents, such as eloBiiphene, human chorionic gonadatropin (IiCG)5 aτ?d menotropins; (88) parathyroid agents such as calcitonin; (89) pituitary hormones, such as desmopressin, gosercliϊi, oxytocin, and vasopressin (ADH); {90} progestins, such as medroxyprogesterone, noretbindroπe, and progesterone; (S)I ) thyroid hormones, such as levo thyroxine; (92) immunobiologic agents, such as interferon beta-lb and interferon gamma- I b; (93) immunoglobulins, such as imrnαπe globulin IM, IMIG, ΪGIM and immune globulin IV, IVIG, IGIY; (94) amide local anesthetics, such &s lidoeaine; (95) ester local anesthetics, such as beπzocaine and procaine; (96) musculoskeletal corticosteroid an.ti-in"flammatory agents, such as bcclornethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone; (97) musculoskeletal anti-inflammatory immunosuppressives, such as azaihioprine, cyclophosphamide, and methotrexate; (98) musculoskeletal nonsteroidal anti-milainmatαry drugs (NSAIDs), such as diclofenac, ibuprofeπ, ketoprofeπ, kelorlac, and naproxen; (99) skeletal muscle relaxants, such as baclofen, cyclobeπzaprine, and diazepam; (100} reverse neuromuscular blocker skeletal muscle relax ants, such as pyridostigmine; (101) neurological agents, such as nimodipiπe, riluϋøle, tacrine and ticlopidine; (102) anticonvulsants, such as carbamazepine, gabapeniin, lamotrigine, phe-nytoin, and valproic acid; (103) barbiturate anticonvulsants, such as plierjobarbita! and primidone; ( 104) benzodiazepine anticonvulsants, such as clonazepam, diazepam, and lonrzcpara; (105) anti-parkisonian agents, such as bromocriptine, levodυpa, carbkiopa, and pefgol ide; (KMV) anti-vertigo agents, such as meclizine; ( 107) opiate agonists, such as codeine, fentanyl, hydromorphone, methadone, and morphine; (108) opiate antagonists, such as naloxone; (109) beta-blocker anti-glaucoma agents, such as timolol; (1 10} miotic anti-glaucoma agents, such as pilocarpine; (111) ophthalmic aminoglycoside
antimfcetivcs, such as gentamicin, neomycin, and tobramycins; (1 12} ophthalmic quinolone anii-infectives, such as ciprofloxacin, norfloxacin, and ofloxacin; {! 13} ophthalmic corticosteroid an ti- inflammatory agents, such as dexamethasone and prednisolone; (1 14) ophthalmic nonsteroidal ami-inflammatory drugs (NSAlOs), such as diclofenac; ( 1 15) antipsychotics, such as clozapine, haioperidol, and risperidone; (1 16) benzodiazepine anxiolytics, sedatives and hypnotics, such as clonazepam, diazepam, ioraz.epara, oxazepam, and prazepam; {! 17) psychostimulants, such as methylplierudate and pemolme; (1 18) antitussives, such as codeine; (119) bronchodilators, such as theophylliiie; ( 120) adrenergic agonist bronchodilators, such as albuterol; (121} respiratory corticosteroid aMi -inflammatory agents, such as dexarnethasαne; (122) antidotes, such as fiumazenii and naloxone; ( 123) heavy metal antagonists/chelating agents, such as penicillamine; (124) deterrent substance abuse agents, such as disulftram, naltrexone, and nicotine; (125) withdrawal substance abuse agents, such as
bromocriptine; (126) minerals, such as iron, calcium, and magnesium; (127) vitamin B compounds, such as eyanocβbalamin (vitamin BI2) and niacin (vitamin B3); (128) vitamin C compounds, such as ascorbic acid; (129) vitamin D compounds, such as ealeitriol; (130) vitamin Λ, vitamin E, and vitamin E compounds; (131 } poisons, such m racim (132) aMi-bleeding agents, such as protamine; ( 133) an ti helminth anti -infectives, such as metronidazole; and ( 134) sclerosants such as talc, alcohol ant! doxyeyeliα
In addition to the foregoing, the following less common drags can also be used: ebJofhexIdme; estradiol eypionate in oik estradiol valerate in oil; flurbiprofen;
ilurbiprofcn sodium; ivermectin; ievodopa; nafarelin; and somatropm. further, the following drugs can also be used: recombinant heta-gkcan; bovine immunoglobulin concentrate; bovine superoxide dismutase: the formulation comprising iiuoroαraeil, epinephrine, and bovine collagen; recombinant hirudin Cr-HIr)5 HlV-I immunogen; human anti-TAC antibody, recombinant human growth hormone (r-hGH); recombinant human hemoglobin fr-Hb); recombinant human mecaserrain (r-fOF-1 }; recombinant interferon beta- Ia; lenograstim (G-CSF); olanzapine; recombinant thyroid stimulating hormone (r-TSH); and topotecan. Further still, the following intraveru)αs products can be used; acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human calcitonin; salmon calcitonin; carboplatin; earmustine; dactinoinyciα, daunorubkin HO; d(ϋ;etaxd; doxorubicin HCl; epoetin alpha; ctoposide (V'P-lό); tluorouracil (S-FU); ganciclovir sodium: gentaiύcin sulfate; interferon alpha; ieuprohde acetate; meperidine HCI;
metliadone HCl; methotrexate sodium; paciitaxel; ranitidine HC); vinbiastm sulfate: and zidovudine (AZT).
Further specific examples of useful pharmaceutical agents from the above categories include: (a) antineoplastics such as androgen inhibitors, antimetabolites, cytotoxic agents, receptor inhibitors, and ύnmunomodoktors; (b) anti-iussives such as dextromethorphan, dextromethorphan hydrobromide, noseapinε, carbetapentaπe citrate, and cMorphediaπoi hydrochloride; (c) antihistamines such as chlorpheniramine maleatε, phenindaminc tartrate, pyrilamine vnaleate, doxylaroine succinate, and phenyltoloxaniiae citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine

Hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonates, magnesium oxide, and other alkali metal and alkaline earth metal salts; (g) ion exchange resins such as cholestyramine:, (h) anti-afrhythrnies such as N-acety!ρrocainaniide; (i) antipyretics and analgesics such as acetaminophen, aspirin ami ihuprofen; (j) appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; (Ic) expectorants such as guaifenesin; (!) antacids such as aluminum hydroxide and magnesium hydroxide; (m) biologicals such as peptides, polypeptides, proteins and amino acids, hormones, interferons or cytokines, and other bioaefive peptidie compounds, such as intertøukins 1-18 including mutants sod analogues, RJNase, DNase, luteinizing hormone releasing hormone (LJ-IRH) and analogues, gonadotropin .releasing hormone CGnRi-I), transforming growth factαr-3.
(TGF-beta), fibroblast growth factor (FGF), tumor necrosis factor-alpha & beta (TNF-uipha & beta), nerve growth factor (NCH-), growth hormone releasing factor (GHRF). epidermal growth factor (EGF), fibroblast growth factor homologous factor (FCiFMF), hepatoeyte growth factor (HGF), insulin growth factor (IGF), invasion inhibiting faetør-2 CllF-2), bone rnorphogenetie proteins 1-? (BMP 1-7), somatostatin, thymosin~alpha-K garπma-giαbuϋn, superoxide dismuta.se (SOD), complement factors, liGH, t.PA,
ANF, EFO and insulin; (n) anti-infective agents such as antifungals, anti-virals, antihekmnths, antiseptics and antibiotics; and (m) oxygen, henioglobin, nitric or sϋver oxide.
Non-limiting examples of broad categories of useful pharmaceutical agents include the following therapeutic categories: anabolic agents, anesthetic agents, antacids, anti-asthmatic agents, anticholesteroleiπic and ant j -lipid agents, anti-coagulants, anticonvulsants, imti-diarrheais, antiemetics, anti-infective agents, ami-inflammatory agents, anti-manic agents, anti-nauseanis, antineoplastic agents, anti-obesity agents, anii -pyretic and analgesic agents, anti -spasmodic agents, anti-thrombotic agents, anϋ-urkexrύe agents, anti-anginal agents, antihistamines, anti-tttssives, appetite suppressants, biologicals, cerebral dilators, coronary dilators, decongestants, diuretics, diagnostic agents, erythropoietic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives.

stimulants, thyroid and ants -thyroid agents, uterine relaxants, vitamins, and prodrugs. Examples of specific drugs that can be used include; asparaginase, bleomycin, busuli'an, capecitahine, carboplatiπ, caπnustine, chlorambucil, cispiaiin, cyclophosphamide, eytarabine, dacarbixine, dacϋαotnyciπ, tfaunorubicin, dexrazoxane, docetaxd, doxorubicin, etoposide, iloxuridlne. fludarabine, iluoruraoil, gerøcitabiπe, hydroxyurea, idarubicin, ifosraraide, irinotecrø, lomustine, medilorethamme, raelphalan,
mereapiϋpurme, methotrexate,, mitomycin, mitotane, mitoxantrone, paclitød, pcntostatin. pLicamycm, premextred procarbazine, muximabe, strcptozociα, teiiiposid, tlϊioguaτime, thiotepa, vinpkstiae, vinehristine, and vinordbine. The currently preferred drugs for lung cancer treatment is paditaxel, pemeirexed, l()-tiydrt>camptothecin, iriπotecan, erlotinihtL'gefetinsb or derivates of these molecules.
Examples of anticancer, antineoplastic agents are caiTiptothecins. These drugs are antineoplastic by virtue of their ability to inhibit, topoisomerase I. Cainpiothecin is a plant alkaloid isolated Iτo.m trees indigenous to China and analogs thereof such as 9-aπύnøcasϊψiothecm, 9-nitrocaBipiothecin, 10-hydroxycamptotbeein, 1OJ 1 -methylenedioxycaπiptothecin, 9-αitro~10, 1 1 -jnethylenehydroxyeasnptothecin, 9-chloro-10, 1 l-methylend^ydroxycaiTiptothecin, 9-amino- 10.1 1 -metbyienehydroxycampi<}tii«ciπ, 7-ethyl-l(}-hydroxyca«ϊptothecift (SN-3S), lopotecan, DX-S9S I , Lurioiecan
(G π 147221 C), and other analogs (collectively referred to herein as eamptotheeiπ. drugs) are presently under study worldwide in research laboratories for treatment of colon, breast, asκl other cancers.
Additionally, the pharmaceutical agent can he a radiosensitizer, such, as metαciopramide, scnsainide or neiisensamide (manuiactured by Oxigene): profu-omyciα (made by Vion); R SR 13 (made by Ailos); THYMΪTAQΦ (made by Agouron), etmiidazole or lobenguane (manufactured by Nycorπcd); gadolinium texaphrin (made by Phaπnacyciics}; BuDR/Broxine (.made by NeoPharm); IPdR (made by Spuria); CR2412 (made by Cell Therapeutic); LlX (made by Terrapin); agents that mimmύe hypoxia, and die like.
The agent can be selected from a biologically active substance. The biologically active substance can be selected from the group consisting of peptides, poly-pep tides, proteins, amino acids, polysaccharides, growth factors, hormones, aαti-angiogenesis factors, interferons or cytokines, elements, and pro-drugs. In useful embodiments, the biologically active substance is a therapeutic drug or pro-drug, most preferably a drug selected from the group consisting of chemotherapeutic agents and other antineoplastics such as paclitaxel, antibiotics, anti-virals, antifungals, anesthetics, aniihelmiπths, anti-inflammatories, and anticoagulants. In certain useM embodiments, the therapeutic drug or pro-drag is selected from the group consisting of chemotherapeutic agents and other antineoplastics such as paeliiaxel, carbøplaϋπ and cisplatin; nitrosourea alkylating antineoplastic agents, such as eamiusiine (BCNU); ffuoroufseil (5-FIj) and gemeitahine; hormonal antineoplastics, such as gosereϋn, leiφroiide, and tamoxifen; receptor inhibitors such as erioiinib, gefeiiπib, sutent or anti-cklt inhibitors, such as GLEBVEC&; natural antineoplastics, such as aldesleukin, interteukin-2, docelaxel, etoposide (VP- 16), interferon alpha, paclitaxel, and tretinoin (ATRA),
Irs another embodiment, the biologically active substance is a nucleic acid sequence. The nucleic acid sequence can be selected from among any DNA or RNA sequence. In certain embodiments, the biologically active substance is & DNA sequence thai encodes a genetic marker selected from among iuciferase gene, β-gaUctosidase gene, .resistance, neomycin resistance, and chloramphenicol acetyl transferase, In certain embodiments, the biologically active substance is a DNA sequence that encodes a lectin, a rnannose receptor, a siaioadhesin, or a retroviral trans-activating factor. In certain embodiments, the biologically active substance is a DNA sequence thai encodes a RNA selected from the group consisting of a sense RNA, an antisense RNA, siRNA and a ribozyrøe.
Biologically active agents amenable for use with the new polymers described herein include, without limitation, medicaments; vitamins; mineral supplements:
substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment. Useful active agents amenable for use in the new compositions include growth factors, such as transforming growth factors (TGFs). fibroblast growth factors (FGFs)3 platelet derived growth factors (PDGFs), epidermal growth factors (HGFs), connective tissue activated peptides (CTAPs)5 osteogenic .factors.

and biologically active analogs, fragments, and derivatives of such growth factors.
Members of the transforming growth factor (TGF) aυpεrgene family, which are multifunctional regulatory proteins, are preferred. Members of the ITrF supergene family include the beta-transforniing growth factors (for example. TGF-M, TGF~b2, and TGF~b3); bone raorphogenetie proteins (for example, BMP-I, BMP-2, BMP-3: BMP-4, BMP-S, BMF-6, BM.P-7, BW-S5 and BMP-9); heparin-binding growth factors (lor example, fibroblast growth factor (FGF)5 epidermal growth factor (EG F), platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF)); mhlbins (for example. lnhibin A, lnhibin B); growth differentiating factors (for example, GDF- 1): and activins (for example, Activin A, Aetivin B, and AcHvin AB),

K, Applications for Polymer / Agent Compositions
The polymers provided herein can be utilized to promote healing or treat or inhibit disease by targeting daig delivery to local and regional areas. The polymers provided herein can also be used for a variety of applications including, but not limited to, production of micro- and aanopariicles, films, tissue scaffolding, coatings, sutures, and orthopedic materials. The polymers can also be used in various cosmetic
applications, such as tissue augmentation. Such materials can be used to repair an injured tissue, organ, bone, or genetic defect. Other uses of the polymers provided herein include treatment of early; late, or previously treated malignancies or to inhibit recurrence of cancers that have been, surgically removed or locally treated, avoidance of locoregional lymph node metastasis, augmentation of local wound healing and decrease in infection, manipulation of structure and abnormal scar formation, and for the treatment of postoperative pain.
hi some embodiments, the polymers provided herein are used to treat cancer. For example, the polymers provided herein can be used to treat king, colon, prostate, pancreas, or breast cancer. They could also be used with bone marrow transplantation to targsi residual tumor ceils in the graft, such as iympohomas and leukemias. The polymeric particles can be injected or infused into or around inoperable tumors to locally deliver drugs, such as chemotherapy or sensitizers, or injected or iri&sed near the site of the operation incision to deliver agents such as antibiotics, anesthetics, or growth or healing factors, thereby avoiding side effects associated with systemic delivery. The polymeric panicles provided herein can be administered at a site of surgery with the Intent of the particles being carried by the lymph fluid to loco-regional nodes. The particles can become trapped at the lymph nodes, allowing delivery of agents to tumor cells that also commonly migrate to lymph nodes. Cells that commonly migrate to lymph nodes include tumor cells and immune cells such as T ceils or dendritic ceils, and thus direct presentation of antigen by the particles can be utilized to enhance the immune system. Thus, the particles can be used to treat tumors systemicalty either by targeting the tumor ceils directly or by upreguiatiiϊg the immune system to fight the tumor,
The polymeric particles and films provided herein can also he administered to sites where tumor regrowtli is likely to occur. The particles and films can be
administered to areas where, as a consequence of disease, such as COPD or inflammatory howl disease, or systemic chemotherapy, poor healing will result in major complications. In addition, the particles and films can be administered to the margins of a surgical excision or resection, or to sites following local ablative therapy, for such applications, the polymeric particles are prepared Io adhere to the surgical margin or be retained within the confines and perimeter of the mass, In other embodiments, the particles or films adhere to the pericardium, cartilage, or collagen for the delivery of anti-cancer or antineoplastic agents, hi other embodiments, the films can be stapled, sutured, and/or glued in place at a site.
hi other erabϋdkπemtx. the films and particles described herein can be used in cosmetic applications. In such an application, the swelling associated with pH changes can be advantageously utilized. For example, many of the acrylate polymers described herein upon delivery to a tissue site swell and increase in size and bulk, filling voids. Such polymers can he used without any agents to fill wrinkles or to increase the size of tissue, e.g., in the lips or checks. Optionally, the polymers could deliver cosmetic agents such as BOTOX® and/or analgesics. The net result of such a treatment could be, e.g., a smoothing of facial tissue, in some embodiments, the polymers used for such an application are, e.g., 3a-6a and 9a and 10a.
Any method of adhering particles to biological tissue can be used for this application. For example, the polymeric particles provided herein can be coated with PluroTiie FI 27. In another embodiment, the particles are entrapped within a gel, hydrυgef > adhesive, sealant or surgical reinforcement strip made from pericardium, TEFLON®, plastic, or other materials or particles that can utilize a specific bound such as biotin-avidirs to increase there resident time at the implant site.
I n addition, other types of surgery can benefit from the use of the polymeric particles and films described herein. For example, films and particles that contain antibiotics can be utilized for local delivery at a surgical site. The release rate of the antibiotics arκi/or analgesics can be prolonged to reduce the risk of post -surgical infection, such as Clostridium difficile infection. This method provides an alternative to the use and risk of systemic antibiotics, 'Hie films and particles can contain anesthetics, such as local amide anesthetics, IY narcotics, or anti-inflammatory agents, such as steroids or NSAlDS, to reduce the discomfort of patients. The use of such polymeric materials can reduce morbidity secondary to delirium and constipation, decrease the length of hospital slays for patients, and reduce overall health care costs.
h\ certain embedments, the polymeric films and particles are in contact with aqueous or organic solutions, or combinations thereof. The aqueous solutions can be selected from among water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates or combinations of any two or more thereof. The organic solutions cars be selected from among DMSO, ethanoL, methanol, THF, dichloromethanc. DMF, hexane or toluene or combinations of any two or more thereof.
The polymeric particles and films can contain genetic materials, e.g., nucleic acid sequences. Such materials can be used to tnmsfeet cells in vitro, ex vivo, or hi vivo. The polymeric particles and films can contain a receptor recognizing a targeting moiety, allowing specific entrance into a cell or activation or inhibition of a cell receptor or subsequent intracellular signaling or apopototic pathway. Thus, the polymeric materials described herein can be used to deliver nucleic acid sequences to a cell or to deliver agents that can be transported to the nucleus of a ceil or effect transcription or translation within a cell, such as steroids or specific transcription factors,
The methods of using the polymeric particles and films described herein can be used separately or they can be combined with one or more therapies to treat a single patient. For example, particles containing one type of therapeutic agent car: be designed and delivered m a manner that results in the particles becoming entrapped at lymph nodes, whereas other particles or films that contain either the same or a different therapeutic agent can be applied to surgical margins or suture sites. Ii should also be recognized that other agents besides chemotherapeatiu agents, e.g.. cytokines, growth factors, and antiinflammatory agents, can be used in these methods and combinations of particles containing a variety of cherπotherapeutie or other agents can be employed, to both kill tumor, foster healing, and decrease pain.
The polymeric mieropariieles, nanopartieies, Sims, gels, and other polymer forms provided herein can be used for in vitro and in vivo manipulation of drug release kinetics. Depending upon the polymer selected, the rate of drug release can be delayed or immediate, In certain embodiments, the polymers provided herein can be used for prolonged drug delivery after an initial period of quiescence to permit surgicai healing to occur, in other embodiments, the polymeric panicles provided herein provide a dual mechanism of delivery where a daig is released from the particles and fee particles swell to destabilize or destroy the cell or cellular compartment {e.g., endosome). Alternatively, the particles cars swell and become lodged, embedded, or otherwise Immobilized at a certain target location due to the enlarged size of the particle. For example, awe! led particles can became lodged or embedded within a cavity, node, tubule, bronchus, or capillary and can be used to occlude blood flow as an embolization agent for bleeding, arteriovenous malformations, or tumor devascαlarization or can be used to prevent airflow to a specific portion of the lung as for endoscopic lung volume reduction surgery, to cite only two examples of potential uses of this property. Particle swelling can be triggered by pi! change from an exogenous agent added to the polymer, a change within a cavity or vessel as can occur in a ischemic or infected tissue or cavity or within an intracellular compartment such as an eπdosαme. Such particles can also be
manufactured to release agents that manipulate healing or fibrosis to facilitate permanent or temporary closure of the occluded lumen or cavity.
Certain embodiments of the invention are directed towards polymeric films that are designed to deliver chemolherapeutic agents locally at surgical sites, with
incorporation into the resection margin. These funis are used, e.g., In the treatment of cancer patients, where delivering drugs locally has the advantage of avoiding side effects associated with systemic drug delivery. These Elms allow the delivery of agents at local concentrations that could not otherwise be achieved due Jo drug toxicity. The films can release agents at the site of surgery and the released agents can dsfϊϋse to areas of close 5 proximity to the implantation site and to the site of metastatic tumor growth. The
implanted polymeric films am deliver one or more anti-cancer agents, e.g., as described herein, thai will act upon cancer or metastatic cells remaining at the surgical margins after luniur excision is performed. Urns, the films can reduce tϊ\c incidence of tumor recurrence at a resection margin after remove] of cancerous tissue.
10 Aii advantage of the films provided herein h the ability to cover larger areas uniformly. For example, the polymeric films can cover the chest wall to treat diseases such as mesothelioma or in other body cavities for diseases such as sarcomas. In
addition, the polymeric films can incorporate local anesthetics or IV narcotics and be applied along an entire surgical incision for peri- operative analgesia, or incorporate

15 growth factors, anti-inflammatory agents in order to maipulate wound healing and
prevent hypertrophic scar or stricture formation.
Polymeric films containing a single or multiple agents can ho applied to a solid surface in a controlled manner to form patterns such as stripes and dots. Single or
multiple agents can be incorporated in any pattern to achieve precise therapeutic delivery

20 of multiple agents simultaneously. More than one type of polymer film can he used to further tune or control the release of the drug, A further embodiment of the invention is the use of multi-layer films to alter the release of the agentCs).
Pur example, a film composed of a polyester-co-carbonate of 80:20 caprøic acid and glycerol-stearic acid can be loaded with a drug, such as taxol, caroptoiheciϊi, or

2.5 pemetrexed. The film can then be coated with another polymer of the same or different composition that does not contain the drug, form ing a multi-layered lϊlm. The top
poϊyiπer layer, which does not have the drug, acts as a sacrificial layer ihat first inhibits the release of the drug from the underlying film, hut as the top layer degrades, the bottom layer starts to release the drug. In this fashion, delayed and controlled release can occur

30 and can be utilized to allow initial wound healing to occur before delivery of
chemotherapy which can inhibit wound healing, as one example. Alternatively, different drugs can be released sequentially and either enhance or prolong the effect of She other drug or protect "normal" ceils from the toxic effects of the second drug or Io rescue cells from the effects of a second agent, for example pre-treatment with folate can limit toxicity of normal, cells to anti-folaie chemotherapies and yet tumor cells remain susceptible.
The polymers provided herein can he used to deliver any agent. Hie agent can be m any pharmaceutically acceptable form, including pharmaceutically acceptable salts. A large number of pharmaceutical agents are known in the art and arc amenable for use in the pharmaceutical compositions of the polymeric materials described herein,
Acceptable agents are described elsewhere herein, and include, but are not limited to, ebemotlierapeiπie agents, such as radiosensitizers, receptor inhibitors and agonists or other antineoplastic agent; immune modulators and bioactive agents, such as cytokines, growth factors or steroids with or without the co-incorporation αf tumor or pathogen antigens to increase the antineoplastic response as a means of vaccine development; local anesthetic agents; antibiotics; or nucleic acids as a means of local geae therapy,
The biologically active substances and agents are used in amounts that are therapeutically effective. While the effective amount of a biologically active substance will depend on the particular material being used, amounts of the biologically active substance from about 1% to about 65% can be desirable. Lesser amounts can be used to achieve efficacious levels of treatment for certain biologically active .substances.
The amount of drug delivered per area of film or per particle will depend on the therapeutic range of the drug, its toxicity when delivered locally, and the clinical characteristics of fee patient being treated. The number of particles or amount of film delivered to a site is selected depending on factors such as 1) the amount of agent delivered per particle, 2} the therapeutic range of the agent, 3) the local toxicity of the agent, and 4) the clinical characteristics of the patient being treated. The development of dosages based on these parameters is routinely performed by those skilled in the art of pharmacology and clinical medicine. For example, between 1 x lit and I x 10" particles/crπ can be administered to a biological area,
The release kinetics of a given polymer film or particle can be fme-amed and adjusted by varying the ratio of monomer units and/or by modifying the .side chains of a given copolymer. In this manner, a family of copolymers with varying release kinetics can. be used to accommodate the delivery of several different drugs with differing desired release kinetics. For example, making more side chains along the polymer that are hydrophilie will generally make the polymer more hydrophilk overall and will also generally increase the release rate of an agent from the polymer,
In certain embodiments, the polymeric particles or films delay release of ehemotherapeutic agents. The delayed release can coincide with wound healing. In certain embodiments, drug delivery is delayed for a period of approximately 0-6 weeks. In otli Cf embodiments, the drug is released over a period of 1-6 weeks, In another embodiment ύm drug is released over a period of 2 weeks. In other embodiments, the drug is released for «p to 3 months. One method of controlling the rate of release from the panicles is by varying the ratio of different monomer units during polymerization. For example, a ratio of 20:80 of glycerol and caproic acid provides polymers and resulting niicroparticles that release drug over live days.
Provided herein are particles, including microparticles and nanoparticles. In certain embodiments, the size of the polymer particles described herein are between 2 arsd 100 nm in diameter, In other embodiments, the size of the polymer particles are between 0.02 - IC) micrometers in diameter, In other embodiments, the size of the polymer particles are between I -50 micrometers in diameter. Other polymeric particles of a larger size can be useful at specific sites, such as where tumor regrαwth is prevalent. For example, polymeric particles of a larger size can be useful at a surgical margin, where suturing or stapling has occurred, or within a naϊve or treated tumor such as an ablated cavity secondary to radiofrequency ablation or other therapy, or within a spontaneous cavity such as occurs in squamous cell carcinoma. Placement of polymeric particles within other spontaneous cavities could be utilized to result in sclerosis of the cavity, cither with rclea.se of specific sclerosing agents such as tale powder, alcohol or dαxvcyeb'n as examples or other inflammatory agents. This approach can then he utilized is the treatment of bullous disease in emphysema or infections diseases such as ecchmococeal cysts, tor example.
The sew monomers and polymers can also be used to prepare biodegradable oligomers, polymers, maerømokcuies, and copolymers using standard techniques. The oligomers, polymers, macromolecules and copolymers can contain alkyi side chains formed between [1 ] a monomer or snacromoiecular unit containing at least one functional side group; {2} alky! chains containing 1-50 carbon units; and, in certain embodiments. 13 J a structurally diftbresit monomer or macromolecular unit. In certain embodiments, the macrornolecular materials can be elastic solids or viscoelastic solids. In various embodiments, the macrorøoiecuiar materials provided herein are hydrophobic or hydrophilic. In other embodiments, a macromolecular material provided herein undergoes a change from hydrophobic to hydrophilic in response to a change m pHL In certain embodiments, the macromolecular materials provided herein swell to a size that destabilizes or destroys a ceil or cellular compartment.

EXAMPLES
The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
Exarap] e I . Synthesis of 5-Methvl-2-{2.4A6-trimethoχγDhenvl )-



5-Mεthyi -2-(2,4,6-trimethøxyphenyl)-[ 1 ,3 ]-5-dk)xaι>5-yl -methanol was prepared according a modification of a previously reported method {Gillies et ai., J Am Cherø Soc 12.v5: 1 1936-43, 2004). First, I1I5] -tήs(hydroxymcthyl)etbane and 2,4,6-frirαethoxybenzaklehyde were dissolved in tetrahydroforaα, and 5 A molecular sieves were added as s desiccant. A catalytic amount of/?-to!uenesul.fonic acid was then added io the mixture, and the reaction was allowed to proceed at room temperature. When the reaction was complete, friethylamme was added to quench the acid. The molecular sieves were then removed using filtration. The solvent was removed via rotary evaporation under reduced pressure, mά the residue dissolved in dichloromethane. This mixture was then Λvashed three times with ! 00 mM pH 8,0 phosphate buffer and dried over anhydrous sodium sulfate. The solvent was subsequently removed using rotary evaporation under reduced pressure, and the residue was purified using silica gel chromatography.
5~lV1ethyi-2-(254,6-triiΩeihoxypbεnyl)-[l J3j-5-diox-aπ.yliϊiethajiol and
tπethylaπύπe were dissolved in diehlororaethaπe and chilled to 0 0C, Melhaeryloyl chloride was then added drop wise to the mixture. After mixing for 16 h, the mixture was then washed three times with 100 mM pH 8.0 phosphate buffer arκl dried over anhydrous sodium sulfate. The solvent was subsequently removed using rotary evaporation under reduced pressure, and the residue, and the title compound was isolated using silica gel chromatography.

Example 2: Synthesis of 5-Methyl~2~ρheoyH ! .31-5-dioxanvh-nethanol



\,l J -Tris(hydrox.yπieihyl)ethane (2.61 g, 21.7 mmol) and p-tolueπesul tonic acid (0.339 g, 1.97 mmol) were dissolved in benzaldehyde (2.S mL, 2.9 g, 28 mmol) and stirred at 45 'T for 1 h, At this time, toluene (1.0 ml) was added to the solution, and toluene/ waier was distilled out of the mixture at 95 0C. Fresh toluene was added, and distillation was carried out again. This process was repealed until no water was observed in the distillate. Sodium bicarbonate was added to quench the acid, and excess sodium bicarbonate was removed using filtration. The remaining toluene was removed via rotary evaporation, leaving a slightly yellow oil. This mixture was then separated using silica gel chromatography. The product was obtained as a white solid at 41.8% yield.



5-Methy!-2-phcπyi-[i3]-5-dioxanyIrnetham>l (0.504 g, 2.42 mmol) and triethylamine (0.68 mL, 0.49 g, 4,8 mmol} were dissolved in dichloromethane and ckiisd to 0 *C, Metbacryloy! chloride (0.35 mL, 0.3? g, 3.6 mmol) was then added drop wise to the mixture. After mixing for 16 hours, the mixture was then washed 100 mM pH 8.0 phosphate buffer (50 ml X 3) and dried over anhydrous sodium sulfate. The solvent was subsequently removed using ro.ary evaporation under reduced pressure, mid the product was isolated using silica gel chromatography at 83,9% yield.

.Example 4: Synthesis of 1 ,3-bis(bcnyyloxy)propan-2-yi .Methacrylate



1 >3-bis(benzyloxy)propan-2-ol (0.45 rnL, 0,50 g? 1.8 mmol) and triethyiamiae (0.52 niL, 0.37 g, 3.7 mrnol) were dissolved in uiehlororaethaπe and chilled to 0 <;C. Meihaeryloyi chloride (0.27 ml, 0.29 g5 2.8 mmol} was then added drop wise to the mixture. Alter mixing for 16 h, the mixture was then washed 1.00 mM pM M) phosphate buffer (50 sit X 3) and dried over anhydrous sodium sulfate. Ilie solvent was subsequently removed using rotary evaporation under reduced pressure, and the product was isolated using silica gel chromatography at 81 .0% yield.

Exarn.pls 5: Poiyfbtmzyioxy glycerol carbαriale-cα-ε~eapfojac:tone)



5-(beri>:ylo.xymethyi}-l,3-dioxan-2-ont! (624 nig, 3 mmoj} and e-eaproiaetoαe were combmed of varying ratios (to a total of 10.0 ramol) in a 10 nil, schJenk Bask and subsequently evacuated and flushed with N> three times. Meanwhile, tfie catalyst (So{αct}>, 6.5 μL 0,02 mniol, monomer/initiator ratio :~ 500) was evacuated in a small flask for 60 minutes. The ScWenk flask was partially submerged in a thermostatted oil bath, preheated to 140 °C. Toluene (400 μL) was added to the catalyst and the mixture was injected via syringe to the monomers. The reaction was stirred for 48 hours, removed from beat, and cooled Io room temperature. The polymer was dissolved m didilorometbane (10 mb) ami precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation, The resulting polymer formed either a viscous oil or white solid precipitate depending on the carbonate content of the copolymer.
Copolymers were formed with the following carbonate mole fractions: 0.05, 0.10, 0,20, 0.30, 0.40, 0.50, 1 .00.

Example 6; FoivChychmv dvceroi carbonatc-co--ε-caprolactone)



PolyChenzyloxy glycerol carbonate-co-ε-caprølaclone} ( 1.0 g, 2.02 mmoi) was dissolved in 50 ml- dry dichlorometliane inside a Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OB}yC (50 mg} were then added to the solution. The reaction mixture was evacuated and purged with hydrogen three times. The flask was then pressurized to 60 psi with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Celite and the filter cake washed with 50 mL diehlororacthane. The solvents were then evaporated to yield the iiπal polymer. The resulting polymer formed either a viscous mi or white solid precipitate depe»dmg on the carbonate content of the copolymer.
Copolymers were formed with the following carbonate mole fractions: 0.05, 0.10, 0,20, 0,30, 0.40, 0.50, 1.00.
Table "I below indicates the composition, molecular weight and thermal data of the different copolymers, which are illustrated by structural formulas below the table, it Table I, CL :~ eaprolactone; CG carbonate of glycerol f zzz mole percent carbonate monomer in polymerization feed; Fcg ,- mole percent carbonate monomer in copolymer; Mn- number average ϊrsoJeeuiar weight: FDl ::: polydixpersiiy index; Tg ::: glass transition temperature; T1. ::: crystallization temperature; T!a~ melting temperature. Hp- heat of fusion.


Example 7; Pα1y(myrisιic acid earhonate-eo-s-eaprolaetont;)



Poiy(l>enzylox.y glycerol carboπate-co-ε~capτolaeUme} (i.O g, 2.02 mrnoi), myristie acid (0.690 g, 3.03 mmol) and draeibylaminopyridhie (DMAP) (0.123 g> 1.0! mmol) were dissolved in 100 mh άry dichlorornethane. Dicyclohexyicarbodiiπύdc (DCC) (0.5(K) g, 2.42 .mmol} was added to the reaction mixture and a white precipitate formed. The mixture was suited for 24 hours at rooτπ temperature under nitrogen. The precipitate* compound was isolated by filtration and the filtrate was concentrated. The concentrated filtrate was dissolved in diebioromeibaπe and precipitated in cold .methanol (25 nil..). The solvent was decanted and subsequently dried by evaporation. The resulting polymer was a white solid precipitate.

Poiyfbeπzyloxy glycerol carbonatc-co~ε-caprofacto.ne) (1.0 g, 2.02 mmol). stearic acid (0.859 g, 3,03 iranoi) and DMAP (0,123 g, 1.01. mmol) were dissolved in 1.00 mL dry diclilorometliane. !3CC (0.500 g, 2.42 rnmol) was added to the reaction niixlure and a white precipitate formed. The mixture was stirred for 24 hours at room temperature under nitrogen. The precipitate compound was isolated fay filtration aacl the filtrate was concentrated, Tbe concentrated filtrate was dissolved in dkhlorornetlwie and precipitated in cold methanol. (25 rat,}. 'The solvent was decanted and subsequently dried by evaporation. The resulting polymer was a white .solid precipitate.

Example 9: Polyfoietc acid carbonat(^co:g:ca|>rolaciogg}
Foly(benzyloxy glycerol carbonate-co-ε-caprolactone) (250 rng, 0,43 mmo!) was dissolved in 25 mL of pyridine and cooled to (FC. Olcoyl chloride (183 mg, 0.65 mmol) was added drop by drop. The mixture was stirred for 24 hours at worn temperature under nitrogen. The pyridine was removed under vacuum, the crude product was dissolved in dichloromethane, and precipitated in cold methanol (25 rat). The solveM was decanted and subsequently dried by evaporation, The resulting polymer was a white solid precipitate.



An amine-deriviiized copolymer ρoly(6~ammo-hexanoic acid 2-oxo-l ,3~dioxan-5-y\ ester -eo-s-caprolactone) was prepared using the foHowiπg methods.
Synthesis ofpa!yffιnσc-6~amiπo~hexanoic acid 2~oxo-f,3~dioxcιn-5-v! esier-co-ε-aiproiaclone)
Fmoe-6-amino-hex.anoϊc acid (11277 g, 0,78 rnol). poly(5-hydrακ.y-I,3-dioxan-2-oπe-co-ε-caprolacloΩe) ( 1.5 g, 2.6 ramol. 22 moi % carbonate), DCC (0.129 g, 0,63 mmol). and DMAP (0.032 g, 0.26 ramol) were dissolved in !3CM (20 mL). The solution was stirred at RT for 18 h. The DCXi was filtered and the solvent evaporated. The product was dissolved in dickioromethaπe (10 mL) and precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation (85% yield). Addition of the amine side chain was determined by the presence of the methylene group nearest the FiTioe protecting group, as well as the Fmoe protecting group itself, with peaks in the 1I-I NMR spectrum at 3.10-3,19 (TO, 2H, OCH2), and 4.45 (s. 2H, PhCH2), 7.24-7.38 (m, 5H, aromatic), respectively.

Deprotecϋon ofpoIy(βnoc~6-Amino-hexanoic add 2-oxo~J .3~tHoxan-5-yl ester-eo~ε-caproiacι<me)
The copolymer (300 mg) was dissolved in a 40 % mixture of piperldine (16 TΠ L) and dry dimethyl formamide (24 mL} and the reaction was stirred for 90 mm. The solvents were evaporated under reduced pressure. The product was dissolved in dkhiørøϋiethaπe (IO mL) and precipitated in cold methanol. The solvent was decanted and subsequently dried by evaporation (quantitative yield). Complete deprotectioπ was determined by ihe absence of the Fmoc protecting group peaks in the 1H NMR spectrum at 4.88-4,95 (m, 211 CB3), and 7.24-7.75 (m, 5 H, aromatic).

Hydroxy! Punctiorsalized Poly Carbonate ol'Glyceroi-co-caprolactoiig



A primary alcohol-derivitized copolymer poly(6-hydroxy-hexanoic acid 2-oxo-13-dioxaπ-5-yI ester-co-s-caprolactone) was synthesized using the following steps.
Synthesis of 6-henzyhxy-hexanoic acid
?>capfθlacκ>ne (10 mL, 0.18 mol). benzyl bromide (13.4 mL, 0.11 mo!}, and potassium hydroxide (1 i.3 g, 0,281 mol) were dissolved m toluene (200 raL). The reaction Oa.sk was placed in a 120 "C pre-hcatcd oil bath and rcfluxed oyαnight under stirring. The mixture was then neutralized using 1 M HC! (300 mL}, the toluene evaporated off, and the product extracted using didilorome-hane (3 x 300 niL) to afford a mixture of mono and di-proiected 6-hydroxy-hexaiioic acid. The crude product was saponiflcated with IM sodium hydroxide (20(J mL) and methanol (200 ml), extracted with dichiorornethaoc (3 x 200 ffiL), and the solvent was evaporated under reduced pressure to afford pure ό-benzyioxy-hexanoic acid (72% yield). !H NMR (CDQj) 1.38- 1.46 (m, 2H, CH2), 1 ,57-1.68 (m, 4H. CH2CH2), 2.32-2.38 (rπ, 2R CPbCOOH), 3.42-3.46 (m, 2H, OCH3), 4.48-4,53 (s, 211 PhCH2X 7.27-7.31 (in. 5 H, aromatic}.
Poϊy(ό-bi-nzyioxy-hexa?u;uc acid 2 -oxo- ! ,3-dioxan-5-yi ester-co-ε-caprulactcme) δ-Benzyloxy-hexanoic acid (0,173 g, 0.78 mrnol), poϊy(5-hydπ>xy»L3-dioxan-2-oπc~co-f>c55|>ix>3actonc) { 1.5 g, 2.6 IΪIΪΪIOΪ, 22 mo! % carbonate), DCC (0.129 g, 0,63 mmol}, ami DMAP (0.032 g, 0.26 rarnol) were dissolved m DCM (20 raL). The solution was stirred at RT for 18 h. The DC(J was filtered and the solvent evaporated. The product was dissolved m dichlororaethane (10 mL) and precipitated in cold .mcUmnoi. The solvent was decanted and subsequently dried by evaporation (86% yield). Addition of the alcohol side chain was determined by the presence of the methylene group nearest the benzyl protecting group, as well as die benzyl protecting group itself, with peaks in the 5I-I NMR spectnrø at 3.40-3.44 (m, 2H; OCR,), and 4.48-4,53 (s? 2H, PhCH2), 7.27-7.31 (ffi, SH, aromatic), respectively.
Deprofeciϊon ofpoiyfό-benzyloxy-kexanoie add 2-oxo- /.3-dioxan~5-yi esfee-co-ε-caproiactone)
The copolymer (300 røg) was dissolved in 50 mL dry dlcMororn ethane inside a Parr bottle. 10% Pd/C (50 mg) and 20% Pd(OH)2/C (50 mg) were tlieiϊ added Io the solution. The reaction mixture was evacuated and purged with hydrogen three times. The flask was then pressurized to 60 psl with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Cclitε and the filter cake washed with 50 mL <3iehlorometlia&e. The solvents were then evaporated to yield the final polymer
(quantitative yield). Complete deprotcction was determined by the absence ofthe benzyl protecting group peaks in the Hi NMR spectrum at 4.48-4.53 (s, 2H, PIiCH3), 7.27-7.31 Cm, 5Ii, aromatic).

Glycerol-co-caprolacloϊie


A carboxyiic acid-derivhixed copolymer poly(hexanedioic acid moπo-{2-oxo-l,3-dioxan-5-y!) ester-ςo-K-caproIactorse} was synthesized using the following steps.
Synthesis ofhexanedioic acid mofiobenryi ester
DOWEX* 50W-X2 (2 g), benzyl formate (H) mL, mol), and adipie acid (2 g, mol) were added to ociaαe (10.mL). The mixture was refluxed for 4 hours at 100 °C, and the- crude product was purified via silica chromatography to yield a clear, colorless liquid (87% yield). 1H NMR (CDCf3) 1 .59-1.78 (m, 411 CHiCH2), 2.33-2.39 (ra, 4H,
CIi2COOH), 5,09 (s; 2IL VhCIi2), 7,25-7.30 (m, 5H, aromatic}.
Fσiyfhaxaiiediok: acid mono~{2-oxo- 1 ,3~ώoxan~5-yl) esler-co-c-caprolactone)
Hexanedioic acid monobenzyl ester (0.184 g, 0.78 mmol), polyCvhydi-oxy-U-dioxan-2-o.nc--co-ε-caproIactone) (1.5 g, 2.6 mnioL 22 mol % carbonate), DCC (0.129 g, 0.63 mmoϊ), mxά DMAP (0.032 g, 0,26 fnrnol) were dissolved in dkhloromethane (20 ml.). The solution was stiried at RT for IS h. The DCU was filtered and the solvent evaporated. The product was dissolved in dichloromethane ( 10 røL) and precipitated m coki methanol. The solvent was decanted and subsequently dried by evaporation (83% yield). Addition of the carboxyiic acid side chain was determined by the presence of the benzyl protecting group, with peaks in the !B MMR spectrum at 5.(56 (s, 2H, PhCH?.), 7.27-7.33 (in, 511 aromatic).
DeproiiX-tion ofρofy(6-benzyloxγ-kexanoic acid 2-oxσ-i,3-dioxan~5-yi ester-co-ε~ caprohickme)
The copolymer (300 mg) was dissolved in 50 mL dry dschloromethane inside a Pan bottle. 10% Pd/C (50 mg) and 20% Fd(OHVC (50 mg) were then added to the solution. The reaction mixture was evacuated and purged with hydrogen three limes. The Il ask was then pressurized to 60 psi with hydrogen and shaken for 24 hours. The reaction mixture was filtered through Celite and the filter cake washed with 50 mL dichlorornethane. The solvents were then evaporated to yield the fmal polymer
(quantitative yield). Complete deprotectioii was determined by the absence of the benzyl protecting group peaks m the ;!i NMR. spectrum at 5.06 (s, 2H, PhCTy, ?.2?-7.33 (m, 511 aromatic).

Example 13: Polyfbenzylϋxy glycerol thiol carhonate-co-g-eaprolactorie)



5~(hen/.yIoxyniethyi)"I ,3-ditrmm~2-one and ε-capro-thiollaetone arc combined with varying ratios (to a lota! of 10,0 mπiol) in a IO mi schleαk flask and subsequently evacuated and Hashed with N? three times. Meanwhile, the catalyst (Sn(oet)2, 6.5 μ.L, 0,02 mmo!, monomer/initiator ratio ™ 500) is evacuated in a small flask for 60 minutes. 'The Schlenk flask is partially submerged in a thermostatted oil hath, preheated to 1400C Toluene (400 μt) is added to the catalyst and the mixture injected via syringe to the monomers. The reaction is stirred for 48 hours, removed from heat, and cooled to room lemperaturg. The polymer is dissolved in dichloromethane ( H) ml.) nnά precipitated in cold methanol The solvent is decanted and subsequently dried by evaporation. The resulting polymer tonus cither a viscous oil or while solid precipitate depending on the carbonate content of the copolymer.

Example 14: Pohi'hvdroxy glvcerol thiol carboftate-co-ε-eaprolaetone}



Polyfbeπzyloxy glycerol thiol carbomtte-co-ε-eaprolactone} is dissolved hi 50 mL dry dkhlor«nietbane inside a Parr bottle. 10% Pd/C (50 mg} and 20% Pd(OF! }2/C (50 mg) are added to the solution. Hie reaction mixture is evacuated and purged with hydrogen three times. The flask is pressurized to (SO psi with hydrogen and shaken for 24 hours. The reaction mixture is filtered through Celiie and the filter cake washed with 50 mL of diditoromethaue. The solvents are evaporated to yield the final polymer.

Example 15: Pol yf stearic acid thiol carbpηate-co-ε-caprolactorse)



Poly(benzyioxy glycerol thiol cafboπate-co-e-caproiactoπe). stearic acid, and P are dissolved in 100 mL dry dϊchloromeihane. OCC is added to the reaction mixture and a white precipitate forms. The .mixture is stirred for 24 hours at room temperature under nitrogen. The precipitate compound is isolated by filtration and the filtrate was concentrated. The concentrated filtrate is dissolved m dichioromethafte and precipitated in cold methanol (25 mL). The solvent is decanted sad subsequently dried by evaporation,



Bioabsorbable poly DX-laetiik-eo-glycoϋde (PLGA) mieroparticics can be used for the delivery of paclitaxcl. The fabrication techniques used to create PLGA microparticles were modified from Edluiid & Albertsson and Wang el. a!. (Edkmd et a.L, Adv. Polymer Sci, 1 57:67- I I 2, 2001 ; Wang ei aL, Cham. Fharm. Bull, (Tokyo) 44: 1935, 1996} and utilized a water in oil emulsion technique. First, 0.5 g of 75 :25 PLGA (Absorbable Polymer International, Birmingham, Alabama) tablets (the greater the ratio of lactic acid to glycolic acid the slower the release) were dissolved in 4 πiL
dichloromethatϊe (Sigma Aldπeh, St. Louis, MO) using a voriexiag device. After the plastic was completely dissolved, SO mg of paclitaxel (Taxol, MP Biomedical Irvine, California) previously solubiiized in -100 μl of dimethyl sulfoxide (DMSO, Fisher Hampton, NH), was added and further vortexed In the fabrication of control PLGA beads only DMSO was added. The solution was placed in 10 mi of 5% polyvinyl alcohol surfactant (Fisher) and vortexed for 15 minutes (or sonicated using a probe tip sαπieator} and stirred overnight. The mieropartieles were collected and washed three times in 30 πi L of distil led/deionized water. Following washing, the rmeropartieles were lyop'bilize-d (ireexe dried) and stored at -2O0C to insure the stability of PaditaxeL The encapsulation efficiency of taxol by the microparlieles was determined to be 74% -f/- 4% by HPLC analysis.

Example 17. Syndiesis of Naπoparticjcs by MiniemulsioR
Nanoparricles were prepared using a modification of a miniemulsioα
polymerization method previously reported (Landfester ei aL, Macromαiecuies 32:5222-8, 1999). Bdelly. 5-methyl-2-(2,4,6-trimethoxyphcriyl)-[i,3]-5-diox-anylmeώyl methaerylate and 2,2S"azobϊs{2-metiiylpropionitrile) (AlBN)5 a free-radieat initiator, were dissolved in dichloromethane, followed by removal of the solvent via roiary evaporstion until a viscous mixture remained. Alternatively, 5-τnethyJ-2-(2,4,δ-trimethoxyphe«yl)-[1 jSj-S-dioK-aiiyimethyl methacrylale, 0.25 mg of paclitaxel, and 2,2'-azobis(2-metbylpiυρiomtτi!e) (AIBN), a free-radical initiator, were dissolved in dichloromethane, followed by removal of the solvent via rotary evaporation until a viscous mixture remained. This viscous mixture was then mixed with a solution of sodium dodecyi sulfate, a stabilizing surfactant, in 10 mM pH 8 phosphate buffer. This mixture was then sonicated for 1 hour (1 second pulses with u 2 second delay) with 30 W of power, forming the nύniemulsion and allowing the solvent to evaporate. Foll.ow.hig somcation, the mim emulsion was transferred onto a temperature-controlled oil bath and stirred at 65 0C for 2 hours to initiate the free-radical polymerization. The resulting polymeric nanopariieks were then clialyzed against 5 mM pi 1 S phosphate buffer over two days to remove excess surfactant and salts.

5-Methyl-2-{2!4,6-tήmethox>phcnyl)-[l ,3]-5-dioxan-5-y3-mcthyl rnethaerysate was dissolved in dichiorom ethane, followed by removal of the solvent via rotary evaporation until a viscous mixture remained. Alternatively, rαc!hyl-2~phenyi-[l ,3 j-5-dioxanylmethyl methacrylate and 0.25 rag of paciitaxd was dissolved m
dichloromethane, followed by removal of the solvent via rotary evaporation until a viscous mixture remained. This viscous oil was then mixed with a solution of sodium dodecyl sulfate, the stabilizing surfactant, in 20 mM triethanoiamme buffer. This mixture was then sonicated for 30 min (I s pulses with a 2 s delay) with 30 W of power, forming the raid emulsion and allowing the solvent to partially evaporate. Following somcaϋon, Eosin Y and I -vinyl-2-pyrrolidone were added to the emulsion Io give final
concentrations of 0.2 rnM and 2 mM., respectively. This mixture was έhesi exposed to H giit from a mercury arc lamp operating at 300 W for 10 min while being stirred
'vigorously, causing polymerization. Following pholopolymerization, the particles were stirred overnight while open to the air to allow any remaining solvent to evaporate. 'The resulting polymeric nanopartieies were then diaiyzed against 5 mM pH S phosphate buffer over two days to remove excess surfactant and salts.

5-Methyi~2-(2,4}6-trimethoxyphenyi>[ 1 ,3]-5-dioxan ylniethyl methacrylate (0.45 g, 1.2 mmol) and benzoyl peroxide (2.6 mg, 0,01 1 mrnol) were dissolved in dry toluene {10 ml.). The flask was evacuated and refilled with nitrogen three times to remove oxygen. The mixture was then stirred at 70 '-1C for 14 hours. 'The solvent was removed by rotary evaporation, a«d the remaining materia! was dissolved in CThC.K (5 mL) and precipitated in cold diethyl ether (50 mL). The solid precipitate was collected by vacuum filtration. The product was obtained as a white powder at 36.5% yield, Na.noρartides were prepared by first dissolving the polymer (50 mg) in Ci-i^Cb (1.0 ml) and dissolving sodium dodecyl sulfate (50 mg} in άeionized water (10 mL). Alternatively, πtanoparticles were prepared by first dissolving the polymer (50 mg) and paclitaxel (0,5 Big) ift CHaCb. (1.0 mL) and dissolving sodktin dodeoyl sulfate (50 nig) m ddomzed water (10 mL). The organic solution was then added to the aqueous surfactant solution, and this mixture was sonicated at 30 W of power for 5 minutes to produce the emulsion. The mixture was stirred while open to the atmosphere overnight to evaporate the excess CHiC1Ii, Dialysis using a membrane with a 3400 molecular weight cutoff was used to remove excess surfactant Nanopartieles prepared using this monomer do not swell at pl l > 1.

Exarnple 20. Fabrication of Folyfhydroxy glycerol earboαate-co-E-ca-prolaetone)
Prug-eiuting Microparti cles
Poly{hydroxy glycerol carbonale-co-ε-eaprolactoϊie} mkrop&rticiεs were used for the delivery ofpemetrexed. The fabrication techniques used to create the røicropartieks utilize a water in oi! in water emulsion technique. First, 0.5 g of 20:80 polyϋhydroxy glycerol earbonate-co-ε-caproJactone) was dissolved in 4 rnL diehtoromethane (Sigma Aldricli, St. Louis, MO) using a vortexing device. Alter the polymer was completely dissolved, 50 mg of peπietrexed previously solubilized m 0,9% NaCL was added ami further vortexed. In the fabrication of control ρoly(hydroxy glycerol carbonate-co-f> caprtilactone) beads only 0.9% NaCl was added. The solution was placed in 1 C) tn\ of 5% poly vinyl alcohol surfactant (Fisher) and vortexed for 15 minutes (or sonicated using a probe tip sonieator) and stirred overnight. The micropmiicles were collected and washed three times in 50 ml of distϋled/deionized water. Following washing, the rnicroparUciεs were lyophilized (freeze dried) and stored at -200C to insure the stability of pernetrexed

Nanoparticles with Fluorescent Taa
7-(dictlwlamino)coumarin-3-carboxylic acid (0.005 g, 19.5 πmolk poly(5-hydroxy-l>3-dioxan~2~onc~co-ε-caprolactoαe) (1.5 g, 2.6 mraoh 22 mol % carbonate),

DCC (0.129 g> 0.63 tnraoi), and DMAP (0.032 g, 0.26 mrno!) were dissolved irs DCM (20 nit). The solution was stirred at RT for 18 hours. The DCU was filtered and the solvent evaporated (quantitative yield). The crude product was rεdissolved in. THF, purified using Sephadex LH -20 chromatography and further dislyzed (Pierce. 3,500 MW(X)) for approximately 4S hours to ensure all residual unbound dye was removed.
Cαumarin-bouπd copolymer particles were prepared by an emulsion/solvent evaporation method. Briefly, 1.0 g of copolymer was dissolved m 20 mL
dichioromethane. The solution was poured into a mixture of 200 mi. deionked water coαtaiπing 0.5% w/v SDS. The emulsion was stirred for 5 minutes before being sonicated (-3O W) tor 30 minutes, and finally dialyzed for approximately 48 hours to remove the SDS.
The nanopartlcle stock solution (5 mg/πiL) was diluted to a final concentration of 0.01 mg/mL with serum- free medium (Dulbecco's Modified Eagle Medium). A549 human lung carcinoma ceils (American 'Type Culture Collection, Maαassas. VA) were plated o.nk> a 96 well phis at a density of 5,000 cells/we!! and incubated overnight, or until about 90% confluence. The medium from each well was removed and replaced with 100 μi, oi'O.QI mg/mL nanoparticle solution and the cells were subsequently incubated with the particles for 2 hours. The nanoparticle suspension was then removed, the ceils were washed directly three times with PBS5 and the cells were imaged immediately via fluorescence microscopy with a FiTC filter.

Example 22: Fabrication. Qf PoIy(M^
The n-anopartieies were prepared by an emulsion/solvent evaporation method, Briefly, poly(atearie acid carbonaie-co-ε-caprolactoπc) was dissolved in 2(J mL dichioromethane. Alternatively, ρoly{ stearic acid carbonate-co-ε-caprolactone) was dissolved in 20 mL dichiororn ethane containing either 1 or 10 wi % pacliiaxel per weight of polymer. The solution was poured into a mixture of 200 mL ikiαruzed water containing 0.5% w/v SDS. The emulsion was stirred lor 5 minutes before being sonicated (--3O W) for 30 minutes, and finally dialyzed for approximately 1 hour to remove the SDS.

Example 23: Nanoparticie Expanding In Acidic. But Not. Neutral Conditio s



A sample of the nanopartieies from Example I S was diluted in buffer at a pH 4, 5, or 7.4 and maintained at 37 0C. The diameter of the particles was then measured at regular time intervals using dynamic light scattering (DLS), showing bow the particles increased m size over time. Poor to each DLS measurement, the samples were sonicated for 5 seconds to break up aggregates. Particle swelling from 100 nm in diameter to near 1 μm in diameter was observed (see Fig. 9), hi addition, the release of free 2,4,6-trimethoxyfaeπxaϊdehyde was observed using U YVYi s spectroscopy at a wavelength of 292 nm, also indicating deprotection of the polymer side groups (see Fig. ! Q).
These particles are useful for controlled release applications as well as for cosmetic applications in whicli the increase in volume could reduce wrinkles of increase trhe sized of tissue into which these polymers are injected,

Example 24: Nanoparticle ami Swelling from A Sugar Analog



Synthesis of 1 ;2;5/><M-0-i8opropyridene-3-0-!netluKry!oyi-a-D-gIuco&nmose: The s>τithesis of this compound was carried out as described by Black ei at and is described briefly, (Black ei aL, Journal of the Chemical Society, 4433-4439, 1963), 1 ,2:5,6-di-O~isopropyHdene-α-D~giucofuranose (1.00 g. 3,86 mmol) and metliacryϋc anhydride (1 ,2 mL, 1.2 g, 8.1 mmol) were dissolved in pyridine (5 ml.) and stirred at 63 °C lbr 3.5 hours. Then water (2.5 ml) was added, and stirring at 65 °C was continued for another 1.5 hours and then at room temperature overnight. The mixture was extracted with hexanes (5 mL X 3), and the combined hexanes extracts were then washed with ! M NaOH (15 ΪTJL X 3} and ddoπixed water (15 BiL)1 followed by drying over Na^SO.;. The .solvent was removed using rotary evaporation, and the remaining compound was dried under high vacuum. The product was obtained as a cleat oil at 74.2% yield.
Nanopartides were prepared from the resulting product by methods described herein. A sample of the nanopartieks was diluted in 0.1 M HCI and maintained at 25 0C. The diameter of the panicles was then measured at regular time intervals using dynamic light scattering CDLS), showing how the particles increased in size over time (Fig. 12). Fig. 12 shows thai at a pH of about 1.0, the particle size changes from about 200 nm to about 1600 nrø over the course of about 24 hoars, whereas at a pH of about 3.0, the particle size is stable over the same time period,

Example 25: Formation of Single-layer Polymer Films
Polymer films were cast onto glass by depositing a polymer soluu'o.π comprised of an individual copolymer including but not limited to poly(siearic acid carbonate- co-ε-capralaetenc), dissolved in dichlorometriarse, tetrahydrofuraα, or toluene, using a rmerosyrmge. 11>e solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours.

Example 2.6: Formation of Multi-layered Polymer Films
Poly( stearic acid carbonato-co-ε-caproiactoϊie) films were adhered between polyClactic-Cϋ-glyeotie acid) dims. A ρo!y(Iactic-co-glyeoiic acid}/dicMoromeihaαe solution was deposited onto glass using a rπierosyringe to form a film, A po!y(stearic acid caτboi\at.e-co-ε-caproiactoi}e)/dichloromethane solution was deposited onto the poly{Iactic-co-glycolic acid) film using a microsyriαge to form a second layer. A poly(lactic-co-glycoiic acid}/dichloroτnethaτie solution was deposited onto tJie poly poly(stcaric acid carbunate-co-K-caprolactone) film using a rnicrosyringe to form a third laver.

Exampje 27; Deposition of Polymer Films OΏ a Substrate
Polymer films were cast onto substrates composed of either glass, collagen, pericardium, TEFLON®, or titanium by depositing a polymer solution comprised of an individual copolymer including hat not limited to po!y(stearic acid carbonate-co~ε-caprolactofie), dissolved in άichlororaethane, tetrahydrofuran, or toluene, using a mierosyringe, The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours.

IJM!^j?lg-^-...McoΦoya^P.^JQ"^y^rPΛycaPtPΦ.ec:'n into Polymer HIms
Drug loaded polymeric films were cast or sprayed onto glass by depositing a polymer solution of poly{stearic acid carbonate-co-ε-caprolactone), dichloromethatie, and 10-hydrox yearn ptolheein5 using a mierosyrmge or aerosol device. The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hoars.

£M?$PJfi_29lJncoiIMaU^^
Patterned drug loaded polymeric films were cast onto glass by using a
microprinter or microsyringe by depositing a polymer solution of poly( stearic acid carbonate-co-ε-eaproiactone), dichioromethane. and lO-hydroxycamptotheein, in a controlled manner to form patterns such as stripes and dots. The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours. This method can also be used with more than one polymer simultaneously.

Exajrvpk_3{_lj$e^
Drug- loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly(caproiaetcme} (5 mg), diehloromethane (50 uL), and K)-hydrosycampioihecin (100 μg), using a microsyringe, Tm solvent was removed by slow evaporation over night, and then placed under reduced pressure for 24 hoars. An initial burst was seen over the first two days, releasing at a rate of about 5 μg/day.
Drug-loaded polymer films were also cast onto glass by depositing a polymer solution comprised of poty(stearie earborsate-eo-ε-eaprolactoBe) (5 mg), diehlotomethane (50 μL}, and paciitaxel (100 μg), using a miero.syri.nge. The solvent was removed by-slow evaporation over night and then placed under reduced pressure lor 24 hours. The resulting films were homogenous and opaque, with good adherence to the glass substrate. The films released taxol over time.

Example 31: Release of 10-Hydroxycaατptothecin or pacJϋaxei from
PoiyC stearic acid carbonate-co-ε-caprolaetone)
Drug-loaded polymer films were east onto glass by depositing a polymer solution comprised of poly( stearic acid carbotiate-co-ε-eaproiaetcme) i5 mg), dichloroinethane- (50 μL}, and l O-bydroxycamplotlieciii (100 μuj, using a niierosyringε. The solvertt was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. A slight initial burst was seen over the first two days, releasing at a rate of about 3 μg/day. Continuous release occurred over at least 30 days at a nearly constant rate of about 1 μg/day.
Alternatively, drug-loaded polymer films were east onto glass by depositing a polymer solution comprised of poϊyi'steaπc carbonate-co-ε-caprolactone) (5 mg), diebloromethane (50 μL), and paciitaxel (1 (K) μg), using is mierosyringe. The solvent was removed by skrw evaporation overnight and then placed under reduced pressure for 24 hours. The resulting films were homogenous and opaque, with good adherence to the glass substrate. The films released taxol over time.

Example 32: Release of iO-Hydroxycamptothecjn from
Folyihydroxy glycerol carbouate-co-g-eaprolactooe)
Drug- loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly(hydroxy glycerol carboπate-co-ε-caprolaetone) (5 Big),
diehlorometliane (50 μL), aαd 10-hydroxycamptomedn (100 μg), using a micros yringe. The solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hows, An initial burst was seen over the first day, releasing at a rate of about 18 μg/day. Continuous release occurred over at least 30 days, hegbmng at a rate of 3 μg/day and slowly decreasing to less than 1 μg/day at four weeks.

Example 33: In Vitro Tumor Cytoxieity with Paciitaxel-toaded


Lewis Lung Carcinoma (LLC) cells were washed with sterile phosphate buffered saline (PSS) and trypsinized. The cells were then counted using a Coulter counter and plated 3,000 cells/well m 96 well plates. Cells were serum starved overnight and then treated with empty nanoparticies, pad itax el-loaded nanoparticles (10% paelitaxel), and paeliiaxel-ioaded nanop&rtieles (1 % paclitaxel) for a five day period. A positive control contained 10% FBS or the same concentration of FBS provided for treated cells, while a negative control lacked FSS. At the completion of the assay the cells were incubated with 50 μL of I x Thiazolyl Blue Tetra^olmm Bromide (MTT, Sigma) dissolved in FBS at 370C for two hours. The .media was then aspirated and 100 μ.L of DMSO was added to each well, The plates were then placed on a shaking device for 10 minutes and the wells turned purple, corresponding wife the numbers of viable mitochondria in the well The plates were placed on an ELISA reader and scanned at a wavelength of 570 nm, The absorbanee values were normalized to values from a known number of stained cells. No cytotoxicity was observed with the empty naxioparticlcs (as a control. H(X ?}, whereas cytotoxicity was observed with the taxol loaded nanopartides, as shown m Figs. 4 ami 5.

Example 34: Release of t Q-Ii ydroxycainptothecin from
PolyCdauric, πiyristsc, palmitic, or stearic). glycerol carbonate-co-s-eaprolactone)
Drug-loaded polymer films were cast onto glass by depositing a polymer solution comprised of poly((faime, rayristie, palmitic, or stearic) earbonate-co-s-caprolaetone) (5 Big), dkhloromeihaπe (50 μL), and 10-hydτoxvcamptothecin (100 μg). using a πiicrosyriπge. The solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. An initial burst was seers over the first day, releasing at a rate of about S-IO μg/day. Continuous release occurred over at least 49 days, begimrhig at a rate of 1-3 μg/day and slowly decreasing to less than 1 μg/day at four weeks (see Fig, 6). FiG. 6 shows that increasing the hydro phobicity of the polymer decreases release from the polymers. Intermediate release profiles to those shown can be obtained by mixing or blending the polymers.

Example.35; Release of IQ-Hydroxycamptot&eein from
FMy(steMk.&lyg^
Drug-loaded polymer films were cast onto pericardium by depositing a pυfvτner solution comprised of poiy(stearic acid carlxmate-co-ε-eaprolactone) (5 nig),
dichloromethaπe (50 μL), and 10-hyάroxycamptothecm (100 μg), using a microsyringe. The solvent was removed by slow evaporation overnight and then placed under reduced pressure for 24 hours. An initial burst was seen over the first day, releasing at a rate of about. LO μg/day. Continuous release occurred over at least 40 days, beginning at a rate of 3 μg/day ant! slowly decreasing to less than ! μg-day at four weeks (see Fig. 7).

Example 36. . Cell Culture and Cell Proliferation Assays
Melanoma Bl 6 {murine). Calu 6 (human lung carcinoma), A549 (human lung carcinoma), and LLC' (murine Lewis Lung Carcinoma) were incubated (3? f'C, 5%€CVs with MEM {with 10% fetal bovine serum (FBS) and 1 % essential amino acids. The media was change once every three days. When not cultured, all. cell lines were stored m itPMI ireezmg media at -800C (with 50% FBS, 40% RPMi ami 1.0% dimethyl sulfoxide (DMSO)). Cell lines were trypsimϊxx! from 15 cm plates and seeded into 96 well plates at a concentration of 3000 ceils per well, All ceil lines were cultured for a period of at least three days before being tested in cell proliferation assays.
Tumor cells were washed with sterile phosphate buffered saline (PBS) and trypsinized. The cells were then counted using a Coulter counter and plated 3,(300 cells/well in 96 well plates. Cells were serum starved overnight and then treated with paditaxd, control microparticles, or pactitaxel loaded mieropartides the next day. A positive control contained 10% FBS or the same concentration of FBS provided for treated cells, while a negative control lacked FBS. At the completion of the assay the ceils were incubated with 50 μl of 1 x Thiazoiy! Blue Tettazolium Bromide (MTT, Sigma) dissolved in PBS at 373C tor two hours. The media was then aspirated and 100 μl of DMSO was added to each well The plates were then placed on a shaking device for 10 minutes and the wεlb turned purple, corresponding with the numbers of viable mitochondria in the well. The plates were placed on an EIJSA reader asid scanned at a wavelength of 570 nm. The absorbance values were normalized to values from a kaowa number of stained cells. The dose of paclitaxei at which 50% of cells are killed, or LD50, was determined to be between 1-10 ng/mL. Approximately 125,000 padmtxe! loaded mseropartides/mL were necessary to achieve similar pad itaxe I concentrations and cell death.

CeI! proliferation assays testing the effects of paciitaxei were performed using three tumor ceil lines, Lewis Lung Carcinoma (LLC), Melanoma and Caksδ (ramian lung cancer) ceil lines were plated at 3,000 cells/well and when established, cultured in .media with/without paelitaxeL Some cultures were maintained with optimal growth factors

(serum) whereas others were serum starved (non-growing} cultures. At the end of 5 days, tumor cell proliferation was assessed via MTT analysis. Dais was plotted by
normalization to the positive and .negative control cultures as 0% and 100% inhibition, respectively. The results indicated that media containing paάitaxe! at a concentration of 1 -10 ng/mL reliably inhibits growth of the LLC, melanoma, and CaI uό tumor cell Lines in proliferation assays. This data was obtained using media containing 10% FBS (positive control).
Ceil proliferation assays were utilized to study the effects of paclitaxd-loaded micropartieies on tumor growth. Tumor cells were plated at 3000 cells/well and positive (serum-rich) and negative (serum-poor) cultures were used to signify 0% and 100% growth inhibition respectively. It was found that the addition of 100,000-500,00O micropaiticles/nil results m inhibition equal to paelitaxel concentrations of --10 ng/mL despite the presence of serum rich media. Inhibition of tumor growth was not present with control (DMSO) microparticles that do not contain paciitaxeL These results demonstrate that paclitaxe! -loaded microparticles are an effective means of drug delivery and specifically result in an effective aπti- tumor response in vitro.
To determine the kinetics of the anti-tumor response elicited by pacliiaxel-loaded microparticles and to assess for a potential "buret effect" of drug release, a cell proliferation assay comparing paciitaxel-løaded microparticles and DMSO (control) roicroparticiεs using the melanoma cell line was run for five consecutive days with s plate undergoing MlT analysis each day for days 2-5. Paelitaxel loaded micropaπieles and DMSO micropartides were added to serum rich media and individually assessed on tumor cells of the same plate. The results demonstrate a dose-dependem inhibition with the admmistrsticrs of paciitaxe! micropartides, but little difference in inhibition for a given dose on day 2 vs. day 5. These findings confirm that paclitaxei micropartides inhibit tumor growth quickly with little difference in growth inhibition following the initial exposure. This is consistent with aa immediate release of drug and maximum burst effect.

Example 38. Naaopaniele Uptake by Cells
Fluorescent nanoparticles were created as describe herein with the addition of 2 mol% of a fluorescent co-raoπomer. Non-small cell lung cancer A549 cells were seeded onto a 96- well piste (20,000 ceils/ well) and incubated overnight at 37 "JC and 5% e&rboii dioxide, 'The media was then removed from the wells and replaced w.h a buffered saline solution containing fluorescent nanoparticles at a concentration of 0.5, 1. or 5 mg/rnL. Controls not containing πanoparticϊcs were also performed. After incubation at 37 0C and 5% carbon dioxide for 0.5, 1, 2, or 4 boars, the particle suspension was removed, and the cells were washed twice with buffered saline and then iysed with 10(1 μ.L of 0.5% Triton X-HJ0Φ in 0.2 M sodium hydroxide. Measuring the fluorescence of the cell lysale samples (excitation wavelength ~ 470 nm, emission wavelength ::: 518 nπs) and comparing to a standard curve gave tie concentration of nanoparticies in the samples. The cells showed increasing uptake over time and with decreased nanoparticle eonceritnUiori in the buffer,

Mesothelioma cell line (MSTO-21 1 H) is incubated (3? 0C. 5%CO2) with MEM

(with 10% fetal bovine serom (FBS), 1% essential amino acids, mά \%
Penieilliiv'StxeptoniyociB with L glutamine (Pen/Strep), F-12 HAM (with 10% FBS asid 1% Pen/Strep) and DMEM (with 10% FBS and 1% Fen/Strep) media respectively, with media changes once every three days. When not cultured, all cell lines were stored in RPMi freezing media ai -80 0C (with 50% FBS, 40% RPMl and iθ% dimethyl sulfoxide (DMSO)). CeI! lines were trypsinixed from 15 cm plates and seeded into % well plates at a concentration of 3000 cells per well All cell lines; were cultured for a period of at least three days before being tested in cell proliferation, assays.

Example 40, j>enietrexed./«.|7?w Mesothelioma Tumor CeH Proliferation Assays
Ceils were washed with sterile phosphate buffered saline (PBS) and trypsiπizcd.

Hie cells were then counted using a Coulter counter and plated 3,000 eelis/weil in 96 well plates. Cells were serum starved overnight and then treated with perαetrexed, contra! poly{ hydroxy glycerol carbonate-co-t-caprolactone) micropartides or pemetrexed loaded poiy(hydroxy glycerol carbonate-eo-e-caprolactoπe) microparticies the next day. A positive control contained 10% FBS or the same concentration of FBS provided for treated CeHs5 while a negative control lacked FBS, At the completion of the assay the cells were incubated with 50 μl of 1 x Thiazoly! Slue Teiraz.oliurø Bromide (MIl", Sigma) dissolved m PBS at 37 0C for two hours. The media was then aspirated and 100 μl of L)MSO was sdded to each well. The piaies were then placed on a shaking device for 10 minutes and the wells turned purple, corresponding to the number of viable mitochondria in the well. The plates were placed on an ELiSA reader and scanned at a wavelength of 570 πm. The aøsorbanee values were normalized to values from a known number of stained cells. 'The dose of pemetrsxcd at which 50% of cells were killed, or LD50, was determined to be between 0.1-1.0 μg/mL. Approximately 250,000-500,CiO(J pemetrexed loaded rmeroparticles/well or -100 microparticles/tumor cell were necessary to achieve similar pemetτexed concentrations and cell death,

In Vitro Tumor Cell Proliferation .AgMYg
Polymer films containing 10- hydroxycamptothecin { 10-1 !CPT) were east onto glass by depositing a polymer solution comprised of polyCsiearie acid earbonaie-c-o-ε-caprolactone) (5 mg}, dichloromethaiie (50 μL) and 10-hydroxycamptotbecin (100 μg) using a microsyringc. Films were exposed to Ultraviolet (UV) radiation overnight prior to being placed into 12-well plates containing 3,000 Lewis Lung Carcinoma (LLC) cells per well Cell cultures were incubated with films for muHiday exposure (Fig. 1} or 24-Iiour (Fig. 2) periods and then assayed for viability using MTT staining protocols. Both exposure durations provided effective inhibition of tumor cell proliferation out to 25 days and the muhidayexposure period continued to effectively kill tumor ceils as late as Day 30. By comparison, exposure to films containing no drug (unloaded films) under the same exposure conditions generated no cytotoxic effects (see Fig. I and 2). These results indicate thai our polymer films containing 10- hydroxycamptothecin ( 10-HOPT) can effectively kill tumor cells for as long as tkrity days.

Example 42: In KΦΌ Tumor Cytoxicity with Paclitaxd-ioadcd NanoparUcjgs
Cultured tumor eel! lines for lung (murine TXC and human A549 and NCI-R460}, melanoma (Blδ), mesothelioma (human MSTO-21 111), breast (human MCF?), human esophageal sarcoma (LM SOS) cancers were cultured at 37 0C / 5% CO> in the appropriate media supplemented with 10% Fetal Bovine Serum (FBS) &nά i%
penicillin/streptomycin with t-ghsiarome, with the exception of MEM media which also contained 1% essential amino acids and I mg/mL of bovine insulin. Bach cell Hoe was seeded at concentrations of 3,000 (LLC, BΪC>, A549, MSTO-21 ΪH, NC1-H46U), 5,000 (MCF7) or 10,000 (LMSO5) cells/well into 96-well assay plates in order to establish the appropriate tumor cell plating density. Cells were co-euitured for 7 days with paelitaxd-ioaded and imloaded 5-methy1-2-{2,4,6-trimethoxyphenyl)-l,3-<.iioxan-5-y1-iT\ethyi methaerylate nanopartides (fabrication described above). After the incubation period, cells were assayed for viability via MIT analysis and plotted as the percentage of viable ceils using a positive control (culture containing no nanopartkles) to rep.rese.nt 100% viability.
Fig. 16 shows the results for LLC and Fig. 17 shows the results for K--1STO-2! 1 H expe.rirae.ats and indicate that paciitaxei-loaded, but not iml.oa.ded, πanopariides reduce eel! proliferation for several different cancer lines at a concentrations as low as 10 μg/mL of polymer nanoparticles (containing approximately 100 ng/mL of Paciitaxel, consistent with the IC=O of free paclitaxe)}. FIG. 18 shows the anti-cancer activity of pacϋtøxef loaded nanopailicie witli LLC cells in vifro. These results indicate that our polwiers have sustained release, and that when loaded with an anti-cancer agent can actively kill cancer cells for sustained periods of time, which we believe may inhibit recurrence of the cancer.

Example 43. Quaiϊtiii cation of Mieropartiele Adherence to Lung
To investigate microparticle attachment to Iufsg tissue, PlXiA rmcropartseJes were suspended in Pluronic NF-127 or water ami each solution was painted onto the intact mouse lungs. The lungs were rocked side-to-side in PBS, simulating the eoLiting of pleural fluid, for differing time periods and the percent of adherent mieropartiebs was determined using a coulter counter. After a one hour exposure to PBS wetting the lung, the supernatant was removed and counted for adherent microparticies. Plates were thoroughly rinsed to avoid counting adhesion to the plate rather then lung. The percent of mieropartieles adhering to lung was found by averaging the number of microparticies released to the supernatant, it was found that there is a much higher percent attachment (S9.9 -!/■■ 10) of iiύcropartieles loaded in Pluronic HIM 27 gel than with microparticies loaded in a water control (28.3 +/- 28). 'The difference in these attachment percentages is statistically significant (P < 0.05), and indicates that adhesives such as P LU RON 1C® NF 127 gel can he used to adhere mioropartilces to tissue, such as long tissue.

Example 44. Anti-Tumor Response In Vivo
Lewis Lung Carcinoma cells (LLC) (750,000) were injected with or witiioui 50 million PLGA-Paclitaxel loaded microparticies subcutaneous! y in C57BL6 mice. It is well established that this tumor dose results in subcutaneous tumor nodules within 1 week with rapid growth requiring sacrifice within 2-3 weeks. In the time following injection it was found that asmor size was significantly decreased in animals receiving LLC cells and PLGA-paditaxel microparticies vs. LLC cells alone. Ai. sacrifice, untreated tumors weighed 3.8 -£ 0.9 grams whereas tumors co-injected with PLGA-paclitaxel loaded mkrαpartieles (n - 7) weighed 1.0 ^ 1.4 grams (Day 13- 17, p < 0.05). The majority of PLGΛ-paclilaxel loaded microparticle treated animals developed minima] evidence of tumor implantation or growth, No toxicity from PLGA-pachtaxel administration was noted. Thus, the data suggests that locally delivered chemotherapy via microparticies can dεier the growth and establishment of lung carcinoma In vivo m this subcutaneous model of tumor implantation.
Fabricated microparticles were ! -5 μm in diameter, smooth, and laek porosity suggesting that they will maintain a relatively constant drug release for a long period of time. It is estimated that paelitaxel has tumorddal effects in the 5-10 πg range, which is estimated to be about 3 rnicropaitleles per cell. In vivo co-injection of ixtmor ceils and Paclstaxe! loaded microparticles denjonsirate that a dose of 100 million rnieropartieies completely inhibits growth and establishment of tumor cells. Proliferation assays and in 5 vivo injections have also demonstrated that the control PLGA røieroparticles are inert and without effect on tumor growth,

ExaπiMg.15:. Ami-Tumor Response of Functio al Loaded Na^opartldeg In .. FjVg
The anO-tαmor effects of chemotherapy-loaded nanopaπieles from Example IS 0 were evaluated in well-established subcutaneous tumor models. Mouse LLC or human MSTO-2 ! !H cancer edl lines were implanted into C57BL6 or nude mice, respectively. Cultured umior cell suspensions were co-injected with drug-ioaded muioparticϊes into the subcutaneous tissues of the back of mice. Both "high" (25 microgram paclϋaxe!) and ''low" (2.5 microgram paclitaxei) doses of fianαparUcies were evaluated. Animals δ injected with tumor ceils alone in PBS, tumor with identical doses of unloaded functional or loaded rsoiv functional (non-expansile) nanoparticles served as controls. Tumor size was monitored biweekly and animals were euthanized if tumors reached 2 cm m ske. As demonstrated Fig. 13, both the high and low doses of paclitax.e-1- loaded functional nanoparticles inhibited tumor growth in mice (p « 0,0001). and were much more 0 effective than even the paciitaxel-ioaded but non-expansiie nanoparticles. "These data clearly demonstrate that the anti-tumor effects of paclitaxel-loaded functional nanopartietes seen in vitro translates to suppression of tumor growth in viva.

.Example 46: Anti-Tμτnρr Response of Subcutaneous Polymer Film Implantation In Vivo 5 The anti-tumor effects of chemotherapy-loaded polymer film implants were also evaluated using a subcutaneous tumor model. After induction of anesthesia, C57BL/6 mice were shaved and skin on the hack of the mouse was prεppεd in a sterile fashion. An incision of 0.8 em was made between the shoulders of the mice. The connective tissue under the skin was dissected with a pair of sterilized tweezers to make a subcutaneous pocket, A piece of sterilized polymer .film dried on a pericardium strip (O.S x. 0.8 cm) was inserted into the subcutaneous pocket with the drag-loaded side of the film placed upward towards the skm, ami the incision was closed with 5-0 sutures. .Mice were monitored until fully recovered from anesthesia, given analgesics and were housed in a SPF {specific pathogen .fee) grade animal facility. Two days were allowed for healing of the incision, before 750,000 mouse LLC tumor cells were injected subeutarieously on top of the implanted film via a 2?-guage needle,
Tumor size was monitored biweekly and animals were euthanized if tumors reached 2 cm in size. Tumor growth aid not occur overtop of polymer films loaded with 30 μg iϋ-hydroxycampiothecin (1 (MiCPT) in any of the experimental mice (see Fig. 14). This is hi contrast to the significant tumor growth thai occurred directly on the unloaded polymer iiims in over 75% of the animals tested. Some animals that had received I 0-HCPT loaded polymer films did develop tumors with delayed foliow-υp but these tumors were always in the periphery of the pocket and away from the film Itself (see Fig. \ S). hi addition to the delay in turner appearance, these tumors were significantly smaller in size (p < 0,005), confirming that the i0-HCPT loaded films prevented and/or delayed local tumor growth in the in vivo tumor model .

Example 47: Ko Delay M ..Wound Healing In the . Presence of Subcutaneous

Polymer iiims were subcutaneously implanted on the back of C57BL/6" mice under anesthesia as described herein. Healing was assessed by inspection in animals that received 1 (M-ICPT loaded polymer films, unloaded polymer iiims or sham surgery where subcutaneous pockets were prepared but no film was implanted. All incisions were closed with S-O suture. There was no evidence of wound dehiscence early or late (up to 21 days) m animals that received loaded or unloaded films, in addition, there was no difference in erythema or wound appearance among animals with films versus sham surgery.

The local drug release pattern of subciuaneousiy implanted drug-loaded polymer films in vivo was examined. Polymer films were subcutaneously implanted on the back of C57BL/6 mice under anesthesia as described above. At weekly intervals following implantation of the films, the surrounding tissues were harvested. These tissues were cut in a radial fashion away from the film and sequentially segmented at I mm distances away from the film, thus providing tissue for assessment at various distances and directions away from the drug-loaded film. The concentration of the drug eluted at the various distances was then ascertained within each tissue segment using MPLC for the specific drug of interest. The gradient of drag concentration within a 2 em diameter of the center of the film was then plotted to establish the drug release kinetics and drug distribution into the surrounding tissues in vivo.

Example 49: Tumor Recurrence Model of Subcotaneous Tumor Resection
The suppression of tumor recurrence by drug-loaded nanopatticles and drug-loaded polymer films are also being examined using a well established in vivo tumor mode) (Qadri et m... Ann Thorae Surg 80:1046-51, 2005). Similar to the subcutaneous tumor niodd utilized in Example 48, 750,000 LLC1 rumor ceils were injected
subcutaneous!? and allowed to grew. The tumor was subsequently resected through a 1.0 em incision parallel to the tumor and the entire tumor is removed and the incision closed in control animals. Unloaded or drug-loaded nanoparticles or polymer films are applied onto the tumor bed of experimental animals and the skin incision is similarly closed. Animals are assessed biweekly for evidence of recurrent tumor growth which our pilot studies have demonstrated occurs aggressively in coitfrol animals thai do not receive drug- loaded naaoparticles or polymer films.

Example 50: In Vivo Intraperitoneal Mesothelioma Animal Experinu-rst with
Paditaxel-Loaded NanoparUdes
The abi lity of drug-loaded nanoparticles to inhibit the growth of human tumor cells in vivo within the intraperitoneal cavity has also been investigated using a murine model of mesothelioma using a well established in vivo tumor model {AdusuπύJU et <</., J Thorac Cardiovasc Sarg. 132:1 ! 79-88, 2006). Cultured mesothelioma tumor cells (5 million MSTO-21 I H) were co-injected with paclitaxel-loaded fcnctional nanoparticles via an i.p. injection into the lower abdomen of NLVJ (nude) mice. Animals injected with tumor cells alone in PBS or tumor with identical doses of loaded r.on-functional (non- expansile) naiioparticles served as consols for tumorigenieity and αanoparticle. toxicity, respectively.

Example 51 ; SEM of Films
Drug-loaded polymer films were cast onto glass by depositing a polymer solution comprised of polyC'slearic earbonate-co-ε-caprolaetone) (5 nig), dichloromiihane (50 μt), and I O-hydroxyearnpioiht'cin (100 μg), using a micro syringe. The solvent was removed by slow evaporation over night and then placed under reduced pressure for 24 hours. Prior to imaging, the films were coated with 7 am of Aa/Pd. The films were imaged using scanning electron microscopy. The surfaces of the films appeared smooth and non-porous with fshrous-lske mierotexiure. As shown in Rg, S, cross-section images also revealed a smooth, non-porous interior with consistent thicknesses throughout She length of the film of approximately 40 microns.

Example 52: SEM of N aripparti cl es
Samples for scanning electron microscope (SEM) imaging were prepared by diluting a sample of nanoparticles io a concentration of 0.25 mg/mL with deionked water, A 10 μL portion of the diluted sample was then placed on a clean aluminum stub ami allowed to air dry. Prior to imaging, the samples were coated with a 5 rim layer of Au-Pt. Samples were then imaged on a Zeiss SUPRA 40VP Held emission SUM using an accelerating voltage of 1 kV. 'The image in Fig. { 1 shows particles from about 1 to 50 microns with most of the particles between 5 and 20 microns.

Example 53: Contact. Angle Measurements
Polymer films were cast onto glass substrates and the contact angle of each film was determined using contact angle goniometry. Contact angles ranged from 75 ■■■• 120". For example, the contact angle of polyCsieaiϊc acid earbonatc-co-ε-caproiactoϊie} was 1 1 δ'l The contact angle of glass is about 35°.

Example 54: .Thermal Transition Measurements
Thermal transitions of each polymer were measured using differential scanning caloήmetry. Polymers composed of ε-caprolactone and beαzyloxy glycerol carbonate monomers were formed with the following carbonate mole fractions: 0,05, 0.10, 0.20, 0.30, 0.40, 0.50, 1.00. Glass transition temperatures ranged from -64 X to -10 0C and melting temperatures ranged from 22 0C ~ 5? "C. Some copolymers were semi- crystailine and other copolymers were amorphous.

Q OTHER EMBODIMENTS
It. is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the 5 following, claims.