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1. WO2020160511 - COMPLEXES DE PÉNÉTRATION CELLULAIRE IMMOLATEURS POUR L'ADMINISTRATION D'ACIDES NUCLÉIQUES AU POUMON

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A cell penetrating complex comprising a nucleic acid non-covalently bound to a cationic amphipathic polymer,

wherein said cationic amphipathic polymer has the formula:


wherein

R1A is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3,

CHCh, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2,

-COOH, -CONH2, -N02, -SH, -SO3H, -SO4H, -S02NH2, -NHNH2, -ONH2,

-NHC(0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)0H, -NHOH,

-OCCI3, -0CF3, -OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R2A is independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3,

CHCh, -CHBr2, -CHF2, -Cffl2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2,

independently -COOH, -CONH2, -N02, -SH, -SO3H, -S0 H, -S02NH2, -NHNH2, -ONH2, independently -NHC(0)NHNH2, - NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)0H, -NHOH,

-0CCI3, -0CF3, -OCBr , -OCI3, -OCHCh, -OCHBr2, -OCHh, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L1 and L2 are independently a bond, -C(0)0-, -0-, -S-, -NΉ-, -C(0)NH-, -NHC(O)-, -S(0)2-, -S(0)NH-, -NHC(0)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

LP1 and LP2 are independently a lipophilic polymer domain;

X1 is a bond, -C(R5)(R6)-, -C(R5)(R6)-C(R7)(R8)-, -0-C(R5)(R6)-, or

-0-C(R5)(R6)-C(R7)(R8)-;

X2 is -O- or -S-;

R1, R2, R5, R6, R7, and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

L4 is independently a bond, -C(0)0-, -O-, -S-, -NF1-, -C(0)NF1-,

-NHC(O)-, -S(0)2-, -S(0)NH-, -NHC(0)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R40, R41, and R42 are independently hydrogen, substituted or unsubstituted alkyl or susbstituted or unsubstituted heteroalkyl;

Z is -S-, -S+R13-, -NR13-, or -N+(R13)(H)-;

R13 is hydrogen, -CCI3, -CBr3, -CF3, -Cl3,-CN, -OH,

=0, -NH¾ -COOH, -CONH2, -SH, -SO3H, S02NH2, -OCCI3, -OCF3, -OCBr3,

-OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

nl is an integer from 0 to 50;

zl and z3 are independently integers from 0 to 100, wherein at least one of zl or z3 is not 0;

z2 is an integer from 2 to 100;

z4 is an integer from 1 to 100;

and

z5 is an integer from 1 to 10.

2. The cell penetrating complex of claim 1, wherein Xi is CTh.

3. The cell penetrating complex of claim 1, wherein L4 is independently substituted or unsubstituted C2-C8 alkylene.

4. The cell penetrating complex of claim 1, wherein L4 is independently unsubstituted C2-C8 alkylene.

5. The cell penetrating complex of claim 1, wherein L4 is independently unsubstituted C2 alkylene, unsubstituted C3 alkylene or unsubstituted C4 alkylene.

6. The cell penetrating complex 0 of claim 1, wherein L4 is independently unsubstituted C3 alkylene or unsubstituted C4 alkylene.

7. The cell penetrating complex of claim 1, wherein R40, R41, and R42 are independently hydrogen or substituted heteroalkyl.

8. The cell penetrating complex of claim 1, wherein R40, R41, and R42 are independently hydrogen or -C(NH)NH2.

9. The cell penetrating complex of claim 1, wherein at least two of R40, R41, and R42 are hydrogen and one is -C( H)NH2.

10. The cell penetrating complex of claim 1, wherein Z is -N+(R13)(H)- and R13 is hydrogen.

11. The cell penetrating complex of claim 1, wherein R1 and R2 are independently hydrogen or substituted or unsubstituted alkyl.

12. The cell penetrating complex of claim 1, wherein nl is 2.

13. The cell penetrating complex of claim 1, wherein X2 is 0

14. The cell penetrating complex of claim 1, wherein zl or z3 are independently integers from 10-40.

15. The cell penetrating complex of claim 1, wherein z2 is independently an integer from 3-20.

16. The cell penetrating complex of claim 1, wherein LP1 has the formula:


wherein

n21 is an integer from 1 to 100;

R201 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

17. The cell penetrating complex of claim 16, wherein n21 is 10-40.

18. The cell penetrating complex of claim 16, wherein R201 is unsubstituted C12 alkyl.

19. The cell penetrating complex of claim 16, wherein LP2 has the formula:


wherein

n22 is an integer from 1 to 100;

R202 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

20. The cell penetrating complex of claim 19, wherein n22 is 10-35.

21. The cell penetrating complex of claim 19, wherein R202 is unsubstituted C12 alkenyl.

22. The cell penetrating complex of any one of claims 1-18, wherein said cationic amphipathic polymer has the formula:


wherein n21 is an integer from 10 to 20;

R201 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and

z2 is independently an integer from 3-10.

23. The cell penetrating complex of claim 22, wherein n21 is 14, R201 is dodecyl and z2 is 8.

24. The cell penetrating complex of claim 1, wherein said cationic amphipathic polymer has the formula:

wherein n22 is an integer from 10 to 35;

R202 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl; and

z2 is independently an integer from 5-20.

25. The cell penetrating complex of claim 26, wherein n22 is 14, R202 is dodecyl and z2 is 7.

26. The cell penetrating complex of claim 1, further comprising a second cationic amphipathic polymer, wherein said second cationic amphipathic polymer is different from said cationic amphipathic polymer.

27. The cell penetrating complex of claim 26, wherein said second cationic amphipathic polymer has the formula:


n23 is an integer from 1 to 100;

z6 is an integer from 5-15;

R3A is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3,

CHCk, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2,

-COOH, -COMB, -N02, -SH, -SO3H, -S04H, -S02M12, -NHNtC, -OMB, -MTC(0)MTMB,

HC(0) H2, -NHSC H, -NHC(0)H, -NHC(0)0H, - HOH, -OCCb, -OCF , -OCBr3, -OCI3

-OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

R203 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl.

28. The cell penetrating complex of claim 27, wherein n23 is 13, z6 is 11 and R203 is dodecyl.

29. A cell penetrating complex comprising a nucleic acid non-covalently bound to a first cationic amphipathic polymer and a second amphipathic polymer,

wherein said first cationic amphipathic polymer has the formula:


or

wherein

R1A is independently hydrogen, halogen, -CCI3, -CBn, -CF3, -CI3,

CHCb, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2,

-COOH, -CONH2, -N02, -SH, -SO3H, -SO4H, -S02NH2, -NHNH2, -ONH2,

-NHC(0)NHNH2, -NHC(0)NH2, -NHSOZH, -NHC(0)H, -NHC(0)0H, -NHOH,

-OCCI3, -0CF3, -OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R2A is independently hydrogen, halogen, -CCI3, -CBr3, -CF3, -CI3,

CHCb, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, independently -COOH, -CONH2, -N02, -SH, -SO3H, -S0 H, -S02NH2, -NHNH2, -ONH2, independently -NHC(0)NHNH2, -NHC(0)NH2, -NHS02H, -NHC(0)H, -NHC(0)0H, -NHOH, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCh, -OCHBr2, -OCHb, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

L1 and L2 are independently a bond, -C(0)0-, -0-, -S-, -NH-, -C(0)NH-, -NHC(O)-, -S(0)2-, -S(0)NH-, -NHC(0)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

LP1 and LP2 are independently a lipophilic polymer domain;

X1 is a bond, -C(R5)(R6)-, -C(R5)(R6)-C(R7)(R8)-, -0-C(R5)(R6)-, or

-0-C(R5)(R6)-C(R7)(R8)-;

X2 is -O- or -S-;

R1, R2, R5, R6, R7, and R8 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

L4 is independently a bond, -C(0)0-, -0-, -S-, -NH-, -C(0)NH-,

-NHC(O)-, -S(0)2-, -S(0)NH-, -NHC(0)NH-, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

R40, R41, and R42 are independently hydrogen, substituted or unsubstituted alkyl or susbstituted or unsubstituted heteroalkyl;

Z is -S-, -S+R13-, -NR13-, or -N+(R13)(H)-;

R13 is hydrogen, -CCh, -CBr3, -CF3, -CI3,-CN, -OH,

=0, -NH2, -COOH, -CONH2, -SH, -S03H, S02NH2, -0CC13, -OCF3, -OCBr3,

-OCI3,-OCHCl2, -OCHBr2, -OCHI2, -OCHF, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

nl is an integer from 0 to 50;

zl and z3 are independently integers from 0 to 100, wherein at least one of zl or z3 is not 0;

z2 is an integer from 2 to 100;

z4 is an integer from 1 to 100;

z5 is an integer from 1 to 10; and

wherein said first cationic amphipathic polymer and said second amphipathic polymer are different.

30. The cell penetrating complex of claim 29, wherein said first cationic amphipathic polymer has the formula:


wherein n21 is an integer from 10 to 20;

R201 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl; and

z2 is independently an integer from 3-10.

31. The cell penetrating complex of claim 30, wherein n21 is 14, R201 is dodecyl and z2 is 8.

32. The cell penetrating complex of claim 29, wherein said first cationic amphipathic polymer has the formula:


wherein n22 is an integer from 10 to 35;

R202 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl; and

z2 is independently an integer from 5-20.

33. The cell penetrating complex complex of claim 32, wherein n22 is 14, R202 is dodecyl and z2 is 7.

34. The cell penetrating complex of claim 29, wherein said second cationic amphipathic polymer has the formula:

wherein n23 is an integer from 1 to 100;

z6 is an integer from 5-15; and

R3A is independently hydrogen, halogen, -CCh, -CBn, -CF3, -CI3,

CHCb, -CHBr2, -CHF2, -CHI2, -CH2C1, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2,

-COOH, -COMB, -N02, -SH, -SO3H, -S04H, -S02Mi2, -NHNH2, -ONH2,

-MfC(0)MiMi2, -NHC(0)NH2, -NHS02H, -NHC(0)H, -MiC(0)OH, -MiOH,

-OCCI3, -OCFs, -OCBr3, -OCI3, -OCHCb, -OCHBr2, -OCHb, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

R203 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or

unsubstituted heteroaryl.

35. The cell penetrating complex of claim 34, wherein n23 is 13, z6 is 11 and R203 is dodecyl.

36. The cell penetrating complex of claim 29, wherein said first cationic amphipathic polymer has the formula:


wherein n21 is 14, R201 is dodecyl and z2 is 8; and

wherein said second cationic amphipathic polymer has the formula:

wherein n23 is 13, R203 is dodecyl and z6 is 11.

37. The cell penetrating complex of claim 34, wherein said first cationic amphipathic polymer has the formula:


wherein said second cationic amphipathic polymer has the formula:


wherein n23 is 13, R203 is dodecyl and z6 is 11.

38. A nanoparticle composition comprising a plurality of cell-penetrating complexes according to claim 1 or 29.

39. A pharmaceutical composition comprising a cell-penetrating complex of claim 1 or 29 and a pharmaceutical excipient.

40. A method of transfecting a nucleic acid into a cell, the method comprising contacting a cell with a cell -penetrating complex of claim 1, 26 or 29.

41. The method of claim 40, wherein said cell is a lung cell.

42. The method of claim 40, wherein said cell is a reticulocyte.

43. The method of claim 40, wherein said cell is a hematopoietic stem cell.

44. A method of transfecting a nucleic acid into a reticulocyte, the method comprising contacting a cell with a cell -penetrating complex of any one of claims 26 or 29.

45. A method of transfecting a nucleic acid into a hematopoietic stem cell, the method comprising contacting a cell with a cell-penetrating complex of any one of claims 26 or 29.

46. A method of delivering a nucleic acid to the lung of a subject in need thereof, said method comprising administering to said subject a cell-penetrating complex of any one of claims 1, 26 or 29.

47. The method of claim 46, wherein said cell-penetrating complex is not directly administered to the lung.

48. The method of claim 46, wherein said cell-penetrating complex is administered intravenously.

49. A method of delivering a nucleic acid to a plurality of tissues in a subject in need thereof, said method comprising administering a cell-penetrating complex of any one of claims 26 or 29.

50. The method of claim 49, wherein said plurality of tissues include at least one of spleen, liver, lungs, kidney, heart, thymus, muscle, brain, ovaries, gut associated lymphoid tissue (GALT), pancreas, bone marrow, lymph nodes, circulating cells of hematopoietic origin or adrenal glands.