Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same

• US 20100330023A1
• Filed: 05/25/2010
• Published: 12/30/2010
• Est. Priority Date: 01/11/2008
• Status: Active Grant

• Current Assignee: Serina Therapeutics, Inc.
• Original Assignee: Serina Therapeutics, Inc.
• Inventors: Bentley, Michael David, Fang, Zhihao, Harris, J. Milton, Yoon, Kunsang, Viegas, Tacey
• Granted Patent: US 8,101,706 B2
• Time in Patent Office: Days
• US Class Current: 424/78.3
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 47/59 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C08G 73/0233 Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups

Abstract

The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.

Claims

1. A target molecule-POZ conjugate comprising at least one target molecule linked to a heterofunctional polyoxazoline derivative of the general structure:

R₁—

{[N(COX)CH₂CH₂]_o—

[N(COR₂)CH₂—

CH₂)]_n}_a—

S-U-W

wherein;

R₁ is an initiating group;

R₂ is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl or an unsubstituted or substituted heterocyclylalkyl group;

U is a linking group;

X is a pendent moiety containing a first functional group;

W comprises a moiety bearing a second functional group;

a is ran which indicates a random copolymer or block which indicates a block copolymer;

o is an integer selected from 1-50;

n is an integer selected from 0-1000; and

wherein the first and second functional groups are chemically orthogonal to one another; and

wherein the at least one target molecule is linked to the polyoxazoline derivative through at least one of the first or second functional groups

2. The target molecule-POZ conjugate of claim 1 wherein the first functional group and the second functional group are each independently selected from the group consisting of:

an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide and an orthopyridyl disulfide.

3. The target molecule-POZ conjugate of claim 1 wherein the second functional group is selected from the group consisting of a carboxylic acid, an activated carboxylic acid, an active ester or an amine.

4. The target molecule-POZ conjugate of claim 2 wherein the carboxylic acid of at least one of the first or second functional group is a negatively charged species and the amine of at least one of the first or second functional group is a positively charged species.

5. The target molecule-POZ conjugate of claim 1 wherein R₁ is a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.

6. The target molecule-POZ conjugate of claim 2 wherein at least one of the first or second functional groups is a negatively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding or wherein at least one of the first or second functional groups is a positively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

7. The target molecule-POZ conjugate of claim 1 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety.

8. The target molecule-POZ conjugate of claim 7 wherein the target molecule linked to the polyoxazoline derivative through the first functional group and the second functional group are independently an organic molecule, a drug, a peptide, a protein, an antibody, an antibody fragment, a carbohydrate or an oligonucleotide.

9. The target molecule-POZ conjugate of claim 1 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a targeting moiety.

10. The target molecule-POZ conjugate of claim 9 wherein the therapeutic moiety is a drug and the targeting moiety is a peptide, a carbohydrate or an organic molecule.

11. The target molecule-POZ conjugate of claim 1 wherein the number of target molecules linked to the polyoxazoline derivative through the first functional group is less than or equal to the value of o.

12. The target molecule-POZ conjugate of claim 11 having the general structure:

13. A target molecule-POZ conjugate comprising at least one target molecule linked to a heterofunctional polyoxazoline derivative of the general structure:

{R₁—

{[N(COX)CH₂CH₂]_o−

[N(COR₂)CH₂—

CH₂)]_n—

[N(COY)CH₂—

CH₂)]_m}_a—

K_k—

}_d—

R-Q_q-Z

wherein;

R₁ is an initiating group;

R₂ is independently selected for each polyoxazoline chain from a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclylalkyl group;

X is a pendent moiety bearing a first functional group;

Y is a pendent moiety bearing a second functional group;

K is a linking moiety linking each polyoxazoline chain to a branching moiety R, K being independently selected for each polyoxazoline chain;

Q is a linking moiety linking the branching moiety R to Z;

R is a branching moiety capable of forming linkages with Z, either directly or through linking group Q, and with each polyoxazoline chain, either directly or through the linking group K;

Z is a moiety containing a third functional group or an inert group;

a independently selected for each polyoxazoline chain from ran which indicates a random copolymer or block which indicates a block copolymer;

d is an integer selected from 2-8;

k is an integer independently selected for each polyoxazoline chain from one or zero;

q is an integer selected from one or zero;

o is an integer independently selected for each polyoxazoline chain from 1-0.50;

m is an integer independently selected for each polyoxazoline chain from 0-50;

n is an integer selected from 0-1000;

wherein at least two of the first, second and third functional groups are chemically orthogonal to one another; and

wherein the at least one target molecule is linked to the polyoxazoline derivative through at least one of the first, second or third functional groups.

14. The target molecule-POZ conjugate of claim 13 wherein m=0 and Z contains the third functional group and the target molecule-POZ conjugate contains the first and third functional groups, the third functional group being chemically orthogonal to the first functional group, or wherein Z is an inert group and m is an integer independently selected for each polyoxazoline chain from 1-50 and the target molecule-POZ conjugate contains the first and second functional groups, the second functional group being chemically orthogonal to the first functional group.

15. The target molecule-POZ conjugate of claim 14 wherein R₁ is independently selected for each polyoxazoline chain from a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.

16. The target molecule-POZ conjugate of claim 14 wherein the first functional group is an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide and the second or third functional group is an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide.

17. The target molecule-POZ conjugate of claim 14 wherein at least one of the first, second or third functional group is a negatively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

18. The target molecule-POZ conjugate of claim 14 wherein at least one of the first, second or third functional is a positively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

19. The target molecule-POZ conjugate of claim 14 wherein Q is a substituted or unsubstituted alkylene.

20. The target molecule-POZ conjugate of claim 14 wherein K is independently selected for each polyoxazoline chain from —

(CH₂)_pO—

, —

(CH₂)_p—

CO—

, —

S—

(CH₂)_pCONH—

, —

S—

(CH₂)_pCO, —

(CH₂)_p—

NHCSO—

, —

(CH₂)_p—

NHCO₂—

, —

NH—

(CH₂)_p, or —

NHCO₂—

, where p is an integer from 0-10.

21. The target molecule-POZ conjugate of claim 14 wherein R is —

NH—

CH—

(CH₂)₃—

CH₂—

NH—

, a nitrogen, an aryl group, or —

CR₃—

, where R₃ is hydrogen or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted aralkyl group.

22. The target molecule-POZ conjugate of claim 14 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second or third functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety.

23. The target molecule-POZ conjugate of claim 22 wherein the target molecule linked to the polyoxazoline derivative through the first functional group, the second functional group and the third functional group are independently an organic molecule, a drug, a peptide, a protein, an antibody, an antibody fragment, a carbohydrate or an oligonucleotide.

24. The target molecule-POZ conjugate of claim 14 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety and the target molecule linked to the polyoxazoline derivative through the third functional group is a targeting moiety or the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a targeting moiety when the target molecule linked to the polyoxazoline derivative through first functional group is a therapeutic moiety or a therapeutic moiety when the target molecule linked to the polyoxazoline derivative through first functional group is a targeting moiety.

25. The target molecule-POZ conjugate of claim 24 wherein the therapeutic moiety is a drug and the targeting moiety is a peptide, a carbohydrate or an organic molecule.

26. The target molecule-POZ conjugate of claim 14 wherein the number of target molecules linked to the polyoxazoline derivative through the first functional group is less than or equal to the value of o the number of target molecules linked to the polyoxazoline derivative through the second functional group is less than or equal to the value of m.

27. A method of treating cancer in a subject in need of such treatment, said method comprising the step of administering to the subject a therapeutically effective amount of a target molecule-POZ conjugate having the general structure:

R₁—

{[N(COX)CH₂CH₂]_o—

[N(COR₂)CH₂—

CH₂]_n}_a—

S-U-W

wherein;

R₁ is an initiating group;

R₂ is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl or an unsubstituted or substituted heterocyclylalkyl group;

U is a linking group;

X is a pendent moiety containing a first functional group;

W comprises a moiety bearing a second functional group;

a is ran which indicates a random copolymer or block which indicates a block copolymer;

o is an integer selected from 1-50;

n is an integer selected from 0-1000;

wherein the first and second functional groups are chemically orthogonal to one another; and

wherein the at least one target molecule is linked to the polyoxazoline derivative through at least one of the first or second functional groups.

28. The method of claim 27 wherein R₁ is independently selected for each polyoxazoline chain from a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.

29. The method of claim 27 wherein the first functional group and the second functional group are each independently selected from the group consisting of:

an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide and an orthopyridyl disulfide.

30. The method of claim 29 wherein the second functional group is selected from the group consisting of a carboxylic acid, an activated carboxylic acid, an active ester or an amine.

31. The method of claim 27 wherein at least one of the first or second functional groups is a negatively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding or wherein at least one of the first or second functional groups is a positively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

32. The method of claim 27 wherein the target molecule-POZ conjugate has the general structure:

33. The method of claim 27 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety.

34. The method of claim 33 wherein the target molecule linked to the polyoxazoline derivative through the first functional group and the second functional group are independently an organic molecule, a drug, a peptide, a protein, an antibody, an antibody fragment, a carbohydrate or an oligonucleotide.

35. The method of claim 27 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a targeting moiety.

36. The method of claim 35 wherein the therapeutic moiety is a drug and the targeting moiety is a peptide, a carbohydrate or an organic molecule.

37. The method of claim 27 wherein the number of target molecules linked to the polyoxazoline derivative through the first functional group is less than or equal to the value of o.

38. A method of treating cancer in a subject in need of such treatment, said method comprising the step of administering to the subject a therapeutically effective amount of a target molecule-POZ conjugate having the general structure:

R₁—

{[N(COX)CH₂CH₂]_o—

[N(COR₂)CH₂—

CH₂)]_n—

[N(COY)CH₂—

CH₂)]_m}_a—

K_k—

}_d—

R-Q_q-Z

wherein;

R₁ is an initiating group;

R₂ is independently selected for each polyoxazoline chain from a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heterocyclylalkyl group;

X is a pendent moiety bearing a first functional group;

Y is a pendent moiety bearing a second functional group;

K is a linking moiety linking each polyoxazoline chain to a branching moiety R, K being independently selected for each polyoxazoline chain;

Q is a linking moiety linking the branching moiety R to Z;

R is a branching moiety capable of forming linkages with Z, either directly or through linking group Q, and with each polyoxazoline chain, either directly or through the linking group K;

Z is a moiety containing a third functional group or an inert group;

a independently selected for each polyoxazoline chain from ran which indicates a random copolymer or block which indicates a block copolymer;

d is an integer selected from 2-8;

k is an integer independently selected for each polyoxazoline chain from one or zero;

q is an integer selected from one or zero;

o is an integer independently selected for each polyoxazoline chain from 1-50;

m is an integer independently selected for each polyoxazoline chain from 0-50;

n is an integer selected from 0-1000;

wherein at least two of the first, second and third functional groups are chemically orthogonal to one another; and

wherein the at least one target molecule is linked to the polyoxazoline derivative through at least one of the first, second or third functional groups.

39. The method of claim 38 wherein m=0 and Z contains the third functional group and the target molecule-POZ conjugate contains the first and third functional groups, the third functional group being chemically orthogonal to the first functional group, or wherein Z is an inert group and m is an integer independently selected for each polyoxazoline chain from 1-50 and the target molecule-POZ conjugate contains the first and second functional groups, the second functional group being chemically orthogonal to the first functional group.

40. The method of claim 39 wherein R₁ is independently selected for each polyoxazoline chain from a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.

41. The method of claim 39 wherein the first functional group an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide and the second or third functional group is an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide.

42. The method of claim 39 wherein at least one of the first, second or third functional group is a negatively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

43. The method of claim 39 wherein at least one of the first, second or third functional group is a positively charged species and at least one target molecule binds the target molecule-POZ conjugate via ionic bonding.

44. The method of claim 39 wherein Q is a substituted or unsubstituted alkylene.

45. The method of claim 39 wherein K is independently selected for each polyoxazoline chain from —

(CH₂)_pO—

, —

(CH₂)_p—

CO—

, —

S—

(CH₂)_pCONH—

, —

S—

(CH₂)_pCO, —

(CH₂)_p—

NHCSO—

, —

(CH₂)_p—

NHCO₂—

, —

NH—

(CH₂)_p, or —

NHCO₂—

, where p is an integer from 0-10.

46. The method of claim 39 wherein R is —

NH—

CH—

(CH₂)₃—

CH₂—

NH—

, a nitrogen, an aryl group, or —

CR₃—

, where R₃ is hydrogen or a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted aralkyl group.

47. The method of claim 39 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second or third functional group is a therapeutic moiety, a diagnostic moiety or a targeting moiety.

48. The method of claim 47 wherein the target molecule linked to the polyoxazoline derivative through the first functional group, the second functional group and the third functional group are independently an organic molecule, a drug, a peptide, a protein, an antibody, an antibody fragment, a carbohydrate or an oligonucleotide.

49. The method of claim 39 wherein the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety and the target molecule linked to the polyoxazoline derivative through the third functional group is a targeting moiety or the target molecule linked to the polyoxazoline derivative through the first functional group is a therapeutic moiety or a targeting moiety and the target molecule linked to the polyoxazoline derivative through the second functional group is a targeting moiety when the target molecule linked to the polyoxazoline derivative through first functional group is a therapeutic moiety or a therapeutic moiety when the target molecule linked to the polyoxazoline derivative through first functional group is a targeting moiety.

50. The method of claim 49 wherein the therapeutic moiety is a drug and the targeting moiety is a peptide, a carbohydrate or an organic molecule.

51. The method of claim 39 wherein the number of target molecules linked to the polyoxazoline derivative through the first functional group is less than or equal to the value of o the number of target molecules linked to the polyoxazoline derivative through the second functional group is less than or equal to the value of m.