Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same

• US 8,101,706 B2
• Filed: 05/25/2010
• Issued: 01/24/2012
• Est. Priority Date: 01/11/2008
• Status: Active Grant

• Current Assignee: Serina Therapeutics, Inc.
• Original Assignee: Serina Therapeutics, Inc.
• Inventors: Yoon, Kunsang, Bentley, Michael David, Harris, J. Milton, Fang, Zhihao, Viegas, Tacey
• Primary Examiner(s): Truong, Duc
• Application Number:
  US12/787,241
• Publication Number:
  US 20100330023A1
• Time in Patent Office: 609 Days
• Field of Search: 528/373, 528/321, 528/403, 424/78.3
• US Class Current: 528/321
• 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 random 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 1 having the general structure:

13. 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 random 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.

14. The method of claim 13 wherein R₁ is independently selected for each polyoxazoline chain from a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.

15. The method of claim 13 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.

16. The method of claim 15 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.

17. The method of claim 13 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.

18. The method of claim 13 wherein the target molecule-POZ conjugate has the general structure:

19. The method of claim 13 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.

20. The method of claim 19 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.

21. The method of claim 13 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.

22. The method of claim 21 wherein the therapeutic moiety is a drug and the targeting moiety is a peptide, a carbohydrate or an organic molecule.

23. The method of claim 13 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.