Endosomolytic Modified Poly(Alcohol) and Poly(Amine) Polymers

• US 20080281044A1
• Filed: 06/17/2008
• Published: 11/13/2008
• Est. Priority Date: 08/18/2006
• Status: Abandoned Application

• Current Assignee: Roche Madison Inc. (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Roche Madison Inc. (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Rozema, David B., Monahan, Sean D., Hagstrom, James E., Wakefield, Darren H., Higgs, Lori, Wolff, Jon A.
• Application Number:
  US12/140,736
• Publication Number:
  US 20080281044A1
• Time in Patent Office: Days
• US Class Current: 525/56
• CPC Class Codes: A01K 2217/058 due to expression of inhibitory nucleic acid, e.g. siRNA, antisense
• CPC Class Codes: A01K 2267/0362 Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 48/0041 the non-active part being polymeric
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 15/87 Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation

Abstract

The present invention is directed to membrane active polymers useful for cellular delivery of compounds. Described are polyconjugates systems that incorporate targeting, anti-opsonization, anti-aggregation, and transfection activities into small biocompatible in vivo delivery conjugates. The use of reversible modification provides for physiologically responsive activity modulation.

Claims

1. A membrane active heteropolymer comprising:

a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups and hydrophobic pendent groups.

2. The membrane active heteropolymer of claim 1 wherein the modified poly(alcohol) comprises a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different.

3. The membrane active heteropolymer of claim 2 wherein said first and second hydrophobic pendent groups are selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

4. The membrane active heteropolymer of claim 3 wherein said first hydrophobic pendent groups consist of a lower hydrophobic groups and said second hydrophobic groups consist of higher hydrophobic groups.

5. The membrane active heteropolymer of claim 4 wherein said first hydrophobic pendent groups consist of a butyl groups and said second hydrophobic groups consist of octadecyl groups.

6. The membrane active heteropolymer of claim 4 wherein said cationic nitrogen-containing groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:

3;

1 ratio.

7. The membrane active heteropolymer of claim 4 wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group.

8. The membrane active heteropolymer of claim 7 wherein said third hydrophobic pendent group is selected from the group consisting of:

aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

9. The membrane active heteropolymer of claim 1 wherein the modified poly(alcohol) comprises modified poly(vinyl alcohol).

10. The membrane active heteropolymer of claim 1 wherein the modified poly(vinyl alcohol) comprises a polymer selected from the group consisting of:

poly(carbonate), poly(carbamate), mixed poly(carbonate)/poly(carbamate), poly(thiocarbonate), and poly(phosphocarbonate).

11. A reversibly masked membrane active heteropolymer comprising:

a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups and hydrophobic pendent groups wherein one or more of said cationic nitrogen-containing groups are linked to masking agents via physiologically labile bonds.

12. The reversibly masked membrane active heteropolymer of claim 11 wherein the modified poly(alcohol) comprises a modified poly(alcohol) wherein hydroxyl groups on the poly(alcohol) are independently modified to contain cationic nitrogen-containing groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different and wherein one or more of said amine groups are linked to masking agents via physiologically labile bonds.

13. The reversibly masked membrane active heteropolymer of claim 12 wherein said first and second hydrophobic pendent groups are selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

14. The reversibly masked membrane active heteropolymer of claim 13 wherein said first hydrophobic pendent groups consist of a lower hydrophobic groups and said second hydrophobic groups consist of higher hydrophobic groups.

15. The reversibly masked membrane active heteropolymer of claim 14 wherein said first hydrophobic pendent groups consist of a butyl groups and said second hydrophobic groups consist of octadecyl groups.

16. The reversibly masked membrane active heteropolymer of claim 14 wherein said cationic nitrogen-containing groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:

3;

1 ratio.

17. The reversibly masked membrane active heteropolymer of claim 14 wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group.

18. The reversibly masked membrane active heteropolymer of claim 17 wherein said third hydrophobic pendent group is selected from the group consisting of:

aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

19. The reversibly masked membrane active heteropolymer of claim 11 wherein said masking agents are selected from the group consisting of:

targeting groups, steric stabilizers, charge modifiers, and combinations of targeting groups, steric stabilizers, and charge modifiers.

20. The reversibly masked membrane active heteropolymer of claim 11 wherein the modified poly(alcohol) comprises modified poly(vinyl alcohol).

21. The reversibly masked membrane active heteropolymer of claim 20 wherein the modified poly(alcohol) comprises a polymer selected from the group consisting of:

poly(carbonate), poly(carbamate), mixed poly(carbonate)/poly(carbamate), poly(thiocarbonate), and poly(phosphocarbonate).

22. A membrane active heteropolymer comprising:

a modified poly(amine) wherein amine groups on the poly(amine) are independently modified to contain amine groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different.

23. The membrane active heteropolymer of claim 22 wherein the modified poly(amine) comprises a polymer selected from the group consisting of:

modified poly(allylamine), modified poly(vinyl amine), and modified poly(amino acid).

24. The membrane active heteropolymer of claim 23 wherein the modified poly(amino acid) comprises a modified poly(lysine) or a modified poly(ornithine).

25. The membrane active heteropolymer of claim 22 wherein said first and second hydrophobic pendent groups are selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

26. The membrane active heteropolymer of claim 25 wherein said first hydrophobic pendent group consists of a lower hydrophobic group and said second hydrophobic groups consists of a higher hydrophobic group.

27. The membrane active heteropolymer of claim 26 wherein said first hydrophobic pendent group consists of a butyl group and said second hydrophobic groups consists of an octadecyl group.

28. The membrane active heteropolymer of claim 26 wherein said amine groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:

3;

1 ratio.

29. The membrane active heteropolymer of claim 26 wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group.

30. The membrane active heteropolymer of claim 29 wherein said third hydrophobic pendent group is selected from the group consisting of:

aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

31. A membrane active heteropolymer comprising:

a modified poly(amine) wherein amine groups on the poly(amine) are independently modified to contain amine groups, first hydrophobic pendent groups, and second hydrophobic pendent groups wherein said first and second hydrophobic pendent groups are different.

32. The membrane active heteropolymer of claim 31 wherein the modified poly(amine) comprises a polymer selected from the group consisting of:

modified poly(allylamine), modified poly(vinyl amine), and modified poly(amino acid).

33. The membrane active heteropolymer of claim 32 wherein the modified poly(amino acid) comprises a modified poly(lysine) or a modified poly(ornithine).

34. The membrane active heteropolymer of claim 31 wherein said first and second hydrophobic pendent groups are selected from the list consisting of:

alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aralkenyl group, and aralkynyl group, each of which may be linear, branched, or cyclic and may can contain one or more substitutions or heteroatoms, sterol, steroid, and steroid derivative.

35. The membrane active heteropolymer of claim 34 wherein said first hydrophobic pendent group consists of a lower hydrophobic group and said second hydrophobic groups consists of a higher hydrophobic group.

36. The membrane active heteropolymer of claim 35 wherein said first hydrophobic pendent group consists of a butyl group and said second hydrophobic groups consists of an octadecyl group.

37. The membrane active heteropolymer of claim 35 wherein said amine groups, lower hydrophobic groups and higher hydrophobic groups are present in a 6:

3;

1 ratio.

38. The membrane active heteropolymer of claim 35 wherein the heteropolymer further comprises one or more third hydrophobic pendent groups wherein said third hydrophobic pendent group is different from said first or second hydrophobic pendent group.

39. The membrane active heteropolymer of claim 38 wherein said third hydrophobic pendent group is selected from the group consisting of:

aryl group, aralkyl group, aralkenyl group, aralkynyl group, sterol, steroid, and steroid derivative.

40. The reversibly masked membrane active heteropolymer of claim 31 wherein said masking agents are selected from the group consisting of:

targeting groups, steric stabilizers, charge modifiers, and combinations of targeting groups, steric stabilizers, and charge modifiers.