Membrane Active Heteropolymers

• US 20090023890A1
• Filed: 05/19/2008
• Published: 01/22/2009
• Est. Priority Date: 08/18/2006
• Status: Active Grant

• Current Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Rozema, David B., Monahan, Sean D., Hagstrom, James E., Wakefield, Darren H., Higgs, Lori, Wolff, Jon A.
• Granted Patent: US 7,985,406 B2
• Time in Patent Office: Days
• US Class Current: 528/422
• 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 a class of membrane active polymers useful for cellular delivery of compounds. Conjugation of the described membrane active polymers to targeting, anti-opsonization, and anti-aggregation agents provides polymers suitable for in vivo delivery. The use of multiple reversible linkages connecting component parts provides for physiologically responsive activity modulation.

Claims

1. A membrane active heteropolymer comprising:

a plurality of amine-containing monomers, a plurality of first hydrophobic monomers, and a plurality of second hydrophobic monomers wherein said first and second hydrophobic monomers each contain pendent groups having 1-30 carbon atoms, wherein said first and second hydrophobic monomers are different and wherein the ratio of amine-containing monomers to first hydrophobic monomers to second hydrophobic monomers is about 6;

3;

1.

2. The membrane active heteropolymer of claim 1 wherein the heteropolymer comprises a random heteropolymer.

3. The membrane active heteropolymer of claim 1 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 group consists of a lower hydrophobic group and said second hydrophobic groups consists of a higher hydrophobic group.

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

6. The membrane active heteropolymer of claim 1 wherein the heteropolymer is soluble in aqueous solution.

7. The membrane active heteropolymer of claim 1 wherein the heteropolymer is soluble in aqueous solution at 1 mg/ml or greater.

8. The membrane active heteropolymer of claim 1 wherein the heteropolymer is selected from the group consisting of:

poly(acrylate), modified poly(alcohol), modified poly(amine), modified poly(allylamine), modified poly(vinyl amine), modified poly(amino acid), modified poly(O₃-aminoester) and poly(vinyl ether).

9. The membrane active heteropolymer of claim 1 wherein the heteropolymer is biodegradable.

10. The membrane active heteropolymer of claim 9 wherein the heteropolymer contains biodegradable bonds within the backbone of the heteropolymer.

11. The membrane active heteropolymer of claim 9 wherein the heteropolymer contains biodegradable bonds within sidechains of the heteropolymer.

12. The membrane active heteropolymer of claim 1 wherein the heteropolymer is larger than about 5 kDa.

13. The membrane active heteropolymer of claim 12 wherein the heteropolymer is larger than about 7.5 kDa.

14. The membrane active heteropolymer of claim 13 wherein the heteropolymer is larger than about 10 kDa.

15. The membrane active heteropolymer of claim 14 wherein the heteropolymer is larger than about 15 kDa.

16. The membrane active heteropolymer of claim 1 wherein the heteropolymer is smaller than about 100 kDa.

17. The membrane active heteropolymer of claim 16 wherein the heteropolymer is smaller than about 50 kDa.

18. The membrane active heteropolymer of claim 12 wherein the heteropolymer is smaller than about 100 kDa.

19. The membrane active heteropolymer of claim 13 wherein the heteropolymer is smaller than about 50 kDa.

20. The membrane active heteropolymer of claim 14 wherein the heteropolymer is smaller than about 30 kDa.

21. The membrane active heteropolymer of claim 1 wherein the amine-containing monomers contain of ethyl amines, propyl amines, or butyl amines.

22. The membrane active heteropolymer of claim 1 wherein one of more targeting groups are covalently linked to the heteropolymer.

23. The membrane active heteropolymer of claim 22 wherein the targeting groups is linked to the polymer via a physiologically labile bond.