Poly(vinyl ester) polymers for in vivo nucleic acid delivery

Patent metadata

Field	Value
Publication number	US-9474804-B2
Application number	US-201514746070-A
Country	US
Kind code	B2
Filing date	Jun 22, 2015
Priority date	Aug 26, 2011
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention is directed membrane active poly(vinyl ester) polymers and compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cells in vivo. RNAi polynucleotides are conjugated to the poly(vinyl ester) polymers and the polymers are reversibly modified to enable in vivo targeted delivery. Membrane activity of the poly(vinyl ester) provides for movement of the RNAi polynucleotides from outside the cell to inside the cell. Reversible modification provides physiological responsiveness.

First claim

We claim:

1. A membrane active poly(vinyl ester) random copolymer having the structure represented by:

wherein:
N is NH 2 ,
Y is (CH 2 ) a or (CH 2 ) 2 —O—(CH 2 ) 2 wherein a is 1, 2, or 3,
R is a hydrophobic group having 2-6 carbon atoms,
m and n are independently integers greater than zero (0),
the ratio m/n is about 1 to about 4,
the poly(vinyl ester) random copolymer is capable of causing red blood cell lysis,
the polydispersity of the polymer is less than or equal to 1.5, and
the molecular weight of the polymer is about 30 kDa to about 100 kDa.

2. The poly(vinyl ester) random copolymer of claim 1 wherein the polydispersity of the polymer is less than or equal to 1.3.

3. The poly(vinyl ester) random copolymer of claim 1 wherein the molecular weight of the polymer is about 30 kDa to about 50 kDa.

4. The poly(vinyl ester) random copolymer of claim 1 wherein the molecular weight of the polymer is about 50 kDa to about 75 kDa.

5. The poly(vinyl ester) random copolymer of claim 1 wherein the ratio m/n is about 1.

6. The poly(vinyl ester) random copolymer of claim 1 wherein the ratio m/n is about 75/25.

7. The poly(vinyl ester) random copolymer of claim 1 wherein Y is (CH 2 ).

8. The poly(vinyl ester) random copolymer of claim 1 wherein Y is (CH 2 ) 2 .

9. The poly(vinyl ester) random copolymer of claim 1 wherein Y is (CH 2 ) 3 .

10. The poly(vinyl ester) random copolymer of claim 1 wherein Y is (CH 2 ) 2 —O—(CH 2 ) 2 .

11. The poly(vinyl ester) random copolymer of claim 1 wherein R is a hydrophobic group having 3 carbon atoms.

12. The poly(vinyl ester) random copolymer of claim 11 wherein Y is (CH 2 ) 3 .

13. The poly(vinyl ester) random copolymer of claim 12 wherein the ratio m/n is about 1.

14. The poly(vinyl ester) random copolymer of claim 12 wherein the ratio m/n is about 3.

15. The poly(vinyl ester) random copolymer of claim 11 wherein Y is (CH 2 ) 2 —O—(CH 2 ) 2 .

16. The poly(vinyl ester) random copolymer of claim 15 wherein the ratio m/n is about 1.

17. The poly(vinyl ester) random copolymer of claim 15 wherein the ratio m/n is about 3.

18. The poly(vinyl ester) random copolymer of claim 11 wherein Y is (CH 2 ) 2 —O—(CH 2 ) 2 .

19. The poly(vinyl ester) random copolymer of claim 18 wherein the ratio m/n is about 3.

20. The poly(vinyl ester) random copolymer of claim 18 wherein the ratio m/n is about 1.

21. A composition for inhibiting gene expression in vivo comprising the poly(vinyl ester) random copolymer of claim 20 and an RNA interference polynucleotide in a pharmaceutically acceptable carrier.

22. The composition of claim 21 wherein the poly(vinyl ester) random copolymer is conjugated to an RNA interference polynucleotide.

23. The composition of claim 21 wherein the RNA interference polynucleotide is conjugated to a hydrophobic group containing at least 20 carbon atoms.

24. The poly(vinyl ester) random copolymer of claim 1 wherein R is a hydrophobic group having 4 carbon atoms.

25. The poly(vinyl ester) random copolymer of claim 24 wherein the hydrophobic group is branched.

26. The poly(vinyl ester) random copolymer of claim 25 wherein Y is (CH 2 ) 3 .

27. The poly(vinyl ester) random copolymer of claim 26 wherein the ratio m/n is about 1.

28. The poly(vinyl ester) random copolymer of claim 26 wherein the ratio m/n is about 3.

29. The poly(vinyl ester) random copolymer of claim 1 wherein greater than 50% of N are reversibly modified by reaction with disubstituted maleic anhydride masking agents, dipeptide-amidobenzyl-carbonate masking agents, or a combination of disubstituted maleic anhydride masking agents and dipeptide-amidobenzyl-carbonate masking agents.

30. The poly(vinyl ester) random copolymer of claim 29 wherein the polymer is conjugated to an RNA interference polynucleotide.

Assignees

• Arrowhead Madison Inc
• Arrowhead Pharmaceuticals Inc

Inventors

• Wakefield Darren H
• Rossi Nicholas A
• Sheik Dan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C08F218/04

  Vinyl esters · CPC title

• A61K47/58

  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 title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C08F218/10

  of monocarboxylic acids containing three or more carbon atoms · CPC title