Poly(vinyl ester) Polymers for In Vivo Nucleic Acid Delivery

• US 20130121954A1
• Filed: 08/23/2012
• Published: 05/16/2013
• Est. Priority Date: 08/26/2011
• Status: Active Grant

• Current Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Original Assignee: Arrowhead Madison Inc (Arrowhead Pharmaceuticals, Inc.)
• Inventors: Wakefield, Darren H., Rossi, Nicholas A., Sheik, Dan
• Granted Patent: US 8,932,572 B2
• Time in Patent Office: Days
• US Class Current: 424/78.17
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08F 218/04 Vinyl esters
• CPC Class Codes: C08F 218/10 of monocarboxylic acids containing three or more carbon atoms
• CPC Class Codes: C08F 218/22 Esters containing nitrogen
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/351 Conjugate
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

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.

Claims

1. A poly(vinyl ester) random copolymer having the structure:

2. The poly(vinyl ester) random copolymer of claim 1 wherein the ratio (m+n)/(p+q) is 1.5-4.

3. The poly(vinyl ester) random copolymer of claim 1 wherein the polydispersity of the polymer is less than 1.5

4. The poly(vinyl ester) random copolymer of claim 1 wherein Y is —

(CH₂)_a—

wherein a is 2, 3, or 4.

5. The poly(vinyl ester) random copolymer of claim 1 wherein Y is —

CH₂CH₂—

CH₂—

CH₂.

6. The poly(vinyl ester) random copolymer of claim 1 wherein R is —

(CH₂)_k—

CH₃ wherein k is 1, 2, 3, 4, or 6.

7. The poly(vinyl ester) random copolymer of claim 1 wherein n is zero.

8. The poly(vinyl ester) random copolymer of claim 7 wherein q is zero.

9. The poly(vinyl ester) random copolymer of claim 1 wherein R1, R2, R3 and R4 are each hydrogen.

10. The poly(vinyl ester) random copolymer of claim 1 wherein:

Y is —

(CH₂)₄—

R is —

(CH₂)₂—

CH₃

R1 and R3 are each hydrogen, and

n and p are each zero.

11. The poly(vinyl ester) random copolymer of claim 10 wherein ratio m/p is 1.3-2.3.

12. The poly(vinyl ester) random copolymer of claim 1 wherein:

Y is —

(CH₂)₂—

R is —

(CH₂)₂—

CH₃

R1 and R3 are each hydrogen, and

n and p are each zero.

13. The poly(vinyl ester) random copolymer of claim 1 wherein:

Y is —

(CH₂)₂—

R is —

(CH₂)₃—

CH₃

R1 and R3 are each hydrogen, and

n and p are each zero.

14. The poly(vinyl ester) random copolymer of claim 1 wherein the polymer is conjugated to an RNA interference polynucleotide.

15. 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.

16. A composition for inhibiting gene expression in vivo comprising the poly(acrylate) random copolymer of claim 16 and an RNA interference polynucleotide in a pharmaceutically acceptable carrier.

17. The composition of claim 16 wherein the RNA interference polynucleotide is covalently linked to the poly(vinyl ester) random copolymer.

18. The composition of claim 16 wherein the RNA interference polynucleotide is conjugated to a hydrophobic group containing at least 20 carbon atoms.

19. A poly(vinyl ester) random copolymer having the structure:

20. The poly(vinyl ester) random copolymer of claim 19 wherein the ratio m/p is 1.5-4.