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

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

wherein:

N is —NH 2 or —N—CO—O—C—(CH 3 ) 3

N′ is —NR 5 H, —NR 5 R 6 , —NR 5 R 6 R 7 , nitrogen heterocycle, aldimine, hydrazide, hydrazone, or imidazole, wherein R 5 , R 6 , and R 7 are independently selected from —CH 3 and —CH 2 —CH 3 ,

Y and Y′ are independently —(CH 2 ) a — or —(CH 2 —CH 2 — 0 ) b —(CH 2 ) c — wherein a , b, and c are independently 1, 2, 3, 4, 5, or 6,

R is a hydrophobic group having 1-7 carbon atoms or an alkoxy ethyl group,

R′ is a hydrophobic group having 12-20 carbon atoms,

R1, R2, R3, and R4 are independently selected from hydrogen (—H) and methyl (—CH 3 ),

m and p are independently integers greater than zero (0),

n and q are independently integers greater than or equal to zero (0),

the ratio (m+n)/(p+q) is 1-9, and

the poly(vinyl ester) random copolymer is is capable of causing red blood cell lysis.

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 —(CH 2 ) a — wherein a is 2, 3, or 4.

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

6. The poly(vinyl ester) random copolymer of claim 1 wherein R is —(CH 2 ) k —CH 3 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 —(CH 2 ) 4 —

R is —(CH 2 ) 2 —CH 3

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 —(CH 2 ) 2 —

R is —(CH 2 ) 2 —CH 3

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 —(CH 2 ) 2 —

R is —(CH 2 ) 3 —CH 3

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

wherein:

N is a primary amine having the form —NH 2 ,

Y is —(CH 2 ) a — or —(CH 2 —CH 2 —O) b —(CH 2 ) c — wherein a , b, and c are independently 1, 2, 3, 4, 5, or 6,

R is a hydrophobic group having 1-7 carbon atoms,

R1 and R2 are independently selected from hydrogen (—H) and methyl (—CH 3 ),

m is an integer greater than zero (0),

p is an integer greater than zero (0),

the ratio m/p is 1-9, and

the poly(vinyl ester) random copolymer is is capable of causing red blood cell lysis.

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