Lipocationic polymers and uses thereof
Polymers produced by ring opening polymerization which comprises an amino group that can be used in compositions to deliver a nucleic acid such as a miRNA or a siRNA. In some embodiments, compositions which comprise the polymers described herein and a nucleic acid are also provided herein. In some embodiments, these compositions are used to silence one or more genes in vivo or treat a disease or disorder.
1. A polymer comprising a formula:
wherein:
X 1 is alkyl (C≦18) or substituted alkyl (C≦18) ;
X 2 is hydrogen, alkyl (C≦18) , or substituted alkyl (C≦18) ;
R 1 is -A-Z;
wherein:
A is an alkanediyl (C≦18) or substituted alkanediyl (C≦18) ;
Z is —NR 3 R 4 ;
wherein:
R 3 and R 4 are each independently selected from hydrogen, alkyl (C≦18) , substituted alkyl (C≦18) ; or R 3 and R 4 are taken together and are alkanediyl (C≦18) or substituted alkanediyl (C≦18) ;
R 2 is alkyl (C≦24) , alkenyl (C≦24) , substituted alkyl (C≦24) , or substituted alkenyl (C≦24) ;
x and y are each independently 0, 1, 2, 3, 4, or 5;
m and n are each independently an integer between 0 and 250, provided that at least one of m and n is greater than 1; and
the repeating units defined by m and n are randomly distributed throughout the polymer;
or a pharmaceutically acceptable salt thereof.
2. The polymer of claim 1 , wherein Z is —NR 3 R 4 ; wherein: R 3 and R 4 are each independently alkyl (C≦18) or substituted alkyl (C≦18) .
3. The polymer of claim 1 , wherein Z is —NR 3 R 4 ; wherein: R 3 and R 4 are taken together and are alkanediyl (C≦18) or substituted alkanediyl (C≦18) .
4. The polymer of claim 1 , wherein R 2 is alkyl (C≦24) .
5. The polymer of claim 1 , wherein m is an integer between 1 and 100.
6. The polymer of claim 1 , wherein n is an integer between 1 and 100.
7. The polymer of claim 1 , wherein the polymer comprises a molar ratio of the m repeating unit and the n repeating unit between about 10:1 to about 1:10.
8. A nanoparticle composition comprising:
(A) a polymer of claim 1 ; and
(B) a nucleic acid.
9. The composition of claim 8 , wherein the nucleic acid is a short (small) interfering RNA (siRNA), a microRNA (miRNA), a messenger RNA (mRNA), a clustered regularly interspaced short palindromic repeats (CRISPR) nucleic acid, a plasmid DNA (pDNA), a double stranded DNA (dsDNA), a single stranded DNA (ssDNA), a single stranded RNA (ssRNA), a double stranded RNA (dsRNA), a locked nucleic acid (LNA), a peptide nucleic acid (PNA), a miRNA mimic, or a anti-miRNA.
10. The composition of claim 9 , wherein the nucleic acid is a siRNA.
11. The composition of claim 8 , wherein the composition further comprises a steroid or steroid derivative.
12. The composition of claim 11 , wherein steroid derivative is a sterol.
13. The composition of claim 8 , wherein the composition further comprises a phospholipid.
14. The composition of claim 13 , wherein the phospholipid is a phosphatidylcholine.
15. The composition of claim 8 , wherein the composition further comprises a PEG lipid.
16. The composition of claim 15 , wherein the PEG lipid is a PEGylated diacylglycerol.
17. The composition of claim 15 , wherein the PEG lipid is:
wherein:
n 1 is an integer from 1 to 250; and
n 2 and n 3 are each independently selected from 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23.
18. The composition of claim 8 , wherein the composition comprises a molar ratio of polymer to steroid to phospholipid to PEG lipid from about 25:15:57:3 to about 75:5:19:1.
19. The composition of claim 8 , wherein the composition comprises a weight ratio of polymer to nucleic acid from about 5:1 to about 500:1.
20. A pharmaceutical composition composing a composition of claim 8 and an excipient.