Polyamine derivatives
Disclosed are compounds, compositions and methods for systemic and local delivery of biologically active molecules.
1. A compound of the formula:
wherein
n1, n2, n3, and n4 are independently 1, 2, 3, or 4;
X and X′ are independently a bond, oxygen, or nitrogen; and
R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds; and
G 1 and G 2 are independently hydrogen or a polymer moiety.
2. A compound according to claim 1 , wherein n1, n2, n3, and n4 are all 1, and X and X′ are both bonds.
3. A compound according to claim 1 , wherein both of —C(O)X—R 1 and —C(O)X′—R 2 represent oleoyl groups.
4. A compound according to claim 1 , where one of G 1 and G 2 is a polymer moiety and the other is hydrogen.
5. A formulation comprising a compound of claim 1 and a molecule selected from the group consisting of:
(a) ribosomal RNA; antisense polynucleotides of RNA or DNA; ribozymes; siRNA; shRNA; miRNA; and polynucleotides of genomic DNA, cDNA, or mRNA that encode for a therapeutically useful protein;
(b) an aptamer; or
(c) proteins, peptides, cholesterol, hormones, small molecule pharmaceutical compounds, vitamins, and co-factors.
6. A method for in vivo delivery of a molecule, said method comprising administering to a mammalian subject a formulation according to claim 5 .
7. An implantable or injectable device containing a formulation of claim 5 entrapped or encapsulated within the device and the device comprises, in addition to the formulation, a biodegradable and/or biocompatible drug release material.
8. A compound according to claim 1 , wherein both of G 1 and G 2 are hydrogen.
9. A compound according to claim 1 , wherein at least one of R 1 and R 2 is a C 8 -C 25 hydrocarbon group containing from 1-4 double bonds.
10. A compound according to claim 1 , wherein R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups containing 1 or 2 double bonds.
11. A compound according to claim 1 , wherein R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups containing 1 double bond.
12. A compound according to claim 1 , wherein R 1 and R 2 are independently C 14 -C 20 hydrocarbon groups containing 1 or 2 double bonds.
13. A compound according to claim 1 , wherein R 1 and R 2 are independently C 14 -C 20 hydrocarbon groups containing 1 double bond.
14. A compound according to claim 4 , wherein one of G 1 and G 2 is a polyoxyalkylene, polyvinylpyrrolidone, polyacrylamide, polydimethylacrylamide, polyvinyl alcohol, dextran, poly (L-glutamic acid), styrene maleic anhydride, poly-N-(2-hydroxypropyl)methacrylamide, or polydivinylether maleic anhydride.
15. A compound according to claim 14 , wherein the polymer comprises at least one linker group between polymer units.
16. A compound according to claim 14 , where the polymer moiety is a polyoxyalkylene.
17. A compound according to claim 16 , where the molecular weight of the polymer is from about 200-10,000 Da.
18. A compound according to claim 15 , wherein the polymer is a polyoxyalkylene where the oxyalkylene groups are independently straight or branched chain polyoxyalkylene groups having from 2-5 carbon atoms in their repeating units.
19. A compound according to claim 1 , which is N,N′-dioleoyl tetrakis(aminomethyl)methane.
20. A compound according to claim 16 , wherein the polyoxyalkylene is a polyoxyethylene.
21. A formulation according to claim 5 , where the compound is N,N′-dioleoyl tetrakis(aminomethyl)methane.
22. A formulation according to claim 21 where the molecule is a siRNA, a shRNA, or a miRNA.