Polyamine derivatives
Disclosed are compounds, compositions and methods for systemic and local delivery of biologically active molecules.
1. A compound of the formula:
n1, n2, and n3 are independently 1, 2, 3, or 4;
X and X′ are independently a bond, oxygen, or nitrogen;
R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds; and
-G 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.
2. A compound according to claim 1 , wherein n1, n2, n3, and n4 are all 1, and X and X′ are bonds.
3. A compound according to claim 1 , wherein R 1 and R 2 are independently C 14 -C 20 hydrocarbon groups containing 1 double bond.
4. A compound according to claim 3 , wherein both of —C(O)X—R 1 and —C(O)X′—R 2 are oleoyl groups.
5. A compound according to claim 1 , wherein G comprises at least one linker group between polymer units.
6. A compound according to claim 1 , G is a polyoxyalkylene.
7. A formulation comprising the compound of claim 1 and a molecule selected from the group consisting of:
(a) ribosomal RNA; antisense polynucleotides of RNA or DNA; aptamers; ribozymes; siRNA; shRNA; miRNA; and polynucleotides of genomic DNA, cDNA, or mRNA that encode for a therapeutically useful protein; or
(c) proteins, peptides, cholesterol, hormones, small molecule pharmaceutical compounds, vitamins, and co-factors.
8. A formulation according to claim 7 , where the formulation comprises particles comprising the compound and the molecule.
9. A formulation according to claim 8 , where the particles have a median diameter of less than about 500 nm.
10. A method of modulating expression of a target sequence, said method comprising administering to a mammalian subject a therapeutically effective amount of the formulation of claim 7 .
11. A formulation comprising a compound of formula A and a compound of Formula B
wherein n1, n2, and n3 are independently 1, 2, 3, or 4;
X and X′ are independently a bond, oxygen, or nitrogen;
R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds; and
in Formula A, G is hydrogen; and
in Formula B, -G 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;
and a molecule selected from the group consisting of:
(a) ribosomal RNA; antisense polynucleotides of RNA or DNA; aptamers; ribozymes; siRNA; shRNA; miRNA; and polynucleotides of genomic DNA, cDNA, or mRNA that encode for a therapeutically useful protein.
12. A method for in vivo delivery of ribosomal RNA; antisense polynucleotides of RNA or DNA; aptamers; ribozymes; siRNA; shRNA; miRNA; and polynucleotides of genomic DNA, cDNA, or mRNA that encode for a therapeutically useful protein to a mammalian subject comprising administering to the subject the formulation of claim 11 .
13. A formulation according to claim 11 , wherein the ratio of the compound of Formula A to the compound of Formula B in the formulation is 1:1 to 10:1.
14. A composition comprising a compound of formula A and a compound of Formula B
wherein n1, n2, and n3 are independently 1, 2, 3, or 4;
X and X′ are independently a bond, oxygen, or nitrogen;
R 1 and R 2 are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds; and
in Formula A, G is hydrogen; and
in Formula B, -G 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 formulation according to claim 14 , wherein the ratio of the compound of Formula A to the compound of Formula B in the formulation is 1:1 to 10:1.