Polyamine derivatives
Disclosed are compounds, compositions and methods for systemic and local delivery of biologically active molecules.
1. A method for treating a disease in a mammalian subject, said method comprising administering to the subject a therapeutically effective amount of a formulation comprising a biologically active molecule, a compound of Formula A and a compound of Formula B:
wherein n1, n2, and n3 in both Formula A and Formula B are independently 1, 2, 3, or 4;
X and X′ in both Formula A and Formula B are independently a bond, oxygen, or nitrogen;
R 1 and R 2 in both Formula A and Formula B are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds;
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 wherein the biologically active molecule is selected from the group consisting of:
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.
2. The method according to claim 1 , wherein in Formula B, G is a polyoxyalkylene.
3. The method according to claim 2 , wherein the polyoxyalkylene is a polyoxyethylene.
4. The method according to claim 1 , wherein the compound of Formula A is dioleoyl monoamine and the compound of Formula B is mPEG-dioleoyl monoamine.
5. The method according to claim 1 , wherein n1, n2, and n3 in both Formula A and Formula B are all 1, and X and X′ in both Formula A and Formula B are bonds.
6. The method according to claim 1 , wherein R 1 and R 2 in both Formula A and Formula B are independently C 14 -C 20 hydrocarbon groups containing 1 double bond.
7. The method according to claim 6 , wherein —C(O)X—R 1 and —C(O)X′—R 2 in both Formula A and Formula B are oleoyl groups.
8. The method according to claim 1 , wherein the disease is characterized by unregulated cell growth in the subject.
9. The method according to claim 8 , wherein the disease is cancer.
10. The method according to claim 9 , wherein the disease is lung cancer.
11. The method according to claim 1 , wherein the formulation is administered to said mammalian subject orally, topically, parenterally, by inhalation, or rectally.
12. The method according to claim 1 , wherein the formulation comprises particles comprising the biologically active molecule, the compound of Formula A, and the compound of Formula B.
13. The method according to claim 12 , wherein the particles have a median diameter of less than about 500 nm.
14. The method according to claim 1 , wherein the formulation comprises a pharmaceutically acceptable excipient.
15. A method for treating a disease in the lung tissue of a mammalian subject, said method comprising administering to the subject a therapeutically effective amount of a formulation comprising a biologically active molecule, a compound of Formula A and a compound of Formula B:
wherein n1, n2, and n3 in both Formula A and Formula B are independently 1, 2, 3, or 4;
X and X′ in both Formula A and Formula B are independently a bond, oxygen, or nitrogen;
R 1 and R 2 in both Formula A and Formula B are independently C 8 -C 25 hydrocarbon groups optionally containing from 1-4 double or triple bonds;
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 wherein the biologically active molecule is selected from the group consisting of:
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.
16. The method according to claim 15 , wherein the compound of Formula A is dioleoyl monoamine and the compound of Formula B is mPEG-dioleoyl monoamine.
17. The method according to claim 15 , wherein the disease is lung cancer.
18. The method according to claim 15 , wherein the formulation is administered to said mammalian subject orally, topically, parenterally, by inhalation, or rectally.
19. The method according to claim 15 , wherein the formulation comprises particles comprising the biologically active molecule, the compound of Formula A, and the compound of Formula B.
20. The method according to claim 19 , wherein the particles have a median diameter of less than about 500 nm.