Liposome compositions
The present disclosure provides lipid-containing compositions, including targeted liposomes encapsulating drug, and pharmaceutical formulations thereof, as well as methods for the making and using the lipid-containing compositions, including the use of the targeted liposomes in the treatment of cancer and other diseases.
1. A targeted liposome comprising one or more phosphatidylcholines, an N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, an encapsulated drug, and at least one additional lipid, which is cholesterol,
wherein the mol % of the phosphatidylcholines is 40-60 mol %, the mol % of the cholesterol is 35-55 mol %, and the mol % of the total of the N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine plus targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-8 mol %, where the total mol % of the phosphatidylcholines, the cholesterol, and the derivatized phosphatidylethanolamines is 100%
wherein the targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises transferrin linked to a second N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and
wherein
the N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,
the second N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,
wherein R 1 , R 2 , R 5 and R 6 are each an acyl group,
wherein the acyl groups are acyl groups from saturated or unsaturated aliphatic carboxylic acids having 18-22 carbon atoms, and
wherein R 1 and R 2 are the same, and R 5 and R 6 are the same; and
m and p are, independently, an integer from 1 to 10; and,
wherein the targeted liposomes contains from about 10 μg transferrin/mg lipid to about 50 μg transferrin/mg lipid; and,
wherein the liposome does not comprise a non-derivatized phosphatidyl ethanolamine, egg phosphatidylcholine, or a hydrophilic polymer used to enhance the circulatory half-life of liposomes.
2. The targeted liposome of claim 1 , wherein the targeted liposome contains from about 10 μg transferrin/mg lipid to about 25 μg transferrin/mg lipid.
3. The targeted liposome of claim 1 , wherein the total mol % of N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-6 mol % of total lipid content.
4. The targeted liposome of claim 1 , wherein the phosphatidylcholine includes a moiety of a saturated fatty acid.
5. The targeted liposome of claim 1 , wherein the one or more phosphatidylcholines is DMPC, DSPC, POPC or DPPC.
6. The targeted liposome of claim 1 , wherein the liposome comprises DMPC.
7. The targeted liposome according to claim 1 , wherein the transferrin is in a holo-form but not in an apo-form.
8. The targeted liposome according to claim 1 , wherein the mean diameter of the liposome is from about 9 nm to about 250 nm.
9. The targeted liposome of claim 1 , wherein R 1 , R 2 , R 5 and R 6 are oleoyl or stearoyl, and m and p are 3.
10. The targeted liposome of claim 9 , wherein the drug is an anticancer agent.
11. The targeted liposome of claim 9 , wherein the one or more phosphatidylcholines is DMPC or DSPC.
12. The targeted liposome of claim 9 , wherein R 1 , R 2 , R 5 and R 6 are oleoyl.
13. The targeted liposome of claim 1 , wherein m and p are each, independently, an integer from 2 to 4.
14. The targeted liposome of claim 1 , wherein m and p are equal and are an integer from 2 to 4.
15. The targeted liposome of claim 13 , wherein m and p are equal and are 3.
16. The targeted liposome of claim 1 , wherein R 1 , R 2 , R 5 and R 6 are oleoyl or stearoyl.
17. The targeted liposome of claim 1 , wherein R 1 , R 2 , R 5 and R 6 are the same.
18. The targeted liposome of claim 1 , wherein the drug is oxaliplatin.
19. The targeted liposome according to claim 1 , wherein the drug is an anticancer agent.
20. The targeted liposome according to claim 1 , wherein the drug is a cytotoxic drug.
21. The targeted liposome according to claim 1 , wherein the drug is a topoisomerase I inhibitor.
22. The targeted liposome according to claim 21 , wherein the topoisomerase I inhibitor is topotecan or irinotecan.
23. The targeted liposome according to claim 1 , wherein the drug is a vinca alkaloid.
24. The targeted liposome according to claim 23 , wherein the vinca alkaloid is vincristine, vinblastine, vinleurosine, vinrodisine, vinorelbine or vindesine.
25. The targeted liposome according to claim 1 , wherein the drug is a nucleic acid.
26. The targeted liposome according to claim 25 , wherein the nucleic acid is an antisense oligonucleotide or a ribozyme.
27. The targeted liposome according to claim 1 , wherein the drug is a platinum compound.
28. The targeted liposome according to claim 17 , wherein the platinum compound is biplatin, cisplatin, carboplatin, ormaplatin, oxaliplatin, zeniplatin, enloplatin, lobaplatin or spiroplatin.
29. The targeted liposome according to claim 28 , wherein the platinum compound is oxaliplatin.
30. The targeted liposome according to claim 29 , wherein R 1 , R 2 , R 5 and R 6 are oleoyl, m and p are 3, and the one or more phosphatidylcholines is DMPC.
31. The targeted liposome of claim 30 , wherein the targeted liposome contains from about 10 μg transferrin/mg lipid to about 25 μg transferrin/mg lipid.
32. The targeted liposome of claim 30 , wherein the total mol % of N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-6 mol % of total lipid content.
33. The targeted liposome according to claim 1 , wherein the drug is an alkylating agent.
34. The targeted liposome according to claim 1 , wherein the drug is a taxane.
35. The targeted liposome according to claim 1 , wherein the drug is a metabolic antagonist.
36. The targeted liposome according to claim 1 , wherein the drug is an antitumour antibiotic.
37. The targeted liposome according to claim 1 , wherein the drug is a hormone therapy drug.
38. The targeted liposome according to claim 1 , wherein the drug is a molecular target drug.
39. The targeted liposome according to claim 29 , wherein the oxaliplatin is dissolved in an aqueous solution of a sugar selected from the group consisting of trehalose, maltose, sucrose, mannose, lactose, mannitol, glycerol and dextrose.
40. The targeted liposome of claim 39 , wherein the sugar is at a concentration of about 300 mM sugar.
41. The targeted liposome of claim 39 , wherein the concentration of oxaliplatin is from about 0.1 mg/ml to about 25 mg/ml within the liposome.
42. The targeted liposome of claim 29 , wherein the transferrin is in a holo-form.
43. The targeted liposome claim 1 , wherein the liposome does not comprise a cationic lipid.
44. The targeted liposome of claim 1 , wherein the liposome does not comprise an anionic lipid.
45. A targeted liposome comprising one or more phosphatidylcholines, an N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, a targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine, an encapsulated drug, and, at least one additional lipid which is cholesterol,
wherein the mol % of the phosphatidylcholines is 40-60 mol %, the mol % of the cholesterol is 35-55 mol %, and the mol % of the total of the N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine plus targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is 2-8 mol %, where the total mol % of the phosphatidylcholines, the cholesterol, and the derivatized phosphatidylethanolamines is 100%
wherein the targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine comprises a transferrin linked to a second N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine; and
wherein
the N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 1,
the second N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is represented by Formula 3,
wherein R 1 , R 2 , R 5 and R 6 are each an acyl group,
wherein R 1 and R 2 are the same, and R 5 and R 6 are the same,
wherein R 1 , R 2 , R 5 and R 6 are not palmitoyl or myristoyl; and
m and p are, independently, an integer from 1 to 10; and,
wherein the targeted liposomes contains from about 10 μg transferrin/mg lipid to about 50 μg transferrin/mg lipid; and,
wherein the liposome does not comprise a non-derivatized phosphatidyl ethanolamine, egg phosphatidylcholine, or a hydrophilic polymer used to enhance the circulatory half-life of liposomes.
46. The targeted liposome of claim 45 , wherein the targeted liposome contains from about 10 μg transferrin/mg lipid to about 25 μg transferrin/mg lipid.
47. The targeted liposome of claim 45 , wherein the total mol % of N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine and targeting factor-modified N-(ω)-dicarboxylic acid-derivatized phosphatidyl ethanolamine is from about 2 to about 6 mol % of total lipid content.
48. A pharmaceutical formulation comprising a targeted liposome according to claim 1 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives.