Liposomal cisplatin compositions for cancer therapy
The present invention provides a composition for the treatment of cancer including zwitterionic liposomes consisting essentially of: 50-65 mol % of a phosphatidylcholine lipid, 30-45 mol % of cholesterol, and 2-8 mol % of a PEG-lipid; and cisplatin. Cisplatin is encapsulated in the liposomes in an amount such that the ratio of the total lipid weight to the cisplatin weight is from about 65:1 to about 95:1. Methods for the preparation of liposomal cisplatin and the treatment of cancer are also disclosed.
1. A composition for the treatment of cancer, comprising:
(a) zwitterionic liposomes consisting essentially of from about 55 mol % to about 75 mol % of a phosphatidylcholine lipid or mixture of phosphatidylcholine lipids, from about 30 mol % to about 45 mol % of cholesterol, and from about 2 mol % to about 8 mol % of a PEG-lipid; and
(b) cisplatin, encapsulated in said liposome in an amount such that the ratio of the total lipid weight to the cisplatin weight is from about 40:1 to about 95:1;
wherein the phosphatidylcholine comprises at least about 40 mol % to about 75 mol % of distearoylphosphatidylcholine (DSPC) or at least about 55 mol % to about 65 mol % of palmitoyloleoylphosphatidylcholine (POPC);
wherein the composition has a maximum tolerated dose greater than about 10 mg/kg and a peak DNA/platinum (Pt) adduct value greater than about 20 pg of Pt per μg of DNA.
2. The composition of claim 1 , wherein said phosphatidylcholine lipid is POPC.
3. The composition of claim 1 , wherein said phosphatidylcholine lipid comprises DSPC and dipalmitoylphosphatidylcholine (DPPC).
4. The composition of claim 1 , wherein said phosphatidylcholine lipid is DSPC.
5. The composition of claim 1 , wherein the PEG-lipid is selected from the group consisting of a diacyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)], an N-acyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)]}, and mixtures thereof.
6. The composition of claim 5 , wherein the PEG-lipid is selected from the group consisting of distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-2000] (DSPE-PEG-2000) and distearoyl-phosphatidylethanolamine-N-[methoxy(polyethene glycol)-5000] (DSPE-PEG-5000).
7. The composition of claim 1 , wherein the zwitterionic liposome comprises about 46 mol % DSPC, about 19 mol % DPPC, about 30 mol % cholesterol, and about 5 mol % DSPE-PEG(2000).
8. The composition of claim 1 , wherein the zwitterionic liposome comprises about 65 mol % DSPC, about 30 mol % cholesterol, and about 5 mol % DSPE-PEG(2000).
9. The The composition of claim 1 , wherein the zwitterionic liposome comprises about 57 mol % POPC, about 38 mol % cholesterol, and about 5 mol % DSPE-PEG(2000).
10. The composition of claim 1 , wherein the ratio of the total lipid weight to the cisplatin weight is about 40:1 to 90:1.
11. The composition of claim 1 , wherein the ratio of the total lipid weight to the cisplatin weight is about 90:1.
12. The composition of claim 1 , wherein said zwitterionic liposomes have an average particle size of from about 75 to about 125 nm (volume mean).
13. The composition of claim 1 , wherein said zwitterionic liposomes have an average particle size of about 90 nm (volume mean).
14. The composition of claim 1 , wherein said zwitterionic liposomes are prepared by a method comprising:
a) forming a lipid solution comprising the phosphatidylcholine lipid, the cholesterol, the PEG-lipid, and a solvent selected from the group consisting of a C 1-4 alkanol and a C 1-4 alkanol/water mixture;
b) mixing the lipid solution with an aqueous buffer to form multi-lamellar vesicles (MLVs); and
c) extruding the rweqMLVs through a porous filter to form small unilamellar vesicles (SUVs);
thereby forming said zwitterionic liposomes.
15. The composition of claim 14 , wherein encapsulation of the cisplatin is conducted by including the cisplatin in the aqueous buffer during formation of the MLVs and removing unencapsulated cisplatin.
16. The composition of claim 14 , wherein the method further comprises;
d) sterile filtering said zwitterionic liposomes.
17. A method of treating cancer, said method comprising administering to a subject in need thereof a composition of claim 1 ,
wherein the cancer is a carcinoma.
18. The method of claim 17 , wherein said composition comprises:
a) zwitterionic liposomes consisting essentially of about 46 mol % DSPC, about 19 mol % DPPC, about 30 mol % cholesterol, and about 5 mol % DSPE-PEG(2000); and
b) cisplatin, encapsulated in said liposome in an amount such that the ratio of the total lipid weight to the cisplatin weight is from about 40:1 to about 90:1.
19. The method of claim 17 , wherein said composition comprises:
a) zwitterionic liposomes consisting essentially of about 57 mol % POPC, about 38 mol % cholesterol, and about 5 mol % DSPE-PEG(2000); and
b) cisplatin, encapsulated in said liposome in an amount such that the ratio of the total lipid weight to the cisplatin weight is from about 70:1 to about 90:1.
20. The method of claim 17 , wherein said composition comprises:
a) zwitterionic liposomes consisting essentially of about 65 mol % DSPC, about 30 mol % cholesterol, and about 5 mol % DSPE-PEG(2000); and
b) cisplatin, encapsulated in said liposome in an amount such that the ratio of the total lipid weight to the cisplatin weight is from about 40:1 to about 90:1.
21. The composition of claim 1 , wherein the composition has greater efficacy in vivo than cisplatin to reduce mean tumor volume.