Increased Cytotoxicity and Reversal of Resistance to cis-Diamminedichloro-platinum(II) with Entrapment of cis-Bis-neodecanoato-tra/is-R,R-1,2-diaminocyclohexaneplatinum(II) in Multilamellar Lipid Vesicles

The role of liposome entrapment in modulating the cytotoxicity of a lipophilic cisplatin derivative was assessed. c/s-Bis-neodecanoato-fnzns-/?,/M,2-diaminocyclohexaneplatinum(II) (NDDP) was tested in suspension (free NDDP) or entrapped in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol (L-NDDP). Against LoVo colon carcinoma cells sensitive to cisplatin, L-NDDP was two times more cytotoxic in vitro than free NDDP and cisplatin (Do 7μM for L-NDDP, 15 μM for free NDDP, and 16 μM for cisplatin). Against LoVo cells resistant to a concentration of 3 μg/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 μM M for L-NDDP, 45 μM for free NDDP, and 48 μM for cisplatin). In in vivo studies, free NDDP was less potent and less active than L-NDDP against i.p. L-1210 leukemia (free NDDP, optimum %T/ C 148 at a dose of 75 mg/kg; L-NDDP, optimum %T/C 185 at a dose of 25 mg/kg) and i.p. L1210/PDD leukemia (free NDDP, optimum %T/C 128 at a dose of 50 mg/kg on Days 1, 5, and 9; L-NDDP, optimum %T/ C 200 at a dose of 12.5 mg/kg on Days 1, 5, and 9). Free NDDP administered i.v. was inactive against liver metastases of M5076 reticulosarcoma (%T/C 102) while L-NDDP showed significant activity (%T/ C 140). The single dose i.v. LDso in mice of free NDDP and L-NDDP were similar (79.4 mg/kg for free NDDP and 64.5 mg/kg for L-NDDP). These studies show that NDDP is a liposome-dependent drug since it can only be satisfactorily formulated in the liposomal form and since the liposomal carrier plays a crucial role in determining its antitumor activity.