Enhanced antitumor activity [correction for activitiy] of trans(+/-)-1,2-diaminocyclo- hexaneglutamatoplatinum(II) formulated with stealth liposome

The antitumor platinum(II) compound, [Pt(dach)(Glu)] (dach=trans(+/-)-1,2-diaminocyclohexane, Glu=glutamate) was formulated with a stealth liposome to improve its biological activity. Liposomes were composed of PC/PEG2000-PE/CH (PC=1,2-diacyl-glycero-3-phosphocholine; PEG2000-PE=poly(ethylene glycol)2000-1,2-diacyl-glycero-3-phosphoethanolamine; CH=cholesterol) involving different acyl moieties of phospholipids such as DO (dioleoyl), DM (dimyristoyl) or DS (distearoyl) group. Among the different acyl groups in the stealth liposomes, the DM formulation was optimal for the preparation of the liposomal [Pt(dach)(Glu)] at the mole ratio of DMPC/PEG2000-DMPE/CH=50/5/45 and at the weight ratio of drug/lipid=1/20, which is represented as L-[Pt(dach)(Glu)]. In vitro cytotoxicity was examined in sensitive A2780 and ME180 and their cisplatin-resistant A2780/PDD and ME180/PDD cancer cells. L-[Pt(dach)(Glu)] was 2 approximately 3 times more cytotoxic than the free complex [Pt(dach)(Glu)] and cisplatin in sensitive cells, and 4 approximately 8 times more cytotoxic in resistant cells. Thus, the resistance index of L-[Pt(dach)(Glu)] was 1.3 approximately 2 while those of the free complex and cisplatin were 5 approximately 6, which indicates that L-[Pt(dach)(Glu)] overcome the cisplatin resistance in both resistant cells. In vivo antitumor activity was assayed against the L1210/S leukemia. The optimal activities (% T/C) of the free complex and L-[Pt(dach)(Glu)] were >459/20 and >442/200 mg/kg, respectively. Considering the amount of the platinum complex in L-[Pt(dach)(Glu)], the liposomal [Pt(dach)(Glu)] displayed 2-fold higher drug potency than the free complex. The biodistribution experiment using LE52 tumor-bearing mouse showed excellent lung targeting property of L-[Pt(dach)(Glu)].