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)].