Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes

A number of highly lipophilic dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes were entrapped in multilamellar vesicles composed of dimyristoyl phosphatidylcholine and dimyristoyl phosphatidyl-glycerol at a molar ratio of 7:3. The entrapment efficiency and stability of liposomal platinum (L-Pt) preparations was > 90%. The subacute mouse LD₅₀ of L-Pt preparations tested ranged from 60 to 104 mg/kg. All L-Pt preparations tested had no significant nephrotoxicity at the LD₅₀ dose except for L-Pt 5, which caused renal dysfunctions (as evidenced by elevated blood urea nitrogen levels) at the LD₅₀ dose. L-Pt preparations had shown good in vivo antitumor activity against i.p. L1210 leukemia when an optimal dose was administered i.p. to mice on days 1, 5 and 9 (% T/C 230-300; cisplatin 220). L-Pt preparations were also markedly active, by the i.p. route, against L1210 leukemia resistant to cisplatin (% T/C 237-355; cisplatin 112). All L-Pt preparations exhibited significant antitumor activity against B16 melanoma when administered i.p. on day 1 (% T/C 144-155; cisplatin 161). L-Pt 1, 3 and 5 were all tested by the i.v. route on days 4, 8 and 12 against M5076 reticulosarcoma, but none of these preparations showed any significant antitumor activity against this tumor system (% T/C 120-127; cisplatin 173). Current studies aimed at optimizing the liposomal formulation of these compounds should result in the selection of a single isomeric L-Pt formulation for clinical development.