TOXICITY AND ANTITUMOR-ACTIVITY OF CIS-BIS-CYCLOPENTENECARBOXYLATO-1,2-DIAMINOCYCLOHEXANE PLATINUM(II) ENCAPSULATED IN MULTILAMELLAR VESICLES

  • 1 December 1986
    • journal article
    • research article
    • Vol. 46  (12) , 6269-6273
Abstract
The potential of multilamellar vesicles (MLVs) as carriers of cis-biscyclopentenecarboxylato-1,2-diaminocyclohexane platinum(II) (CPDP), a lipophilic cisplatin derivative, was assessed. MLVs composed of dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), and cholesterol at different molar ratios were tested. The MLV-CPDP preparation with the highest antitumor activity against L1210 leukemia in vivo was DMPC:DMPG 7:3-CPDP. The encapsulation efficiency of this preparation was 66 .+-. 4% (SD), the stability in 0.9% NaCl solution at 4.degree. C was 89% at 14 days and 93% 18 h after incubation in human AB serum at 37.degree. C. The toxicities of DMPC:DMPG 7:3-CPDP and free CPDP (suspended in hydroxypropyl cellulose) administered i.p. were similar (50% lethal dose = 75 versus 91 mg/kg; blood urea nitrogen values 96 h after the administration of the 50% lethal dose = 32.0 versus 34.4 mg/dl). The mean %T/C [(median survival time of treated mice .div. median survival time of control mice) .times. 100] obtained after a single i.p. injection of the optimal dose of each preparation tested was 215 (range 200 to 232) for DMPG:DMPG 7:3-CPDP, 175 (range 158 to 209) for DMPC-CPDP, 162 (range 136 to 179) for free CPDP, and 178 (range 169 to 189) for cisplatin. Using a multiple i.p. injection schedule (injections on Days 1, 5, and 9), DMPC:DMPG 7:3-CPDP was more active than free CPDP and cisplatin (%T/C: 403, 284, and 253% respectively). DMPC:DMPG 7:3-CPDP is less toxic and more active against L1210 leukemia in vivo than is cisplatin. The encapsulation of CPDP in MLVs composed of DMPC:DMPG 7:3 provides an adequate vehicle for the administration of this lipophilic compound and enhances it''s antitumor activity against L1210 leukemia.