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Lipophilic Cisplatin Analogues Entrapped in Liposomes: Role of Intraliposomal Drug Activation in Biological Activity¹

Department of Medical Oncology (Section of Head, Neck, and Thoracic Medical Oncology [R. P-S.] and Section of Pharmacology [A. R. K.]), The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP), a lipophilic cisplatin analogue containing two branched leaving groups of 10 carbon atoms, is undergoing clinical evaluation in a liposomal formulation. In previous studies, NDDP entrapped in multilamellar vesicles composed of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) at a 7:3 molar ratio was non-nephrotoxic in humans, not cross-resistant with cisplatin in different in vitro and in vivo systems, and more active than cisplatin against murine models of experimental liver metastases whereas free NDDP was devoid of in vivo antitumor activity at the optimal dose of L-NDDP and barely active at higher doses. To elucidate the mechanisms by which the liposomal carrier enhances the biological properties to this class of antitumor agents, we studied the effect of the liposome composition, size of the branched leaving groups of the platinum compound, and pH and composition of the aqueous phase on the entrapment efficiency, drug leakage, drug stability, and in vivo toxicity and antitumor activity of different liposomal formulations of these agents. In experiments using normal saline as aqueous phase, the presence of DMPG in the lipid bilayer resulted in a decreased stability and an increased biological activity of NDDP, whereas NDDP entrapped in liposomes composed of DMPC alone (not containing DMPG) was stable but devoid of antitumor activity. In studies with structurally related analogues with branched leaving groups of 5, 6, 7, and 9 carbon atoms, similar trends were observed. In addition, the number of carbon atoms in the leaving groups was directly and inversely related to the entrapment efficiency and stability of the analogues, respectively, independently of lipid composition; increasing the size of the branched leaving groups resulted in an increased in situ degradation of the platinum compound and enhanced biological activity and potency. These results suggest that this class of platinum compounds exerts its biological activity through the formation of active intermediates in situ within the lipid bilayers and that the activation reaction is highly dependent on the presence of DMPG and the size of the lipophilic leaving group.

¹ This study was supported in part by Grants CA 45423 and CA 41581 from the National Cancer Institute, Department of Health and Human Services, and was presented in part at the 82nd Annual Meeting of the American Association for Cancer Research, Houston, TX, 1991.

² To whom requests for reprints should be addressed, at Section of Head, Neck, and Thoracic Medical Oncology, Department of Medical Oncology, Box 80, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030.

Received 6/16/92. Accepted 9/11/92.

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