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Enhanced Therapeutic Effects of Liposome-associated 1-O-Octadecyl-2-O-methyl-sn-glycero-3-phosphocholine

The Liposome Company, Inc., Princeton, New Jersey 08540

The ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH₃) has anticancer activity, but systemic toxicity has restricted its therapeutic use. In this report "free" ET-18-OCH₃ and a stable, well-characterized, liposome-based formulation of ET-18-OCH₃ (ELL-12) were compared for in vivo toxicity in normal mice and for therapeutic efficacy in three mouse tumor model systems. The entrapment of ET-18-OCH₃ in liposomes decreased the acute toxicity of ET-18-OCH₃ after i.v. administration. The maximum tolerated dose for a single i.v. dose of free ET-18-OCH₃ was found to be 25 mg/kg, whereas the maximum tolerated dose for ELL-12 was approximately 200 mg/kg. ELL-12 was much less hemolytic in vivo than ET-18-OCH₃. The therapeutic efficacy of free ET-18-OCH₃ and ELL-12 was investigated against i.p. P388 leukemia, Lewis lung cancer lung metastases, and B16/F10 melanoma (lung tumor nodules) in mice. Although ET-18-OCH₃ had some anticancer activity, it was found that ELL-12 was more effective than ET-18-OCH₃ in all three tumor models at lower and nontoxic dose schedules. These results suggest that association of ET-18-OCH₃ in stable, well-characterized liposomes transforms it into an effective antitumor agent.

¹ To whom requests for reprints should be addressed, at The Liposome Company Inc., One Research Way, Princeton, New Jersey 08540. Phone: (609) 452-7061; Fax: (609) 520-8250.

Received 11/ 4/96. Accepted 3/24/97.

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