Preclinical and Clinical Experience with Liposome-Encapsulated Mitoxantrone

Abstract

Mitoxantrone (MTO) was encapsulated by different preparation techniques into liposomes of different lipid compositions. MTO complexed to liposomes containing phosphatidic acid (PA, PA/MTO-liposomes) had blood pharmacokinetics which were comparable to the free drug. Accumulation in liver and spleen was significantly higher with PA/MTO-liposomes. Acute toxicity was 2.5 fold lower and the liposomal preparation had better antitumor effects in the L1210 leukemia and in a large cell lung cancer model. In a phase I study in patients with advanced breast cancer the maximal tolerable dose of PA/MTO-liposomes was 18 mg/m². The PA/MTO-liposomes were well tolerated, granulocytopenia was the dose-limiting effect. Clinical responses were seen in soft-tissues, liver and bone metastases. The properties of new liposome formulations with MTO were evaluated MTO-liposomes prepared by the pH-gradient loading method and modified with polyethylene glycol(2000)-diphosphatidylethanolamine (PEG(2000)-DPPE) had pharmacokinetic properties which were significantly superior to the PAJMTO-liposomes. Compared to free MTO and PA/MTO-liposomes, ΔpH MTO-liposomes containing PEG(2000)-DPPE, prepared with a ΔpH of 5 across the liposome membrane produced a 40-fold increase of the area under the curve (AUC). The new MTO-liposome formulations have excellent antitumor activities in the LI210 leukemia model. These results and further preclinical evaluation of the ΔpH MTO-liposomes support the initiation of a phase I study.