Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity

Programmable fusogenic vesicles (PFVs) are lipid-based drug-delivery system s that exhibit time-dependent destabilization. The rate at which this desta bilization occurs is determined by the exchange rate of a bilayer-stabilizi ng component, polyethylene glycol-phosphatidylethanolamine (PEG-PE) from th e vesicle surface. This exchange rate is controlled, in turn, by the acyl c hain composition of the PEG-PE. We describe in vitro and in vivo studies us ing PFVs as delivery vehicles far the anticancer drug mitoxantrone. We demo nstrate that the PEG-PE acyl composition determined the rate at which PFVs are eliminated from plasma after intravenous administration, and the rate o f mitoxantrone leakage from PFV, The nature of the PEG-PE component also de termined the antitumor efficacy of mitoxantrone-loaded PFV in murine and hu man in murine and human xenograft tumor models. Increased circulation time and improved activity were obtained for PN containing PEG-PE with an 18-car bon acyl chain length, as a result of slower vesicle destabilization.