Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity.
Programmable fusogenic vesicles (PFVs) are lipid-based drug-delivery systems that exhibit time-dependent destabilization. The rate at which this destabilization occurs is determined by the exchange rate of a bilayer-stabilizing component, polyethylene glycol-phosphatidylethanolamine (PEG-PE) from the vesicle surface. This exchange rate is controlled, in turn, by the acyl chain composition of the PEG-PE. We describe in vitro and in vivo studies using PFVs as delivery vehicles for the anticancer drug mitoxantrone. We demonstrate that the PEG-PE acyl composition determined the rate at which PFVs are eliminated from plasma after intravenous administration, and the rate of mitoxantrone leakage from PFV. The nature of the PEG-PE component also determined the antitumor efficacy of mitoxantrone-loaded PFV in murine and human in murine and human xenograft tumor models. Increased circulation time and improved activity were obtained for PFV containing PEG-PE with an 18-carbon acyl chain length, as a result of slower vesicle destabilization.
Adlakha-Hutcheon
G
G
Department of Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
Bally
M B
MB
Shew
C R
CR
Madden
T D
TD
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004337:Drug Carriers; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D008942:Mitoxantrone