Oxidized phospholipid based pH sensitive micelles for delivery of anthracyclines to resistant leukemia cells in vitro

Abstract

A self-assembled micelle drug delivery system was constructed with an oxidized phospholipid for anthracycline anti-cancer drug delivery. An oxidized phospholipid, 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazPC), was chosen to fabricate micelles via both electrostatic and hydrophobic interactions for delivery of doxorubicin (DOX) and idarubicin (IDA). The formation of ion–pair complexes between PazPC and DOX was first investigated under different pH conditions. Drug-loaded PazPC micelles at a 5:1 molar ratio of lipid/drug at pH 7.0 were then prepared by the solvent evaporation method. The empty and drug-loaded PazPC micelles exhibited a small particle size (∼10 nm) and high encapsulation efficiency. In vitro stability and release profile indicated that the micelles were stable at physiological conditions, but exhibited pH-sensitive behavior with accelerated release of DOX or IDA in an acidic endosome environment. Finally, in vitro uptake and cytotoxicity were evaluated for leukemia P388 and its resistant subline P388/ADR. The drug-loaded PazPC micelles enhanced drug uptake and exhibited higher cytotoxicity in both leukemia cells in comparison to free drugs. In conclusion, we developed a novel pH sensitive oxidized phospholipid-based micellar formulation which could potentially be useful in delivering anthracycline anti-cancer drugs and provide a novel strategy for increasing the therapeutic index while overcoming multidrug resistance for leukemia treatment.