(512a) pH-Triggered Leaky Heterogeneities On Rigid Lipid Bilayers Accelerate Intracellular Trafficking of Doxorubicin and Improve the Therapeutic Potential of Targeted Liposomal Immunochemotherapy

Intracellular trafficking of delivered therapeutics determines their biological activity. After intracellular localization, triggering extensive release of therapeutics from their carrier is the first step toward improving the therapeutic potential. This study aims to maximize the therapeutic potential of targeted immunochemotherapy using anti-HER2/neu liposomal doxorubicin by exploiting the formation of leaky heterogeneities on rigid lipid bilayers to extensively release doxorubicin during endocytosis. We have previously demonstrated¹ that pH-dependent formation of phase-separated lipid heterogeneities on the plane of a bilayer membrane increases the permeability of lipid bilayers when they are composed of lipid pairs with rigid non-matching chain lengths. It was suggested that this is due to defective packing among non-matching acyl chains of lipids residing at the interfaces of lipid domains. Here we design nanometer-size antiHER2/neu-labeled PEGylated lipid vesicles composed of lipid pairs with longer non-matching acyl tails (n = 18 and 21). We show that these vesicles exhibit superior killing efficacy of cancer cells compared to established liposome formulations for immunochemotherapy, and that their killing efficacy is similar to the effect of combined free doxorubicin and free antiHER2/neu antibody. Our findings suggest that intracellular trafficking of doxorubicin delivered by these immunolabeled vesicles is comparable to trafficking of the free agent. Other transport-related properties are unaffected: (1) blood circulation times are comparable to the circulation of commercial liposome formulations, and (2) specific binding and internalization by cancer cells are identical to antiHER2/neu-labeled commercial liposome formulations. These results demonstrate the potential of these long circulating, environmentally responsive lipid vesicles with triggered membrane permeability to increase the therapeutic potential of targeted immunochemotherapy.

1.Karve, S.; Bajagur Kempegowda, G.; Sofou, S. Heterogeneous domains and membrane permeability in phosphatidylcholine- phosphatidic acid rigid vesicles as a function of pH and lipid chain mismatch Langmuir 2008, 24, 5679-5688.