(414e) Targeted Liposomes with pH-Triggered Leaky Heterogeneities Increase the Therapeutic Potential of Targeted Immunochemotherapy

During endocytosis, pH-triggered release of encapsulated therapeutics from delivery carriers may accelerate their intracellular trafficking increasing therapeutic efficacy. To improve the therapeutic potential of targeted immunochemotherapy using anti-HER2/neu liposomal doxorubicin, we exploit the formation of leaky heterogeneities on rigid lipid bilayers to extensively release doxorubicin during endocytosis. We have previously demonstrated that pH-dependent formation of phase-separated lipid heterogeneities on the plane of a bilayer membrane increases the permeability of bilayers when they are composed of lipid pairs with rigid non-matching acyl chain lengths. This was suggested to be due to defective packing among lipids residing at the interfaces of lipid domains. Here we design nanometer-size antiHER2/neu-labeled PEGylated vesicles composed of lipid pairs with longer non-matching acyl chain lengths (n = 18 and 21). In vitro, these vesicles exhibit superior killing efficacy of cancer cells compared to established liposome formulations, and their killing efficacy is similar to the effect of combined free doxorubicin and free antiHER2/neu antibody. Other transport-related properties such as liposome blood circulation times, and specific binding and internalization by cancer cells are unaffected. In vivo, in a murine vascularized breast cancer model, these antiHER2/neu vesicles loaded with doxorubicin exhibit superior tumor control compared to established formulations of liposomal doxorubicin labeled with identical antiHER2/neu antibodies. These results demonstrate the potential of targeted vesicles with pH-triggered leaky heterogeneities to increase the therapeutic potential of targeted immunochemotherapy.