Targeted internalization and activation of glycosidic switch liposomes by a biological macromolecule mPEG×EphA2 increases therapeutic efficacy against lung cancer.

Glycosidic switch liposome (GSL) technology efficiently encapsulates and stabilizes potent anticancer drugs in liposomes using a reversible glucuronide ester. Enzymatic hydrolysis of the glucuronide switch in target cell lysosomes produces parental drug. Our study examined the potential of a bispecific macromolecule, a polyethylene glycol (PEG) engager (mPEG×EphA2), generated by fusing a humanized anti-methoxy PEG (mPEG) Fab with an anti-EphA2 single-chain antibody, to increase GSL uptake into cancer cells and boost the anticancer activity by targeting PEG on GSL and an internalizing tumor antigen. Combining GSL with the PEG engager creates αEphA2/GSL, targeting cancer cells to generate topoisomerase I poison 9-aminocamptothecin (9 AC) for cell killing. Targeted liposomes can bind CL1-5 human lung adenocarcinoma cells and increase GSL internalization from 0 % to 62.4 % in 60 min. αEphA2/GSL showed slightly higher cellular cytotoxicity than non-targeted GSL, but targeted GSL increased 9 AC intratumoral concentrations by 8.4 fold at 24 h. The 9 AC tumor/blood ratio of αEphA2/GSL was nearly 6-fold higher than αDNS/GSL (control engager GSL). Using targeted GSL, five of seven mice with solid CL1-5 tumors were cured. The mPEG×EphA2 engager can enhance GSL drug uptake and generation, boosting lung cancer treatment efficacy, suggesting that αEphA2/GSL is a promising treatment for tumors overexpressing EphA2.