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

Kai-Wen Ho; Yen-Ling Liu; Bo-Cheng Huang; Shih-Ting Hong; Shih-Hung Yang; Tzu-Yi Liao; En-Shuo Liu; Yu-Tung Chen; Yi-Zhong Huang; Yu-Lin Leu; Chiao-Yun Chen; Bing-Mae Chen; Steve R Roffler; Tian-Lu Cheng

doi:10.1016/j.ijbiomac.2025.140138

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

Int J Biol Macromol. 2025 Jan 20:140138. doi: 10.1016/j.ijbiomac.2025.140138. Online ahead of print.

Authors

Kai-Wen Ho¹, Yen-Ling Liu², Bo-Cheng Huang³, Shih-Ting Hong⁴, Shih-Hung Yang⁵, Tzu-Yi Liao², En-Shuo Liu², Yu-Tung Chen⁴, Yi-Zhong Huang⁴, Yu-Lin Leu⁶, Chiao-Yun Chen⁷, Bing-Mae Chen⁸, Steve R Roffler⁹, Tian-Lu Cheng¹⁰

Affiliations

¹ Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁴ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁵ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Biomedical Translation Research Center, Academia Sinica, Taiwan.
⁶ Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
⁷ Department of Radiation Oncology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Imaging, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁸ Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
⁹ Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: [email protected].
¹⁰ Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: [email protected].

PMID: 39842595
DOI: 10.1016/j.ijbiomac.2025.140138

Abstract

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.

Keywords: Drug delivery systems; Glycosidic switch liposomes; PEG engager (mPEG×EphA2).