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Abstract
Ovarian cancer is highly metastatic, with a high frequency of relapse, and is the most fatal gynecologic malignancy in women worldwide. It is important to elevate the drug susceptibility and cytotoxicity of ovarian cancer cells, thereby eliminating resident cancer cells for more effective therapeutic efficacy. Here, we developed a bispecific antibody (BsAb; mPEG × HER2) that can easily provide HER2+ tumor tropism to mPEGylated liposomal doxorubicin (PLD) and further increase the drug accumulation in cancer cells via receptor-mediated endocytosis, and improve the cytotoxicity and therapeutic efficacy of HER2+ ovarian tumors. The mPEG × HER2 can simultaneously bind to mPEG molecules on the surface of PLD and HER2 antigen on the surface of ovarian cancer cells. Simply mixing the mPEG × HER2 with PLD was able to confer HER2 specificity of PLD to HER2+ ovarian cancer cells and efficiently trigger endocytosis and enhance cytotoxicity by 5.4-fold as compared to non-targeted PLD. mPEG × HER2-modified PLD was able to significantly increase the targeting and accumulation of HER2+ ovarian tumor by 220% as compared with non-targeted PLD. It could also significantly improve the anti-tumor activity of PLD (P < 0.05) with minimal obvious toxicity in a tumor-bearing mouse model. We believe that the mPEG × HER2 can significantly improve the therapeutic efficacy, potentially reduce the relapse freqency and thereby achieve good prognosis in ovarian cancer patients.
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1 Kaohsiung Medical University, Department of Laboratory Medicine, School of Medicine, College of Medicine, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University, Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University, Drug Development and Value Creation Research Center, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University Hospital, Department of Medical Research, Kaohsiung, Taiwan (GRID:grid.412027.2) (ISNI:0000 0004 0620 9374); Kaohsiung Medical University, Department of Laboratory Medicine, Post Baccalaureat Medicine, College of Medicine, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696)
2 Kaohsiung Medical University, Drug Development and Value Creation Research Center, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University, Department of Biomedical Science and Environmental Biology, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696)
3 Kaohsiung Medical University, Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696)
4 National Sun Yat-Sen University, Institute of Biomedical Sciences, Kaohsiung, Taiwan (GRID:grid.412036.2) (ISNI:0000 0004 0531 9758)
5 National Kaohsiung University of Science and Technology, Department of Aquaculture, Kaohsiung, Taiwan (GRID:grid.412111.6) (ISNI:0000 0004 0638 9985)
6 Kaohsiung Medical University Hospital, Department of Radiation Oncology, Cancer Center, Kaohsiung, Taiwan (GRID:grid.412027.2) (ISNI:0000 0004 0620 9374)
7 Changhua Christian Hospital, Endoscopic and Oncoplastic Breast Surgery Center, Comprehensive Breast Cancer Center, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372); Changhua Christian Hospital, Division of General Surgery, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372); Changhua Christian Hospital, Comprehensive Breast Cancer Center, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372); Minimal Invasive Surgery Research Center, Changhua Christian Hospital, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372)
8 Kaohsiung Medical University, Graduate Institute of Medicine, College of Medicine, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University, Drug Development and Value Creation Research Center, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696); Kaohsiung Medical University Hospital, Department of Medical Research, Kaohsiung, Taiwan (GRID:grid.412027.2) (ISNI:0000 0004 0620 9374); Kaohsiung Medical University, Department of Biomedical Science and Environmental Biology, Kaohsiung, Taiwan (GRID:grid.412019.f) (ISNI:0000 0000 9476 5696)