期刊
ACTA BIOMATERIALIA
卷 111, 期 -, 页码 386-397出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2020.04.029
关键词
Bispecific antibody; mPEGylated liposomal doxorubicin; HER2; Methoxy poly (ethylene glycol); Combination therapy; Targeted therapy
资金
- Ministry of Science and Technology, Taipei, Taiwan [MOST 107-2320-B-037-024-MY3, MOST 107-2320-B-037-028-MY2, MOST 108-2311-B-037-001-MY2]
- National Health Research Institutes, Taiwan [NHRI-EX108-10729EI]
- Academia Sinica, Taiwan [AS-TP-107-L11]
- Ministry of Education, Taiwan [108RSB0029]
- Program for Translational Innovation of Biopharmaceutical Development Technology Supporting Platform Axis, Academia Sinica, Taiwan [AS-KPQ-106-TSPA]
- KMU-KMUH Co-Project of Key Research [KMU-DK109001]
- Kaohsiung Medical University, Taiwan [KMU-DK109004]
- Kaohsiung Medical University Research Center Grant (Drug Development and Value Creation Research Center) [KMU-TC108A03]
Targeted antibodies and methoxy-PEGylated nanocarriers have gradually become a mainstream of cancer therapy. To increase the anti-cancer effects of targeted antibodies combined with mPEGylated liposomes (mPEG-liposomes), we describe a bispecific antibody in which an anti-methoxy-polyethylene glycol scFv (alpha mPEG scFv) was fused to the C-terminus of an anti-HER2 (alpha HER2) antibody to generate a HER2 x mPEG BsAb that retained the original efficacy of a targeted antibody while actively attracting mPEG-liposomes to accumulate at tumor sites. HER2 xmPEG BsAb can simultaneously bind to HER2high expressing MCF7/HER2 tumor cells and mPEG molecules on mPEG-liposomal doxorubicin (Lipo-Dox). Pre-incubation of HER2 x mPEG BsAb with cells increased the endocytosis of Lipo-DiD and enhanced the cytotoxicity of Lipo-Dox to MCF7/HER2 tumor cells. Furthermore, pre-treatment of HER2 x mPEG BsAb enhanced the tumor accumulation and retention of Lipo-DiR 2.2-fold in HER2-high expressing MCF7/HER2 tumors as compared to HER2-low expressing MCF7/neol tumors. Importantly, HER2 x mPEG BsAb plus Lipo-Dox significantly suppressed tumor growth as compared to control BsAb plus Lipo-Dox in MCF7/HER2 tumor-bearing mice. These results indicate that HER2 x mPEG BsAb can enhance tumor accumulation of mPEG-liposomes to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy. Statement of Significance Antibody targeted therapy and PEGylated drugs have gradually become the mainstream of cancer therapy. To enhance the anti-cancer effects of targeted antibodies combined with PEGylated drugs is very important. To this aim, we fused an anti-PEG scFv to the C-terminal of HER2 targeted antibodies to generate a HER2xmPEG bispecific antibody (BsAb) to retain the original efficacy of targeted antibody whilst actively attract mPEG-liposomal drugs to accumulate at tumor sites. The present study demonstrates pretreatment of HER2xmPEG BsAb can enhance tumor accumulation of mPEG-liposomal drugs to improve the therapeutic efficacy of combination treatment. Anti-mPEG scFv can be fused to any kind of targeted antibody to generate BsAbs to actively attract mPEG-drugs and improve anti-cancer efficacy. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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