1. Dual-Targeted Extracellular Vesicles to Facilitate Combined Therapies for Neuroendocrine Cancer Treatment
- Author
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Yingnan Si, Seulhee Kim, Yuanxin Xu, Jia-Shiung Guan, X. Margaret Liu, Renata Jaskula-Sztul, Lufang Zhou, and Kai Chen
- Subjects
combined chemotherapies ,medicine.drug_class ,lcsh:RS1-441 ,Pharmaceutical Science ,Monoclonal antibody ,Mertansine ,Article ,Microtubule polymerization ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,chemistry.chemical_compound ,Chemokine receptor ,0302 clinical medicine ,In vivo ,medicine ,030304 developmental biology ,0303 health sciences ,mAb-EV ,Verrucarin A ,dual targeting delivery ,chemistry ,neuroendocrine cancer ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Preclinical imaging - Abstract
Neuroendocrine (NE) cancers arise from cells within the neuroendocrine system. Chemotherapies and endoradiotherapy have been developed, but their clinical efficacy is limited. The objective of this study was to develop a dual-targeted extracellular vesicles (EV)-delivered combined therapies to treat NE cancer. Specifically, we produced EV in stirred-tank bioreactors and surface tagged both anti-somatostatin receptor 2 (SSTR 2) monoclonal antibody (mAb) and anti-C-X-C motif chemokine receptor 4 (CXCR4) mAb to generate mAbs-EV. Both live-cell confocal microscopy imaging and In Vivo Imaging System (IVIS) imaging confirmed that mAbs-EV specifically targeted and accumulated in NE cancer cells and NE tumor xenografts. Then the highly potent natural cytotoxic marine compound verrucarin A (Ver-A) with IC50 of 2.2&ndash, 2.8 nM and microtubule polymerization inhibitor mertansine (DM1) with IC50 of 3.1&ndash, 4.2 nM were packed into mAbs-EV. The in vivo maximum tolerated dose study performed in non-tumor-bearing mice indicated minimal systemic toxicity of mAbs-EV-Ver-A/DM1. Finally, the in vivo anticancer efficacy study demonstrated that the SSTR2/CXCR4 dual-targeted EV-Ver-A/DM1 is more effective to inhibit NE tumor growth than the single targeting and single drug. The results from this study could expand the application of EV to targeting deliver the combined potent chemotherapies for cancer treatment.
- Published
- 2020