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Dual-responsive nanoparticles loading bevacizumab and gefitinib for molecular targeted therapy against non-small cell lung cancer

Zi-tong Zhao1,2, Jue Wang2, Lei Fang2, Xin-di Qian2, Ying Cai2, Hai-qiang Cao2, Guan-ru Wang2, Mei-lin He3, Yan-yan Jiang1, Dang-ge Wang2,3, Ya-ping Li2,4,5
1 School of Pharmacy, Fudan University, Shanghai 201203, China
2 State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai 264000, China
4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264000, China
5 School of Pharmacy, Yantai University, Yantai 264005, China
Correspondence to: Yan-yan Jiang: yanyanjiang@fudan.edu.cn, Dang-ge Wang: dgwang@simm.ac.cn, Ya-ping Li: ypli@simm.ac.cn,
DOI: 10.1038/s41401-022-00930-6
Received: 25 March 2022
Accepted: 26 May 2022
Advance online: 15 June 2022

Abstract

The combination of vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKIs) is newly available for molecular targeted therapy against non-small cell lung cancer (NSCLC) in clinic. However, the therapeutic benefits remain unsatisfying due to the poor drug delivery to targets of interest. In this study, we developed bevacizumab-coated gefitinib-loaded nanoparticles (BCGN) with dual-responsive drug release for inhibiting tumor angiogenesis and phosphorylation of epidermal growth factor receptor (EGFR). Through an exogenous corona strategy, bevacizumab is easily coated on gefitinib-loaded nanoparticles via electrostatic interaction. After intravenous injection, BCGN are efficiently accumulated in NSCLC tumors as confirmed by dual-model imaging. Bevacizumab is released from BCGN upon oxidation in tumor microenvironment, whereas gefitinib is released after being internalized by tumor cells and disassembled in reduction cytoplasm. The dual-responsive release of bevacizumab and gefitinib significantly inhibits tumor growth in both A549 and HCC827 human NSCLC models. Our approach provides a promising strategy to improve combinational molecular targeted therapy of NSCLC with precisely controlled drug release.
Keywords: nanoparticles; molecular targeted therapy; non-small cell lung cancer; dual-responsive; controlled release

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