Spatiotemporally Targeted Nanomedicine Overcomes Hypoxia-Induced Drug Resistance of Tumor Cells after Disrupting Neovasculature

• Published in: Nano letters Vol. 20; no. 8; pp. 6191 - 6198
• Main Authors: Chen, Jinjin, Jiang, Zhongyu, Xu, Weiguo, Sun, Tianmeng, Zhuang, Xiuli, Ding, Jianxun, Chen, Xuesi
• Format: Journal Article
• Language: English
• Published: American Chemical Society 12.08.2020
• Subjects: spatiotemporally targeted drug delivery; vascular disrupting agent; shell-stacked nanoparticle; combination cancer therapy; cytostatic drug
• ISSN: 1530-6984; 1530-6992; 1530-6992
• DOI: 10.1021/acs.nanolett.0c02515

Vascular disrupting agents (VDAs) are emerging anticancer agents, which show rising demand for combination with cytostatic drugs (CSDs), owing to inadequate tumor inhibition when applied singly. Nevertheless, the combination remains a challenge due to the different working sites of VDAs and CSDs and hypoxia-induced drug resistance after disrupting neovasculature by VDAs. Herein, we developed a shell-stacked nanoparticle (SNP) for coencapsulation of a VDA combretastatin A-4 phosphate (CA4P) and a proteasome inhibitor bortezomib (BTZ). The SNP could spatiotemporally deliver CA4P to tumor neovasculature and BTZ to tumor cells mediated by the site-specific stimuli-activated drug release. Moreover, the SNP also reversed the drug resistance caused by the overexpressed ABCG2 under CA4P-induced hypoxic conditions. The spatiotemporally targeted combination therapy significantly inhibited the growth of both the human A549 pulmonary adenocarcinoma xenograft model and patient-derived xenograft (PDX) model of colon cancer in mice, providing a promising strategy for treating advanced cancers.