Nitric oxide-releasing micelles with intelligent targeting for enhanced anti-tumor effect of cisplatin in hypoxia

Journal of Nanobiotechnology

Yakai Yan¹  Jinghan Chang¹  Yan Chen¹  Chuanchuan He¹  Yao Lu¹  Ruicong Yan¹  Guangya Xiang¹  Chuanrui Xu¹  Xiaojuan Zhang¹  Lei Fang¹  Chen Chen¹  Weixin Zhou¹ 

[1] School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China;

关键词: Hypoxia;    Drug resistance;    Metastasis;    HIF-1α;    Cisplatin;    Nitric oxide;    Chitosan oligosaccharide;   

DOI  :  10.1186/s12951-021-00989-z

来源: Springer

【 摘 要 】

BackgroundHypoxic tumor microenvironment (TME) promotes tumor metastasis and drug resistance, leading to low efficiency of cancer chemotherapy. The development of targeted agents or multi-target therapies regulating hypoxic microenvironment is an important approach to overcome drug resistance and metastasis.MethodsIn this study, chitosan oligosaccharide (COS)-coated and sialic acid (SA) receptor-targeted nano-micelles were prepared using film dispersion method to co-deliver cisplatin (CDDP) and nitric oxide (NO) (denoted as CTP/CDDP). In addition, we explored the mechanisms by which NO reversed CDDP resistance as well as enhanced anti-metastatic efficacy in hypoxic cancer cells.ResultsBecause of the different affinities of COS and SA to phenylboronic acid (PBA) under different pH regimes, CTP/CDDP micelles with intelligent targeting property increased cellular uptake of CDDP and enhanced cytotoxicity to tumors, but reduced systemic toxicity to normal organs or tissues. In addition, CTP/CDDP showed stimulus-responsive release in TME. In terms of anti-tumor mechanism, CTP/CDDP reduced CDDP efflux and inhibited epithelial-mesenchymal transition (EMT) process of tumor by down-regulating hypoxia-inducible factor-1α (HIF-1α), glutathione (GSH), multidrug resistance-associated protein 2 (MRP2) and matrix metalloproteinase 9 (MMP9) expression, thus reversing drug resistance and metastasis of hypoxic tumor cells.ConclusionsThe designed micelles significantly enhanced anti-tumor effects both in vitro and in vivo. These results suggested that CTP/CDDP represented a promising strategy to treat resistance and metastatic tumors.Graphic abstract

【 授权许可】

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