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

Abstract

BACKGROUND:

Hypoxic 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.

METHODS:

In 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.

RESULTS:

Because 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.

CONCLUSIONS:

The 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.

• Authors: Yan Chen, Lei Fang, Weixin Zhou, Jinghan Chang, Xiaojuan Zhang, Chuanchuan He, Chen Chen, Ruicong Yan, Yakai Yan, Yao Lu, Chuanrui Xu, Guangya Xiang
• Journal: Journal of nanobiotechnology (J Nanobiotechnology) Vol. 19 Issue 1 Pg. 246 (Aug 16 2021) ISSN: 1477-3155 [Electronic] England
• PMID: 34399762 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Antineoplastic Agents
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Micelles
• Multidrug Resistance-Associated Protein 2
• Nitric Oxide
• Chitosan
• Matrix Metalloproteinase 9
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• BALB 3T3 Cells
• Cell Line, Tumor
• Chitosan (chemistry)
• Cisplatin (pharmacology)
• Drug Delivery Systems
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Hypoxia (drug therapy)
• Hypoxia-Inducible Factor 1, alpha Subunit
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Micelles
• Multidrug Resistance-Associated Protein 2 (metabolism)
• Nitric Oxide (chemistry, pharmacology)
• Particle Size
• Tumor Microenvironment (drug effects)