A glutathione responsive nitric oxide release system based on charge-reversal chitosan nanoparticles for enhancing synergistic effect against multidrug resistance tumor

Nanomedicine. 2019 Aug:20:102015. doi: 10.1016/j.nano.2019.102015. Epub 2019 May 29.

Abstract

The combination therapy of nitric oxide (NO) and anticancer drug was developed for reversing multidrug resistance (MDR). In order to avoid NO release during the blood circulation, and realize pinpointed release in the tumor cells, we designed a tumor-specific NO-release system based on 10-hydroxycamptothecin (HCPT)-loaded charge-reversal chitosan nanoparticles and covalently linked phenylsulfonyl furoxan (glutathione (GSH)-responsive NO donor) on the surface. The results showed that only 6.0% of NO was eventually released under physiology condition (pH 7.4 and 2 μM GSH) within 8 h. In contrast, 93.0% of NO was released within 4 h in the presence of 10 mM GSH. Western blot result displayed the P-glycoprotein expression was significantly decreased by 50.1%. Hence, this system performed remarkable cytotoxicity in vitro and the highest tumor inhibition rate (79.7%) comparing with free HCPT group (20.7%) in vivo. Such GSH-responsive NO-release system is a promising candidate with prominent therapeutic effect against MDR tumor.

Keywords: Chitosan nanoparticle; Drug delivery; GSH-responsive; Multidrug resistance; Nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Cell Death
  • Chitosan / chemistry*
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Endocytosis
  • Female
  • Glutathione / metabolism*
  • Humans
  • MCF-7 Cells
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nanoparticles / chemistry*
  • Neoplasms / drug therapy*
  • Nitric Oxide / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Nitric Oxide
  • Chitosan
  • Glutathione