Glutathione-triggered release of SO2 gas to augment oxidative stress for enhanced chemodynamic and sonodynamic therapy

Biomater Sci. 2024 Apr 30;12(9):2341-2355. doi: 10.1039/d3bm02027d.

Abstract

Recently, gas therapy has emerged as a promising alternative treatment for deep-seated tumors. However, some challenges regarding insufficient or uncontrolled gas generation as well as unclear therapeutic mechanisms restrict its further clinical application. Herein, a well-designed nanoreactor based on intracellular glutathione (GSH)-triggered generation of sulfur dioxide (SO2) gas to augment oxidative stress has been developed for synergistic chemodynamic therapy (CDT)/sonodynamic therapy (SDT)/SO2 gas therapy. The nanoreactor (designed as CCM@FH-DNs) is constructed by employing iron-doped hollow mesoporous silica nanoparticles as carriers, the surface of which was modified with the SO2 prodrug 2,4-dinitrobenzenesulfonyl (DNs) and further coated with cancer cell membranes for homologous targeting. The CCM@FH-DNs can not only serve as a Fenton-like agent for CDT, but also as a sonosensitizer for SDT. Importantly, CCM@FH-DNs can release SO2 for SO2-mediated gas therapy. Both in vitro and in vivo evaluations demonstrate that the CCM@FH-DNs nanoreactor performs well in augmenting oxidative stress for SO2 gas therapy-enhanced CDT/SDT via GSH depletion and glutathione peroxidase-4 enzyme deactivation as well as superoxide dismutase inhibition. Moreover, the doped iron ions ensure that the CCM@FH-DNs nanoreactors enable magnetic resonance imaging-guided therapy. Such a GSH-triggered SO2 gas therapy-enhanced CDT/SDT strategy provides an intelligent paradigm for developing efficient tumor microenvironment-responsive treatments.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Glutathione* / chemistry
  • Glutathione* / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Nanoparticles / chemistry
  • Oxidative Stress* / drug effects
  • Silicon Dioxide / chemistry
  • Sulfur Dioxide* / chemistry
  • Sulfur Dioxide* / pharmacology
  • Ultrasonic Therapy

Substances

  • Glutathione
  • Sulfur Dioxide
  • Silicon Dioxide