Tumor Microenvironment Responsive Hollow Nanoplatform for Triple Amplification of Oxidative Stress to Enhance Cuproptosis-Based Synergistic Cancer Therapy

Adv Healthc Mater. 2023 May;12(13):e2202949. doi: 10.1002/adhm.202202949. Epub 2023 Feb 16.

Abstract

Cuproptosis is a recently discovered form of programmed cell death and shows great potential in cancer treatment. Herein, a copper-dithiocarbamate chelate-doped and artemisinin-loaded hollow nanoplatform (HNP) is developed via a chelation competition-induced hollowing strategy for cuproptosis-based combination therapy. The HNP exhibits tumor microenvironment-triggered catalytic activity, wherein liberated Cu2+ catalyzes artemisinin and endogenous H2 O2 to produce C-centered radicals and hydroxyl radicals, respectively. Meanwhile, the disulfide bonds-rich HNP can deplete intracellular glutathione, thus triply amplifying tumor oxidative stress. The augmented oxidative stress sensitizes cancer cells to the cuproptosis, causing prominent dihydrolipoamide S-acetyltransferase oligomerization and mitochondrial dysfunction. Moreover, the HNP can activate ferroptosis via inhibiting GPX4 activity and trigger apoptosis via dithiocarbamate-copper chelate-mediated ubiquitinated proteins accumulation, resulting in potent antitumor efficacy. Such a cuproptosis/ferroptosis/apoptosis synergetic strategy opens a new avenue for cancer therapy.

Keywords: artemisinin; cuproptosis; disulfiram; oxidative stress; tumor therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Artemisinins*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Copper / pharmacology
  • Neoplasms* / drug therapy
  • Oxidative Stress
  • Tumor Microenvironment

Substances

  • artemisinin
  • Artemisinins
  • Copper