ATP Suppression by pH-Activated Mitochondria-Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition

Small. 2020 Jun;16(23):e2001747. doi: 10.1002/smll.202001747. Epub 2020 May 6.

Abstract

Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid-activated mitochondria-targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α-cyclodextrin (α-CD) and acid-cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria-targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria-targeting capability under tumor extracellular pH (6.5). Such specific mitochondria-targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P-glycoprotein-related bioactivities and formation of tumor-derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid-activated mitochondria-targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO-relevant cancer treatments.

Keywords: cancer metastasis; drug delivery; drug resistance; energy suppression; nitric oxide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate
  • Drug Resistance
  • Humans
  • Hydrogen-Ion Concentration
  • Mitochondria
  • Nanoparticles*
  • Neoplasms* / drug therapy
  • Nitric Oxide

Substances

  • Nitric Oxide
  • Adenosine Triphosphate