pH-Dependent Chloride Transport by Pseudopeptidic Cages for the Selective Killing of Cancer Cells in Acidic Microenvironments

Angew Chem Int Ed Engl. 2019 Sep 2;58(36):12465-12468. doi: 10.1002/anie.201905965. Epub 2019 Aug 1.

Abstract

Acidic microenvironments in solid tumors are a hallmark of cancer. Inspired by that, we designed a family of pseudopeptidic cage-like anionophores displaying pH-dependent activity. When protonated, they efficiently bind chloride anions. They also transport chloride through lipid bilayers, with their anionophoric properties improving at acidic pH, suggesting an H+ /Cl- symport mechanism. NMR studies in DPC micelles demonstrate that the cages bind chloride within the lipid phase. The chloride affinity and the chloride-exchange rate with the aqueous bulk solution are improved when the pH is lowered. This increases cytotoxicity towards lung adenocarcinoma cells at the pH of the microenvironment of a solid tumor. These properties depend on the nature of the amino-acid side chains of the cages, which modulate their lipophilicity and interactions with the cell membrane. This paves the way towards using pH as a parameter to control the selectivity of cytotoxic ionophores as anticancer drugs.

Keywords: NMR spectroscopy; anionophores; cancer; host-guest systems; supramolecular chemistry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology*
  • Cell Proliferation*
  • Chlorides / metabolism*
  • Humans
  • Hydrochloric Acid / chemistry*
  • Hydrogen-Ion Concentration
  • Lipid Bilayers / metabolism*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Tumor Cells, Cultured
  • Tumor Microenvironment*

Substances

  • Chlorides
  • Lipid Bilayers
  • Hydrochloric Acid