A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals

Timothy A. Su, Diyala S. Shihadih, Wendy Cao, Tyler C. Detomasi, Marie Heffern, Shang Jia, Andreas Stahl, Christopher J. Chang

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Copper deficiency is implicated in a variety of genetic, neurological, cardiovascular, and metabolic diseases. Current approaches for addressing copper deficiency rely on generic copper supplementation, which can potentially lead to detrimental off-target metal accumulation in unwanted tissues and subsequently trigger oxidative stress and damage cascades. Here we present a new modular platform for delivering metal ions in a tissue-specific manner and demonstrate liver-targeted copper supplementation as a proof of concept of this strategy. Specifically, we designed and synthesized an N-acetylgalactosamine-functionalized ionophore, Gal-Cu(gtsm), to serve as a copper-carrying "Trojan Horse" that targets liver-localized asialoglycoprotein receptors (ASGPRs) and releases copper only after being taken up by cells, where the reducing intracellular environment triggers copper release from the ionophore. We utilized a combination of bioluminescence imaging and inductively coupled plasma mass spectrometry assays to establish ASGPR-dependent copper accumulation with this reagent in both liver cell culture and mouse models with minimal toxicity. The modular nature of our synthetic approach presages that this platform can be expanded to deliver a broader range of metals to specific cells, tissues, and organs in a more directed manner to treat metal deficiency in disease.

Original languageEnglish (US)
Pages (from-to)13764-13774
Number of pages11
JournalJournal of the American Chemical Society
Volume140
Issue number42
DOIs
StatePublished - Oct 24 2018
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Fingerprint Dive into the research topics of 'A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals'. Together they form a unique fingerprint.

  • Cite this

    Su, T. A., Shihadih, D. S., Cao, W., Detomasi, T. C., Heffern, M., Jia, S., Stahl, A., & Chang, C. J. (2018). A Modular Ionophore Platform for Liver-Directed Copper Supplementation in Cells and Animals. Journal of the American Chemical Society, 140(42), 13764-13774. https://doi.org/10.1021/jacs.8b08014