Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo

Edgar Deu, Ingrid T. Chen, Erica M W Lauterwasser, Juan Valderramos, Hao Li, Laura E Edgington, Adam R. Renslo, Matthew Bogyo

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (FeII) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an FeII-sensitive "trigger," making drug release contingent on FeII-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the FeII-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its FeII-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.

Original languageEnglish
Pages (from-to)18244-18249
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number45
DOIs
Publication statusPublished - 5 Nov 2013
Externally publishedYes

Keywords

  • Combination therapy
  • Dipeptidyl peptidase
  • Iron-mediated delivery
  • Targeted prodrugs

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