1. Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo
- Author
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Ingrid Chen, Hao Li, Matthew Bogyo, Juan Valderramos, Adam R. Renslo, Laura E. Edgington, Edgar Deu, and Erica M. W. Lauterwasser
- Subjects
Electrophoresis ,Plasmodium berghei ,Biology ,Pharmacology ,Dipeptidyl peptidase ,combination therapy ,dipeptidyl peptidase ,Ferrous ,Mice ,Drug Delivery Systems ,Rare Diseases ,Drug Therapy ,Heterocyclic Compounds ,In vivo ,Animals ,Ferrous Compounds ,iron-mediated delivery ,Dipeptidyl-Peptidases and Tripeptidyl-Peptidases ,Cytotoxicity ,Cancer ,Polyacrylamide Gel ,Multidisciplinary ,Biological Sciences ,biology.organism_classification ,Malaria ,Vector-Borne Diseases ,Infectious Diseases ,Orphan Drug ,Good Health and Well Being ,Photochemotherapy ,Biochemistry ,Targeted drug delivery ,5.1 Pharmaceuticals ,Delayed-Action Preparations ,Combination ,Drug delivery ,Drug Therapy, Combination ,Electrophoresis, Polyacrylamide Gel ,Development of treatments and therapeutic interventions ,Infection ,targeted prodrugs ,Biotechnology - 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 (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-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 Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-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.
- Published
- 2013