title: Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo.
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.
authors.affiliation: Departments of Pathology and Microbiology and Immunology, Stanford School of Medicine, Stanford, CA 94305.
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Ingrid T
authors.initials: IT
authors.lastname: Chen
authors.forename: Erica M W
authors.initials: EM
authors.lastname: Lauterwasser
authors.forename: Juan
authors.initials: J
authors.lastname: Valderramos
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Laura E
authors.initials: LE
authors.lastname: Edgington
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000494:pharmacology*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors; D016503:Drug Delivery Systems / Q000379:methods*; D004359:Drug Therapy, Combination; D004591:Electrophoresis, Polyacrylamide Gel; D005296:Ferrous Compounds / Q000008:administration & dosage / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000378:metabolism; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D010778:Photochemotherapy / Q000379:methods*; D010962:Plasmodium berghei / Q000187:drug effects*
chemical_list: C503429:1,2,4-trioxane; D003692:Delayed-Action Preparations; D005296:Ferrous Compounds; D006571:Heterocyclic Compounds; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C059010:dipeptidyl aminopeptidase B
keywords: combination therapy; dipeptidyl peptidase; iron-mediated delivery; targeted prodrugs