title: Ferrous iron-dependent delivery of therapeutic agents to the malaria parasite.
abstract: BACKGROUND
  The malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free unbound ferrous iron heme as a side product of hemoglobin degradation. The presence of these chemically reactive forms of iron, rare in healthy cells, presents an opportunity for parasite-selective drug delivery. Accordingly, our group is developing technologies for the targeted delivery of therapeutics to the intra-erythrocytic malaria parasite. These so-called 'fragmenting hybrids' employ a 1,2,4-trioxolane ring system as an iron(II)-sensing 'trigger' moiety and a 'traceless' retro-Michael linker to which a variety of partner drug species may be attached. After ferrous iron-promoted activation in the parasite, the partner drug is released via a β-elimination reaction.
  
  
  METHODS
  In this report, we describe three orthogonal experimental approaches that were explored in order to generate in vitro proof-of-concept for ferrous iron-dependent drug delivery from a prototypical fragmenting hybrid.
  
  
  CONCLUSIONS
  Studies of two fragmenting hybrids by orthogonal approaches confirm that a partner drug species can be delivered to live P. falciparum parasites. A key advantage of this approach is the potential to mask a partner drug's intrinsic bioactivity prior to release in the parasite.
authors.affiliation: Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, Byers Hall 503D, 1700 4th Street, San Francisco, CA 94158, USA.
authors.forename: Sumit S
authors.initials: SS
authors.lastname: Mahajan
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D016503:Drug Delivery Systems; D004912:Erythrocytes / Q000469:parasitology; D005296:Ferrous Compounds / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D005296:Ferrous Compounds; D011355:Prodrugs