title: Rapidly reversible hydrophobization: an approach to high first-pass drug extraction.
abstract: We have investigated a rapidly reversible hydrophobization of therapeutic agents for improving first-pass uptake in locoregional drug therapy. This approach involves the attachment of a hydrophobic moiety to the drug by highly labile chemical linkages that rapidly hydrolyze upon injection. Hydrophobization drastically enhances cell-membrane association of the prodrug and, consequently, drug uptake, while the rapid lability protects nontargeted tissues from exposure to the highly active agent. Using the membrane-impermeable DNA intercalator propidium iodide, and melphalan, we report results from in vitro cellular internalization and toxicity studies. Additionally, we report in vivo results after a single liver arterial bolus injection, demonstrating both tumor targeting and increased survival in a mouse tumor model.
authors: Mirus Bio Corporation, 505 South Rosa Road, Madison, WI 53719, USA. sean.monahan@mirusbio.com
authors: Sean D
authors: SD
authors: Monahan
authors: Vladimir M
authors: VM
authors: Subbotin
authors: Vladimir G
authors: VG
authors: Budker
authors: Paul M
authors: PM
authors: Slattum
authors: Zane C
authors: ZC
authors: Neal
authors: Hans
authors: H
authors: Herweijer
authors: Jon A
authors: JA
authors: Wolff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008113:Liver Neoplasms / Q000188:drug therapy; D008558:Melphalan / Q000008:administration & dosage; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics*; D011419:Propidium; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D011419:Propidium; D008558:Melphalan