Rapidly reversible hydrophobization: an approach to high first-pass drug extraction.
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.
Monahan
Sean D
SD
Mirus Bio Corporation, 505 South Rosa Road, Madison, WI 53719, USA. sean.monahan@mirusbio.com
Subbotin
Vladimir M
VM
Budker
Vladimir G
VG
Slattum
Paul M
PM
Neal
Zane C
ZC
Herweijer
Hans
H
Wolff
Jon A
JA
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
D000970:Antineoplastic Agents; D011355:Prodrugs; D011419:Propidium; D008558:Melphalan