Rapidly Reversible Hydrophobization: An Approach to High First-Pass Drug Extraction
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- 作者：Sean D. Monahan ; Vladimir M. Subbotin ; Vladimir G. Budker ; Paul M. Slattum ; Zane C. Neal ; Hans Herweijer ; Jon A. Wolff
- 关键词：CHEMBIOL
- 刊名：Chemistry & Biology
- 出版年：2007
- 出版时间：21 September 2007
- 年：2007
- 卷：14
- 期：9
- 页码：1065-1077
- 全文大小：1670 K
文摘
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.