Folate-Targeted PEG as a Potential Carrier for Carboplatin Analogs. Synthesis and in Vitro Studies

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• 作者：Olga Aronov ; Aviva T. Horowitz ; Alberto Gabizon ; and Dan Gibson
• 刊名：Bioconjugate Chemistry
• 出版年：2003
• 出版时间：May 2003
• 年：2003
• 卷：14
• 期：3
• 页码：563 - 574
• 全文大小：319K
• 年卷期：v.14,no.3(May 2003)
• ISSN：1520-4812

文摘

Like most low molecular weight drugs, carboplatin has a short blood circulation time, which reducestumor uptake and intracellular DNA binding. Drugs conjugated to PEG carriers benefit from prolongedblood circulation, but suffer from reduced cell permeability. In this work we attempted to developlong-circulating PEGylated carboplatin analogues with improved cell permeation abilities, byconjugating the platinum moiety to folate-targeted PEG carriers capable of utilizing the folate receptor-mediated endocytosis (FRME). Two bifunctional FA-PEG conjugates, FA-PEG-Pt and FA-PEG-FITC, were prepared, and their cell uptake, DNA binding, and cytotoxicity were studied by fluorescentmicroscopy, FACS, and platinum analysis. Folate-targeted PEG conjugates enter the cells efficientlyby the FRME pathway but form relatively few DNA adducts and have higher IC₅₀ values thancarboplatin and their nontargeted analogues. Nontargeted PEG-Pt conjugates have a lower cellularuptake but produce higher levels of DNA binding and improved cytotoxicity. Carboplatin, used as acontrol, has the fastest cellular uptake, but after 16 h of postincubation a large percentage of thedrug is excreted from the cells. The findings of this study suggest that folate-targeted conjugatessuch as FA-PEG-Pt, may not be an optimal prodrug for the carboplatin family compounds, becausethe conjugates or the active moieties are neutralized or blocked during the FRME process and do notmanage to effectively reach the nuclear DNA.