GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

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• 作者：Theodoros Karampelas ; Orestis Argyros ; Nisar Sayyad ; Katerina Spyridaki ; Charalampos Pappas ; Kevin Morgan ; George Kolios ; Robert P Millar ; George Liapakis ; Andreas G. Tzakos ; Demosthenes Fokas ; Constantin Tamvakopoulos
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：April 16, 2014
• 年：2014
• 卷：25
• 期：4
• 页码：813-823
• 全文大小：556K
• 年卷期：v.25,no.4(April 16, 2014)
• ISSN：1520-4812

文摘

Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing Hormone-Receptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake, and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely, GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG showed a significant advantage in tumor growth inhibition when compared to gemcitabine.