Scopine as a Novel Brain-Targeting Moiety Enhances the Brain Uptake of Chlorambucil

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• 作者：Xinyi Wang ; Jianbo Li ; Chaoqun Xu ; Yanping Li ; Tao Gong ; Xun Sun ; Yao Fu ; Qin He ; Zhirong Zhang
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：November 19, 2014
• 年：2014
• 卷：25
• 期：11
• 页码：2046-2054
• 全文大小：416K
• ISSN：1520-4812

文摘

The blood brain barrier (BBB) represents the biggest challenge for therapeutic drugs to enter the brain. In our study, we selected chlorambucil (CHL), an alkylating agent, as the model therapeutic agent, and used scopine as a novel brain-targeting moiety. Here, we synthesized Chlorambucil-Scopine (CHLS) prodrug and evaluated its brain-targeting efficacy. The tissue distribution study after i.v. injection revealed that the AUC_0-t and C_max of CHLS in the brain were 14.25- and 12.20-fold of CHL, respectively. Specifically, CHLS accumulated in bEnd.3 and C6 cells in an energy-dependent manner. In C6 cells, superior anti-glioma activity with a significantly decreased IC₅₀ of 65.42 nM/mL was observed for CHLS compared to CHL (IC₅₀ > 400 nM/mL). The safety evaluation, including acute toxicity, pathology, and hematology study, showed minimal toxicity toward nontargeting tissues, and also reached a lower systemic toxicity at 5 mg/kg (i.v.). Our results suggested that scopine is a potential brain-targeting moiety for enhancing the brain uptake efficiency of CHL.