摘要/Abstract

喜树碱在弱碱性生理介质中主要以无生物活性的开环羧酸盐形式存在，肿瘤微环境具有弱酸性，而超分子有机框架可以富集和输送负离子药物至肿瘤微环境和肿瘤细胞内.为评估通过超分子有机框架富集和输送喜树碱类开环羧酸盐到肿瘤微环境及肿瘤细胞内，利用肿瘤弱酸性微环境驱动其内酯化，从而发展羧酸盐为前药的可能性，利用透析实验研究了两个超分子有机框架对喜树碱，SN-38和10-羟基喜树碱开环羧酸盐负离子的吸收和保留效应，利用吸收光谱研究了三个羧酸盐在弱酸性生理盐水介质中内酯化形成活性喜树碱分子的动力学.结果表明超分子有机框架对三个羧酸盐均具有显著的保留效应，在pH为6.5的弱酸性介质中，羧酸盐转化为相应内酯的（表观）半衰期分别为120，22和31 h，远短于临床应用的喜树碱类药物伊立替康和拓扑替康重复用药间隔时间（14和21 d），为后续研究提供了依据.
关键词: 喜树碱, SN-38, 10-羟基喜树碱, 开环羧酸盐, 超分子有机框架, 负载, 内酯化动力学
Camptothecin derivatives exist mainly as inactive open ring carboxylates in physiological media. Tumor microenvironment is generally weakly acidic, whereas supramolecular organic frameworks can adsorb and deliver anionic antitumor drugs into tumor cells. In principle, supramolecular organic frameworks (SOFs) can adsorb and deliver camptothecin open ring carboxylates to tumor microenvironment and the delivered carboxylates can undergo lactonization to afford active molecules due to the weak acid character of the tumor microenvironment, which may lead to efficient utilization of the carboxylates as predrugs. To explore this potential, dialysis experiments for the open ring carboxylates of camptothecin, SN-38 and 10-hydroxycamptothecin in the presence of two SOFs were conducted, which revealed important adsorption and retaining capacity of the SOFs for the carboxylates. Absorption spectroscopy was also utilized to evaluate the lactonization kinetics of the three carboxylates in weakly acidic saline solution. The result reveals that at pH=6.5, the half lives of the conversion are 120, 22 and 31 h, respectively, which are considerably shorter than the time gap for repeated administrations of clinically used irinotican (14 d) or topotecan (21 d), which provides the experimental basis for further study.
Key words: camptothecin, SN-38, 10-hydroxycamptothecin, open ring carboxylate, supramolecular organic frameworks, loading, lactonization kinetics


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