肿瘤细胞外膜蛋白MMP-14提高透膜性细胞穿透肽共轭物膜外周选择性富集的研究

Effective delivery of therapeutic molecules to their target is a challenging issue. Innovations in drug delivery systems have improved the efficiency of many therapeutic molecules. Among several different drug delivery routes, application of cell-penetrating peptides (CPPs) in the drug delivery systems has recently garnered tremendous attention. However, improvement of selective enrichment of CPPs at the tumor site is a challenging issue. Theoretically, introduction of the catalytic amplification of tumor associated membrane-bound protease would improve the concentration of CPP-drug conjugates at the tumor site. The restricted localization of the protease would lead to selective enrichment of its proteolytic substrate at tumor site. This project focuses on factors that influence the selective enrichment of CPP-conjugated molecules at the tumor site which triggered by protease using membrane-bound MMP-14 as a research model. Structure features of masked CPP-conjugated molecules; enzyme kinetics of unmasking of CPP-conjugated molecules by MMP-14; the ability of selective enrichment at tumor site of proteolytic unmasked CPP-conjugated molecules; as well as the relationship between penetrating ability of unmasking CPP-conjugated molecule and enzyme kinetics will be discussed. All these data will shed light to research on development of new drug delivery system.

实现抗肿瘤药物的选择性给药，是当前抗肿瘤药物研究急待解决的问题。如能够使细胞穿透肽（CPP）导引的透膜共轭物高选择性地富集于肿瘤细胞膜外周，将有助于发展具备选择性给药的抗肿瘤药物。理论上来说，利用膜外周蛋白酶反应，可以产生酶产物的局部浓度放大效应，从而实现细胞穿透肽共轭物在肿瘤细胞膜外周的选择性富集。这类酶在肿瘤细胞膜外周的选择性表达以及可锚定性，将影响酶降解产物在肿瘤细胞膜外周的选择性富集。本课题拟以肿瘤细胞选择性表达的胞外膜型基质金属蛋白酶MMP-14为实验对象，研究MMP-14可降解的屏蔽型CPP共轭物（潜透膜物）的结构要求，MMP-14去屏蔽CPP透膜共轭物的酶动力学，酶降解产物（解屏蔽CPP共轭物）在肿瘤细胞膜外周选择性富集能力，以及解屏蔽CPP共轭物的细胞穿透能力与酶降解动力学的匹配要求，以达到解屏蔽CPP共轭物对肿瘤细胞的高选择性透膜目标，进而为新型递药系统的发展提供新思路。

实现抗肿瘤药物的选择性给药，是当前抗肿瘤药物研究急待解决的问题。如能够使细胞穿透肽（CPP）导引的透膜共轭物高选择性地富集于肿瘤细胞膜外周，将有助于发展具备选择性给药的抗肿瘤药物。利用膜外周蛋白酶反应，可以产生酶产物的局部浓度放大效应，从而实现细胞穿透肽共轭物在肿瘤细胞膜外周的选择性富集。这类酶在肿瘤细胞膜外周的选择性表达以及可锚定性，将影响酶降解产物在肿瘤细胞膜外周的选择性富集。本项目通过设计构建了一个蛋白酶MMP激活型递药系统，其是一个屏蔽型的透膜性CPP共轭物。项目以所构建的系统为研究模型，分别从酶水平、细胞水平及动物水平系统研究了MMP对透膜性CPP共轭物去屏蔽以及引起的CPP共轭物在肿瘤部位选择性富集的能力。体内和体外的实验结果均显示，在MMP激活下，该系统能较好地实现抗肿瘤药物特别是蛋白质药物的肿瘤靶向给药。此外，系统的生物相容性分析结果表明，该系统具有较好的生物相容性，具备临床应用的巨大潜力。本项目的开展为新型递药系统的开发和研究，提供了新思路及宝贵的模型和实验数据参考。

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