纤维激活蛋白-α(FAP-α)响应的PEG化修饰提高透明质酸纳米粒递药效率机制的研究

Despite hyaluronic acid were highly appreciated in the field of nanocarrier design because of CD44 receptor targeting, hyaluronic acid-based nanoparticles face a complex series of barriers in biodistribution, intratumoral delivery and cellular uptake processes that severely limit site-specific bioavailability. In our prophase research, we found that pegylation changed the biodistribution profiles of hyaluronic acid based nano carrier and enhanced it accumulation in tumor tissue. While intratumoral delivery and cellular uptake played an important role in site-specific bioavailability of nanoparticles, thus we intended to develop the fibroblast activation protein sensitive peg tailored hyaluronic acid–based micelle, find key factors involved in site-specific bioavailability of hyaluronic acid based nanoparticles and establish the relationships between nanoparticles components and performances in vivo. We specially focused on the relationships between “blood long circulation”, “ tumor targeting”of nanoparticles and pegylation (peg length, peg density and sensitivity), hyaluronic acid(molecular weight), furthermore we planned to investigate basing on CD44 receptor co-targeting CAF and tumor cells, nanoparticle modulation of the tumor microenvironment, additionally, we intended to establish the qualitative and quantitative relationships between cellular uptake and pegylation (peg length, peg density and sensitivity), hyaluronic acid(molecular weight, degree of substitution). The results of this project will provide a solid scientific basis for selecting hyaluronic acid based nano carrier with desirable performance in vivo.

CD44受体靶向性使得透明质酸在纳米载体设计中受到青睐，然而组织分布、瘤内转运、细胞摄取过程中的多重屏障，影响了其递药效率。在前期工作中，申请人发现PEG修饰可以改变透明质酸纳米粒组织分布行为，提高其肿瘤组织蓄积量。然而近期研究发现瘤内转运和细胞摄取同样影响着纳米粒递药效率，因此本课题拟构建纤维激活蛋白-α(FAP-α)响应型PEG修饰的透明质酸聚合物胶束，评价透明质酸纳米粒体内行为的关键环节和制剂影响因素，总结影响递药效率的要素，解析透明质酸纳米粒组成与体内行为的相关性。着重考察纳米粒的“长循环特性”、“体内靶向性”与PEG修饰（长度、密度和响应性）和透明质酸分子量之间的关系；探讨CD44受体作为CAF和肿瘤细胞共靶点，重塑肿瘤微环境的可行性；量化透明质酸分子量、取代度、PEG修饰与“细胞摄取”的关系。本项目成果将为体循环长、靶向性好、药效佳的“透明质酸化”纳米载体的筛选提供科学依据。

针对透明质酸等天然配体体内靶向性差，肝脏吞噬现象严重等问题，本课题以透明质酸-姜黄素接枝物为基础，考察了影响透明质酸纳米载体递药效率的关键因素。具体研究内容包括：课题设计并合成了透明质酸-姜黄素接枝物（HA-CUR），该接枝物生物相容性良好，具有良好的自组装和肿瘤细胞靶向等功能。为了考察影响HA的递药效率的因素，本研究合成了隐形功能（PEG长链）、成纤维激活蛋白α响应功能的高分子材料（PFHC）介导阿霉素（DOX）的高效递送，并对其进行了系统的表征和功能性验证。在体外表征基础上，课题组进一步研究其入胞转运行为，结果发现，PEG修饰可以明显降低DOX/PFHC在肝脏的聚集情况，有效阻断了透明质酸与分布在不同细胞表面的受体之间的识别，体内循环时间延长。整体动物研究表明：DOX/PFHC显著增强在肿瘤组织中的富集，降低了肿瘤组织中的纤维量。综上，本项目从体内分布和改变肿瘤微环境两个层面出发，克服了透明质酸纳米粒递药系统中的多重屏障，实现了透明质酸载体的高效递药，对内源性配体递药效率的改善提供了新思路。

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