高分子修饰金属有机框架材料作为纳米药物载体的研究

Nano Drug Delivery System using nano particles from one to hundreds of nanometers as carrier or medium for drug delivery to realize targeted drug delivery. Metal organic frameworks (MOF) are highly morphology and size controllable, and thus received extensive attention. Recently, they have been used in the field of biological medicine. However, most researches are focused on in vitro experiments, the reports on in vivo is very limited. This project intends to use ZIF-8 (Zeolite Imidazolate Framework), which is topologically isomorphic with zeolites, as the drug carrier. The drug loading and surface capping are completed simultaneously in the preparation process of ZIF-8 nanoparticle. The surface of nanoparticle is modified with hyaluronic acid (HA) through host-guest supramolecular interaction of alfa-cyclodextrin and hexyl group (capping agent). The nanoparticles accumulated in tumor tissue by the targeting ligand of HA, which can specific bind with over-expressed CD44 from tumor cells. Then, the included drug is sustained released with the dissociation of ZIF-8 at the low pH environment of tumor tissue. This nanoparticle has several advantages, i.e., high biocompatibility, high loading efficiency, low toxicity, targeted transportation, pH responsibility, and biodegradable. We believe this novel drug delivery nanoparticle promises great potential in practical clinical application.

纳米药物传递系统利用一至数百纳米的粒子作为药物传递的载体或介质，实现药物在体内的定向输送。金属有机框架材料（MOF）因具有尺寸和形貌的高度可调性，受到了广泛关注，并已开始应用于生物医药领域。然而，目前的研究主要集中在体外实验，关于体内的研究还鲜有报道。本项目拟利用类沸石结构ZIF-8作为纳米药物载体，在其制备的过程中，进行药物的负载及表面的封端(正己基封端)。通过正己基与透明质酸（HA）侧链上alfa-环糊精的主客体超分子作用，在ZIF-8表面进行HA的修饰。再利用HA与肿瘤细胞过度表达的CD44的特异性结合的特性，实现药物的靶向输送，并在肿瘤组织低pH环境下，伴随ZIF-8的解离实现药物的缓释。该纳米粒子具有生物相容性好、载药量高、毒性低、靶向输送、pH响应、可降解等一系列优点，具备实际临床应用前景。

药物传递系统具有靶向输送及降低药物毒性等优点，且从最初的脂质体有机纳米胶束逐步过渡到了无机纳米多孔材料。金属有机框架材料（MOF）因其具备较大的比表面积和高度规则的多孔结构，近年来作为新兴的高载药率的纳米药物传递材料而备受瞩目。ZIF-8为沸石咪唑酯骨架类MOF，因其尺寸可控（纳米级）、低毒性、pH响应性等诸多优点，被认为相对理想的药物传递材料。但另一方面，MOF用作药物传递材料也存在着一些缺陷，例如生物相容性差、极易在水溶液环境中聚集、以及靶向能力弱等，这些都严重阻碍着其在药物传递系统中的发展。.本研究着眼于解决上述问题，将生物高分子透明质酸（HA）附着到载有姜黄素（CCM）的ZIF-8表面，从而得到新型纳米复合粒子CCM@ZIF-8/HA。透明质酸为高生物相容性的天然高分子，可通过特异识别恶性肿瘤表面过分表达的CD44而具备靶向能力。通过与未被HA修饰的CCM@ZIF-8进行对比，发现CCM@ZIF-8/HA在水溶液中分散性显著提高。体外药物释放、细胞摄取及细胞存活试验进一步证明CCM@ZIF-8/HA具有良好的生物相容性、降解性、低毒性、及靶向输送和 pH 响应能力。因此，该研究为MOF在药物传递中的实际应用提供了一条全新的思路，使其离实际临床应用又近了一步。