基于透明质酸的多重靶向纳米顺铂前药智能递送系统的构建与功效

No chemotherapeutic drug can be effective until it is delivered to its target site. Nano-sized drug carriers bring the hope of tumor-targeted drug delivery. But nanocarriers still have to overcome a series of obstacles to enter tumor cells from the injection site to the site of action, such as clearance by renal filtration and the reticuloendothelial system, extravasation through the enlarged endothelial gaps in tumors, tumor dense extracellular matrix, cell membrane barrier and drug-resistance. Enhanced enrichment of nanoscale delivery systems in the tumor site and drug release within the cell under the intracellular stimuli-responsive microenvironment can effectively reduce the serious side effects and improve the treatment effect and drug bioavailability. Using hydrophobic cisplatin (Pt) as the anti-cancer drug model, this project intends to combine the properties of magnetic targeting induced enrichment of nanocarriers in tumor, FA/RGD cooperative target tumor cell through the specific binding with different surface expression receptors, disulfide bond sensitive to the reductive intracellular microenvironment and enzyme degradation of hyaluronic acid (HA) to prepare the intelligent organic-inorganic hybrid nano prodrug vehicle [FA/RGD-HA-g-SS-(PEG/Pt)@Fe3O4 NPs] with the properties of tumor tissue/cells target and intracellular controlled drug release. The synergy relations and the law of "magnetic target-FA/RGD cooperative target - intracellular responsive release" the tumor tissues will be revealed at the cell, tumor tissue and animal model. Reasonable combination plans to prepare the security nano prodrug carriers with tumor tissue and cell targeting properties will be established to obtain intelligent multifunctional nano prodrug vehicles with clinical application prospect.

由于传统化疗药物不能在到达靶点之前发挥功效，纳米载体为药物的靶向递送提供了可行性方法。纳米载体从注射点到达靶点过程中仍须克服血液循环系统、肿瘤组织和肿瘤细胞所带来的阻碍。促进纳米递送系统在肿瘤部位的富集和增强药物在细胞内的刺激响应释放，可有效降低抗癌药物化疗产生的严重毒副作用，改善治疗效果，提高药物生物利用度。本项目以疏水顺铂为抗癌药物模型，拟结合磁靶向诱导递送系统在肿瘤组织的富集、FA/RGD协同靶向肿瘤细胞表面表达的特异性不同受体、以及二硫键在细胞内还原敏感断裂性能和透明质酸（HA）的酶解等特性，形成肿瘤组织/细胞靶向以及胞内控释的有机/无机复合纳米前药智能载体。在细胞、肿瘤组织和动物模型水平上，揭示“磁靶向-FA/RGD协同靶向-胞内响应性释放”在肿瘤组织内的作用关系和规律，建立纳米前药与肿瘤组织靶向和细胞靶向的组合方案，获得具有临床应用前景的肿瘤系统给药的多功能纳米前药智能载体。

肿瘤微环境、正常器官和组织间的差异使肿瘤微环境响应性高分子纳米药物载体受到广泛关注，利用其特性，可以实现抗癌药物的靶向给药和可控释放，显著提高治疗效果。基于肿瘤微环境特点，在研究过程中，利用RAFT聚合及相关合成技术，制备了pH响应抗癌纳米前药，pH和氧化还原双响应型纳米前药，pH和氧化还原双敏感半乳糖靶向纳米粒，以及pH和氧化还原双敏感半乳糖/叶酸双靶向可逆交联纳米粒。研究了聚合物结构，纳米自组装行为，药物负载、体外药物释放等性能，并在细胞水平上，评价了各种载体的抗肿瘤细胞增殖抑制活性。结果发现，利用多功能协同策略可以提高纳米药物载体进入细胞的能力和胞内快速释放的效果，提高了药物利用度，为多功能载体设计提供了理论借鉴。