多胺介导的抗纤维化药物肺靶向传递系统研究

Pulmonary fibrosis is a chronic lung disease, which has been well recognized as an irrevisible process. The mortality rate is high and there is no effective way to cure this disease yet. Anti-fibrosis drug had great potential for treating pulmonary fibrosis in early stage. Polyamine transport system (PTS) is a overexpression membrane protein on the alveolar epithelial cell, which mediate polyamine (PA) selectively into cells. In the research, a novel lung targeting nanoparticle, namely SPD-AKF-PLGA/NPs was designed and constructed. The new drug delivery system utilized the affinity of SPD and polyamine transport system (PTS), by which the drug was able to specifically accumulate in lung. This was a new method and technique of increasing the efficiency of anti-fibrosis drug and reducing side effects. An important attempt on targeting theory was made in the research, which will be proven useful in looking for a feasible way for the treatment of pulmonary fibrosis. It also contributed to the complement of lung targeting theory. The innovative method could be applied to the design of new formulas of drug with anti-pulmonary fibrosis efficacy.

肺纤维化是一种缺乏有效治疗手段的严重疾病。干预多肽介质/细胞因子释放和胶原等细胞外基质（EMC）的合成与沉积是最可能阻断纤维化进程的手段，基于这一机制的抗纤维化药物在临床有效。但该类药物的肺浓度低而不利于疗效发挥，提高肺组织药物浓度是增强其疗效的有效手段。肺上皮细胞高表达的多胺转运系统（PTS）是一种可选择性逆浓度差摄取多胺（PA）入胞的膜蛋白。利用PA（如亚精胺SPD）与PTS的亲和力，可介导载抗纤维化药物纳米粒靶向富集于肺组织。本课题以抗纤维化药物氟非尼酮（AKF）为模型，以PLGA-PEG包载AKF，并由SPD介导该纳米粒经PTS进入肺泡上皮细胞，提高抗肺纤维化作用。课题通过对该给药系统的构建规律、表征、体内外靶向能力及抗纤维化作用研究，探讨SPD修饰对AKF在抗肺纤维化作用的影响因素。研究结果为抗纤维化药物的疗效发挥提供新的解决方案，也为PA介导药物PTS靶向传递系统提供实践依据。

本研究构建了一类基于多胺转运系统的肺靶向微粒递药系统，以靶向配体精胺或亚精胺进行化学修饰增强其细胞摄取，利用共聚物材料两亲性特征自组装成纳米粒或纳米胶束。表面多胺分子修饰可促进纳米粒的细胞主动摄取，将抗肺纤维化药物（氟非尼酮）、抗肿瘤药物（多柔比星/紫杉醇）包载于疏水核心，可在肿瘤微环境中迅速释放起效。通过对载体材料合成、纳米粒制备、理化性质研究、体外细胞摄取和体内示踪、组织分布和药效学评价，系统探索了多胺分子介导的多胺转运系统肺主动靶向纳米粒的基本规律。这些研究不仅为肺纤维化的早期干预和治疗提供了参考，也为肺靶向制剂研究提供了新的思路。该课题相关研究成果已发表在《International Journal of Nanomedicine》、《RSC Advances》、《Frontiers in Pharmacology》等SCI收录杂志，共发表SCI论文4篇。