兼具预防肿瘤复发及淋巴转移功能的肿瘤切除术切缘粘合用纳米药物递释系统研究

This project proposes a new nanoparticle drug delivery system for incisal margin adhesion and prevention of tumor recurrence and metastasis after surgical removal of tumors. Multiple-functional biodegradable nanoparticles are designed to adhere biological tissue, locally release anti-tumor drug in a sustained manner and selectively deliver drug to lymphatic metastasis. After administration to the incisal margin, nanoparticles first play the bioadhesion role by nanobridging of nanoparticles and binding between phenylboronic acid groups on nanoparticles and polysaccharide structures present in tissue components. Then anti-tumor drug will be locally and slowly released, killing residual tumor cells adjacent to the incisal margin. Finally the boron ester formed between phenylboronic acid and tissue components will be hydrolyzed due to the pH decrease caused by gradual hydrolysis of PLGA in nanoparticles, allowing nanoparticles to enter lymphatic systems and subsequently be targeted to metastatic tumor cells with the aid of LyP-1 which has tissue penetrating and lymphatics/lymphatic metastasis-targeting capacities. This study will include parameter optimization of nanoparticle surface properties, composition and size as well as morphology, in vitro characterization, in vivo fate after incisal margin administration, systematic evaluation of bioadhesion, drug sustained-release, in vitro and in vivo lymphatic metastasis targeting, efficiency of preventing tumor recurrence and metastasis as well as preliminary safety evaluation.

针对肿瘤切除术后常复发、多转移的难题，本项目拟设计一种用于肿瘤切除手术切缘给药的纳米药物传释系统，以载抗肿瘤药物的PLGA纳米粒为核心，覆以聚多巴胺外层，表面修饰以苯硼酸基团和靶向多肽（如LyP-1）。该纳米粒兼具切缘粘合、局部缓释及肿瘤淋巴转移靶向三重功能：①首先依靠纳米桥联机制以及纳米粒上的苯硼酸基团与组织成分中多糖结构形成硼酯，粘合切缘，促进愈合；②局部缓释药物，杀死切缘周边残存肿瘤细胞；③随着硼酯因PLGA缓慢水解所致局部pH下降而水解，在淋巴系统对微粒的引流机制和靶向多肽介导的组织穿透性及淋巴转移肿瘤靶向作用下，实现对淋巴肿瘤转移的靶向递药。本研究将在优化纳米粒粒径形态、表面性质、释药过程等参数的基础上，探究其手术切缘施用后的体内命运，对其组织粘合、局部缓释过程、淋巴转移肿瘤靶向等性能、抗肿瘤复发及转移效果及安全性进行较为系统的评价。

本项目以高肿瘤亲和力和淋巴靶向性为目标，围绕适用于局部用药的抗肿瘤新型纳米制剂开展了一系列研究，主要研究内容包括：建立了1种难溶性药物高载药量纳米制剂平台——纳米药物结晶，将其应用在紫杉醇、伊马替尼、拉帕替尼等多种疏水性药物，制剂载药量可达30%以上；探索了2条纳米药物结晶表面功能化技术路径——聚多巴胺包被和磷脂包被法，改善了颗粒的亲水性及稳定性；尝试了3种加强制剂-组织相互作用策略——叶酸化、阳离子化和苯硼酸化。综合优选方案，得到了一种局部用药抗肿瘤效果显著的功能化紫杉醇纳米晶，在体积100 mm3模型瘤（模拟可能的手术残留）单次瘤旁给药，有效制剂（1% FA修饰）组能够完全抑制肿瘤长大，在体积300 mm3模型瘤瘤旁单次给药时，有效制剂（1% FA修饰）2周后瘤体积减小至初始瘤体积的1/7，其平均重量抑瘤率2倍于泰素对照组。上述成果为围手术期局部化疗用药开拓了新思路。项目开展期间，发表标注本基金号的SCI论文5篇（含1区期刊论文1篇，其中4篇为第一标注），获中国发明专利授权1项，申请中国发明专利4项，负责人获北京市科学技术奖二等奖（2018，排名4），培养硕士研究生4名（其中2名已毕业）。