脑转移瘤是肿瘤化疗领域的难点，解决问题的关键是克服血-肿瘤屏障(BTB)。本项目拟合成生物可降解的聚赖氨酸-聚乳酸-羟基乙酸共聚物作为载体，乳化-溶剂挥发法制备共载硫酸米诺地尔和紫杉醇的纳米粒；通过纳米粒表面氨基和双功能团聚乙二醇连接可跨BTB的脑转移瘤靶向配体透明质酸，构建透明质酸和硫酸米诺地尔协同克服BTB的脑转移瘤靶向纳米粒。本项目预期：①透明质酸介导纳米粒跨BTB主动靶向脑转移瘤；②硫酸米诺地尔打开BTB紧密连接，介导纳米粒通过旁路途径被动蓄积脑转移瘤；③透明质酸介导的脑转移瘤靶向和硫酸米诺地尔的缓慢释放可增效对BTB通透性提高的效应程度和时间；④硫酸米诺地尔介导的脑转移瘤被动蓄积可增效透明质酸介导的转移瘤细胞对纳米粒的摄取；⑤紫杉醇缓慢释放，诱导肿瘤细胞凋亡。本项目拟设计策略可有效提高纳米粒克服BTB和蓄积脑转移瘤的效率；对探索高效低毒的抗脑转移瘤制剂具有重要理论意义和实用价值。

It is a major challenge to achieve highly efficient chemotherapy for brain metastases. Overcoming the blood-tumor barrier (BTB) is considered as the key to solve the challenge. In this application, we propose to synthesize biodegradable poly(lysine)-b-poly(lactic-co-glycolic acid) copolymer as the basic carrier and then construct minoxidil sulfate and paclitaxel co-loaded nanoparticles (NPs) via the emulsion-solvent evaporation process. NPs are further modified by brain metastases-targeting hyaluronic acid which can efficiently cross the BTB using bi-functional a-Malemidyl-u-N-hydroxysuccinimidyl polyethyleneglycol. The final brain metastases-targeted NPs can synergistically overcome the BTB through the combination of hyaluronic acid and minoxidil sulfate. We hypothesize that 1) hyaluronic acid can render NPs the ability to cross BTB and actively target brain metastases; 2) minoxidil sulfate can open the BTB tight junctions and endow NPs with the ability to passively accumulate in brain metastases through paracellular pathway; 3) hyaluronic acid-mediated brain metastases-targeting and minoxidil sulfate’s slow release can improve the extent and duration of minoxidil sulfate-induced open of tight junction; 4) the passive accumulation through paracellular pathway by minoxidil sulfate can improve hyaluronic acid-mediated tumor cellular uptake of NPs; 5) the slowly-released paclitaxel can induce tumor cell apoptosis. The strategy proposed in this application can significantly enhance NPs' ability to overcome the BTB and accumulate in brain metastases. This project is of great theoretical significance and practical value for the exploration of highly-efficient and low toxic drug delivery systems to treat brain metastases.