Jiangsu Key Laboratory of Neuropsychiatric Diseases Research, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, China.
Stake Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China.
Adv Healthc Mater. 2021 May;10(9):e2001997. doi: 10.1002/adhm.202001997. Epub 2021 Mar 18.
Microvessels of the blood-brain barrier (BBB) exclusively express the major facilitator superfamily domain-containing protein 2a (Mfsd2a), which is the key transporter for docosahexaenoic acid uptake into the brain. Mfsd2a suppresses caveolae-mediated transcytosis to regulate BBB transcellular permeability via controlling lipid composition of BBB endothelial cells. It is speculated that Mfsd2a can restrain BBB crossing efficiency and brain accumulation efficiency of brain-targeting drug delivery systems, which penetrate the BBB often through the receptor-mediated transcytosis pathway. Transcytosis across the BBB is a crucial bottleneck for targeted chemotherapy of brain metastases. To overcome this issue, a pair of priming nanoparticles (NPs) and following drug-loaded NPs are designed. Tunicamycin-(TM)-loaded transcytosis-targeting-peptide-(TTP)-decorated NPs (TM@TTP) are used to boost BBB transcytosis via inhibiting Mfsd2a. Doxorubicin (DOX)-loaded TTP and CD44-specific hyaluronic acid (HA)-comodified NPs (DOX@TTP-HA) are designed as following drug-loaded NPs. The brain accumulation efficacy of following DOX@TTP-HA with priming is 4.30-fold higher than that without priming through the enhanced transcytosis pathway rather than the tight junction opening. Effective BBB crossing and brain accumulation, selective tumor uptake, excellent antitumor efficacy, and low hepatotoxicity are achieved by TM@TTP and DOX@TTP-HA, suggesting this tactic as a significant therapeutic strategy against breast cancer brain metastases.
血脑屏障（BBB）的微血管专门表达多溶质家族超家族域蛋白 2a（Mfsd2a），它是将二十二碳六烯酸摄取到大脑的关键转运蛋白。Mfsd2a 抑制 caveolae 介导的胞吞作用，通过控制 BBB 内皮细胞的脂质组成来调节 BBB 的细胞间通透性。据推测，Mfsd2a 可以抑制 BBB 穿越效率和脑靶向药物递送系统的脑积累效率，这些系统通过受体介导的胞吞作用途径穿透 BBB。穿过 BBB 的胞吞作用是脑转移靶向化疗的关键瓶颈。为了克服这个问题，设计了一对启动纳米粒子（NPs）和随后载药的 NPs。使用衣霉素（TM）负载的转胞吞靶向肽（TTP）修饰的 NPs（TM@TTP）通过抑制 Mfsd2a 来促进 BBB 的转胞吞作用。设计了载多柔比星（DOX）的 TTP 和 CD44 特异性透明质酸（HA）共修饰的 NPs（DOX@TTP-HA）作为随后载药的 NPs。通过增强的转胞吞作用途径而不是紧密连接的开放，具有启动作用的随后载 DOX@TTP-HA 的脑积累效率比没有启动作用时高 4.30 倍。TM@TTP 和 DOX@TTP-HA 实现了有效的 BBB 穿越和脑积累、选择性肿瘤摄取、优异的抗肿瘤疗效和低肝毒性，表明该策略是治疗乳腺癌脑转移的重要治疗策略。
