Influence of nanoparticle size on blood-brain barrier penetration and the accumulation of anti-seizure medicines in the brain
Influence of nanoparticle size on blood-brain barrier penetration and the accumulation of anti-seizure medicines in the brain
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纳米颗粒尺寸对血脑屏障穿透和抗癫痫药物在大脑中积聚的影响
DOI：
10.1039/d1tb02015c
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发表时间：
2021-11-26
影响因子：
7
通讯作者：
Huang, Yubin
中科院分区：
文献类型：
--
作者：
Meng, Qian;Meng, Hongmei;Huang, Yubin
抗癫痫药物是治疗癫痫的常见但重要的方法。然而，其中一些与严重的副作用有关，包括肝毒性和过敏。此外，血脑屏障（BBB）是大脑药物输送难以克服的障碍。幸运的是，引入纳米颗粒进行药物输送是克服这些障碍的可行方法。将药物封装到纳米颗粒中并将其输送到特定位点在提高药物输送效率和降低全身毒性方面显示出巨大的潜力。一些体内研究已经研究了纳米颗粒尺寸对小鼠体内生物分布的影响，但很少研究其对穿过血脑屏障时有效药物输送的影响。因此，我们设计了甲氧基聚丙交酯乙交酯-b-聚乙二醇甲醚（mPEG-PLGA）纳米颗粒递送系统，并探讨了不同尺寸纳米颗粒的细胞摄取效率及其在携带卡马西平（CBZ）时穿透血脑屏障的能力。负载CBZ的纳米粒子在高浓度下可以显着降低CBZ对L929细胞的细胞毒性。人脑微血管内皮细胞/D3的内吞实验结果表明，负载DiR的mPEG(5K)-PLGA(10K)纳米粒子具有最高的细胞摄取效率。 30 min时胞吞效率达到90%，远远超过其他组。此外，从随后获取小鼠离体器官的荧光图像的实验中也获得了类似的结果。总而言之，我们的研究表明，使用纳米载体向大脑输送药物是尺寸依赖性的。粒径最小的纳米粒子可以更有效地内化，并且容易穿透血脑屏障，并在大脑中积聚。
Anti-seizure medicines constitute a common yet important modality to treat epilepsy. However, some of them are associated with serious side effects including hepatotoxicity and hypersensitivity. Furthermore, the blood-brain barrier (BBB) is an insurmountable obstacle for brain drug delivery. Fortunately, the introduction of the nanoparticles for drug delivery is a feasible approach to overcome these obstacles. Encapsulating drugs into nanoparticles and delivering them to specific sites shows great potential for improving the efficiency of drug delivery and reducing systemic toxicity. Several in vivo studies have investigated the effect of nanoparticle size on biodistribution in mice, but very few have investigated its effects on efficient drug delivery while crossing the BBB. Therefore, we designed a methoxy poly(lactide-co-glycolide)-b-poly(ethylene glycol) methyl ether (mPEG-PLGA) nanoparticle delivery system and explored the cell uptake efficiency of nanoparticles with different sizes and their ability to penetrate the BBB while carrying carbamazepine (CBZ). CBZ-loaded nanoparticles could significantly reduce the cytotoxicity of CBZ to L929 cells at high concentrations. Results from the endocytosis experiment involving human cerebral microvessel endothelial cell/D3 showed that the DiR-loaded mPEG(5K)-PLGA(10K) nanoparticles possessed the highest cell uptake efficiency. The endocytosis efficiency was 90% at 30 min, which far exceeded that of the other groups. Moreover, similar results were obtained from subsequent experiments where fluorescence images of the isolated organs of the mice were acquired. To summarize, our study demonstrated that drug delivery to the brain using nanocarriers is size dependent. Nanoparticles with the smallest particle size can be internalized more effectively, and easily penetrate the BBB, and accumulate in the brain.