Effect of Nanoparticle Composition, Size, Shape, and Stiffness on Penetration Across the Blood-Brain Barrier
Effect of Nanoparticle Composition, Size, Shape, and Stiffness on Penetration Across the Blood-Brain Barrier
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DOI：
10.1021/acsbiomaterials.0c00743
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发表时间：
2020-09-01
影响因子：
5.8
通讯作者：
Mitragotri, Samir
中科院分区：
文献类型：
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作者：
Brown, Tyler D.;Habibi, Nahal;Mitragotri, Samir
以有效、无创的方式将治疗药物递送至大脑仍然是药物递送领域中未满足的主要需求。物理且动态的血脑屏障（BBB）的存在是大脑输送的一个重大障碍。尽管目前存在许多且通常很复杂的突破血脑屏障的策略，但从血液中充分输送有效治疗药物的水平仍然很低。纳米技术已成为一种很有前途的大脑输送工具，但人们对影响输送的重要粒子参数知之甚少。在这里，我们合成并表征了具有不同特性（包括尺寸、形状、刚度和成分）的纳米颗粒库，以研究和确定影响大脑输送的颗粒摄取和运输的关键属性。为了完成这项任务，我们使用人脑微血管内皮细胞 (hCMEC/D3) 开发并验证了体外人 BBB 模型。然后确定每个颗粒组的颗粒吸收和表观渗透系数（P-app）。为了阐明不同参数对颗粒摄取和跨 BBB 运输的作用，还研究了内吞作用的主要机制。我们的结果表明，颗粒成分对 BBB 模型的渗透影响最大。这项工作为粒子参数对 BBB 穿透的作用奠定了基础并提供了新的见解。
The delivery of therapeutics to the brain in an efficient, noninvasive manner continues to be a major unmet need in the field of drug delivery. One significant impediment to brain delivery results from the existence of the physical yet dynamic blood-brain barrier (BBB). Despite the many, often complex strategies that currently exist to breach the BBB, adequate delivery of effective therapeutics from the bloodstream continues to remain quite low. Nanotechnology has emerged as a promising tool for brain delivery, but little is known about the important particle parameters that influence delivery. Here, we synthesized and characterized a library of nanoparticles with distinct properties ranging from size, shape, stiffness, and composition to investigate and identify the key attributes influencing particle uptake and transport for brain delivery. To accomplish this task, an in vitro human BBB model was developed and validated using human cerebral microvascular endothelial cells (hCMEC/D3). Particle uptake and apparent permeability coefficients (P-app) were then determined for each particle group. To elucidate the roles of different parameters on particle uptake and transport across the BBB, the predominant mechanisms of endocytosis were also investigated. Our results show that particle composition yielded the greatest impact on penetration across the BBB model. This work lays the foundation and provides new insights into the role of particle parameters on penetration across the BBB.