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.

中文翻译：

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纳米颗粒组成，大小，形状和刚度对跨血脑屏障渗透的影响

以有效的，非侵入性的方式将治疗剂递送至大脑仍然是药物递送领域中的主要未满足需求。物理但动态的血脑屏障（BBB）的存在是导致大脑输送的一大障碍。尽管目前存在许多突破BBB的策略，但通常都很复杂，但是从血液中有效治疗的有效输送仍然很低。纳米技术已经成为一种有前途的大脑输送工具，但是对于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性质（范围从大小，形状，刚度和成分到范围）的纳米粒子库，以研究和确定影响粒子摄取和转运至脑部的关键属性。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率和表观渗透系数（P _app）。为了阐明不同参数对颗粒吸收和穿越血脑屏障的作用，还研究了内吞作用的主要机制。我们的结果表明，颗粒成分对整个BBB模型的渗透率影响最大。这项工作奠定了基础，并为粒子参数对BBB渗透的作用提供了新的见解。