Biointerfaces Institute and Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States.
Wyss Institute of Biologically Inspired Engineering, Harvard University, 3 Blackfan Circle, Boston, Massachusetts 02115, United States.
Langmuir. 2022 May 10;38(18):5603-5616. doi: 10.1021/acs.langmuir.2c00200. Epub 2022 Apr 21.
Nanoparticle-based delivery of therapeutics to the brain has had limited clinical impact due to challenges crossing the blood-brain barrier (BBB). Certain cells, such as monocytes, possess the ability to migrate across the BBB, making them attractive candidates for cell-based brain delivery strategies. In this work, we explore nanoparticle design parameters that impact both monocyte association and monocyte-mediated BBB transport. We use electrohydrodynamic jetting to prepare nanoparticles of varying sizes, compositions, and elasticity to address their impact on uptake by THP-1 monocytes and permeation across the BBB. An human BBB model is developed using human cerebral microvascular endothelial cells (hCMEC/D3) for the assessment of migration. We compare monocyte uptake of both polymeric and synthetic protein nanoparticles (SPNPs) of various sizes, as well as their effect on cell migration. SPNPs (human serum albumin/HSA or human transferrin/TF) are shown to promote increased monocyte-mediated transport across the BBB over polymeric nanoparticles. TF SPNPs (200 nm) associate readily, with an average uptake of 138 particles/cell. Nanoparticle loading is shown to influence the migration of THP-1 monocytes. The migration of monocytes loaded with 200 nm TF and 200 nm HSA SPNPs was 2.3-fold and 2.1-fold higher than that of an untreated control. RNA-seq analysis after TF SPNP treatment suggests that the upregulation of several migration genes may be implicated in increased monocyte migration (ex. integrin subunits α M and α L). Integrin β 2 chain combines with either integrin subunit α M chain or integrin subunit α L chain to form macrophage antigen 1 and lymphocyte function-associated antigen 1 integrins. Both products play a pivotal role in the transendothelial migration cascade. Our findings highlight the potential of SPNPs as drug and/or gene delivery platforms for monocyte-mediated BBB transport, especially where conventional polymer nanoparticles are ineffective or otherwise not desirable.
基于纳米颗粒的治疗药物递送到大脑的方法由于血脑屏障（BBB）的挑战而具有有限的临床影响。某些细胞，如单核细胞，具有穿过 BBB 的迁移能力，使其成为基于细胞的脑递药策略的有吸引力的候选物。在这项工作中，我们探索了影响单核细胞关联和单核细胞介导的 BBB 转运的纳米颗粒设计参数。我们使用电动力学喷射来制备具有不同大小、组成和弹性的纳米颗粒，以解决它们对 THP-1 单核细胞摄取和穿过 BBB 的渗透的影响。使用人脑血管内皮细胞（hCMEC/D3）建立了一个人类 BBB 模型，用于评估迁移。我们比较了不同大小的聚合物和合成蛋白纳米颗粒（SPNP）以及它们对细胞迁移的影响。结果表明，SPNP（人血清白蛋白/HSA 或人转铁蛋白/TF）促进了单核细胞介导的穿过 BBB 的转运增加。TF SPNP（200nm）易于结合，平均每个细胞摄取 138 个颗粒。研究表明，纳米颗粒的加载会影响 THP-1 单核细胞的迁移。负载 200nm TF 和 200nm HSA SPNP 的单核细胞的迁移是未经处理的对照组的 2.3 倍和 2.1 倍。TF SPNP 处理后的 RNA-seq 分析表明，几种迁移基因的上调可能与单核细胞迁移增加有关（例如整合素亚基α M 和α L）。整合素β 2 链与整合素亚基α M 链或整合素亚基α L 链结合形成巨噬细胞抗原 1 和淋巴细胞功能相关抗原 1 整合素。这两种产物在跨内皮迁移级联中都起着关键作用。我们的研究结果突出了 SPNP 作为单核细胞介导的 BBB 转运的药物和/或基因递送平台的潜力，特别是在传统聚合物纳米颗粒无效或其他不理想的情况下。
