Joseph Andrea, Liao Rick, Zhang Mengying, Helmbrecht Hawley, McKenna Michael, Filteau Jeremy R, Nance Elizabeth
Department of Chemical Engineering University of Washington Seattle Washington USA.
Molecular Engineering and Sciences Institute University of Washington Seattle Washington USA.
Bioeng Transl Med. 2020 Aug 15;5(3):e10175. doi: 10.1002/btm2.10175. eCollection 2020 Sep.
Cerebral ischemia is a major cause of death in both neonates and adults, and currently has no cure. Nanotechnology represents one promising area of therapeutic development for cerebral ischemia due to the ability of nanoparticles to overcome biological barriers in the brain. ex vivo injury models have emerged as a high-throughput alternative that can recapitulate disease processes and enable nanoscale probing of the brain microenvironment. In this study, we used oxygen-glucose deprivation (OGD) to model ischemic injury and studied nanoparticle interaction with microglia, resident immune cells in the brain that are of increasing interest for therapeutic delivery. By measuring cell death and glutathione production, we evaluated the effect of OGD exposure time and treatment with azithromycin (AZ) on slice health. We found a robust injury response with 0.5 hr of OGD exposure and effective treatment after immediate application of AZ. We observed an OGD-induced shift in microglial morphology toward increased heterogeneity and circularity, and a decrease in microglial number, which was reversed after treatment. OGD enhanced diffusion of polystyrene-poly(ethylene glycol) (PS-PEG) nanoparticles, improving transport and ability to reach target cells. While microglial uptake of dendrimers or quantum dots (QDs) was not enhanced after injury, internalization of PS-PEG was significantly increased. For PS-PEG, AZ treatment restored microglial uptake to normal control levels. Our results suggest that different nanoparticle platforms should be carefully screened before application and upon doing so; disease-mediated changes in the brain microenvironment can be leveraged by nanoscale drug delivery devices for enhanced cell interaction.
脑缺血是新生儿和成年人死亡的主要原因，目前尚无治愈方法。由于纳米颗粒能够克服血脑屏障，纳米技术是脑缺血治疗发展中一个有前景的领域。体外损伤模型已成为一种高通量替代方法，它可以重现疾病过程，并能够对脑微环境进行纳米级探测。在本研究中，我们使用氧糖剥夺（OGD）来模拟缺血性损伤，并研究纳米颗粒与小胶质细胞的相互作用，小胶质细胞是大脑中的常驻免疫细胞，在治疗递送方面越来越受到关注。通过测量细胞死亡和谷胱甘肽的产生，我们评估了OGD暴露时间和阿奇霉素（AZ）处理对脑片健康的影响。我们发现，暴露于0.5小时的OGD会引发强烈的损伤反应，立即应用AZ后有有效的治疗效果。我们观察到OGD诱导小胶质细胞形态向异质性和圆形度增加转变，小胶质细胞数量减少，治疗后这种情况得到逆转。OGD增强了聚苯乙烯-聚（乙二醇）（PS-PEG）纳米颗粒的扩散，改善了其转运和到达靶细胞的能力。虽然损伤后小胶质细胞对树枝状大分子或量子点（QD）的摄取没有增强，但PS-PEG的内化显著增加。对于PS-PEG，AZ处理将小胶质细胞的摄取恢复到正常对照水平。我们的结果表明，在应用不同的纳米颗粒平台之前应仔细筛选，这样做的话，纳米级药物递送装置可以利用脑微环境中疾病介导的变化来增强细胞相互作用。
