The blood brain barrier (BBB) is the bottleneck of brain-targeted drug development. Due to their physico-chemical properties, nanoparticles (NP) can cross the BBB and accumulate in different areas of the central nervous system (CNS), thus are potential tools to carry drugs and treat brain disorders. In vitro systems and animal models have demonstrated that some NP types promote neurotoxic effects such as neuroinflammation and neurodegeneration in the CNS. Thus, risk assessment of the NP is required, but current 2D cell cultures fail to mimic complex in vivo cellular interactions, while animal models do not necessarily reflect human effects due to physiological and species differences. We evaluated the suitability of in vitro models that mimic the human CNS physiology, studying the effects of metallic gold NP (AuNP) functionalized with sodium citrate (Au-SC), or polyethylene glycol (Au-PEG), and polymeric polylactic acid NP (PLA-NP). Two different 3D neural models were used (i) human dopaminergic neurons differentiated from the LUHMES cell line (3D LUHMES) and (ii) human iPSC-derived brain spheroids (BrainSpheres). We evaluated NP uptake, mitochondrial membrane potential, viability, morphology, secretion of cytokines, chemokines and growth factors, and expression of genes related to ROS regulation after 24 and 72 h exposures. NP were efficiently taken up by spheroids, especially when PEGylated and in presence of glia. AuNP, especially PEGylated AuNP, effected mitochondria and anti-oxidative defense. PLA-NP were slightly cytotoxic to 3D LUHMES with no effects to BrainSpheres. 3D brain models, both monocellular and multicellular are useful in studying NP neurotoxicity and can help identify how specific cell types of CNS are affected by NP.

中文翻译：

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3D人脑球形模型区分金和聚乳酸纳米颗粒的毒性作用以评估脑药物输送的生物相容性的适用性

血脑屏障（BBB）是脑靶向药物开发的瓶颈。由于其物理化学性质，纳米颗粒（NP）可以穿过BBB并积聚在中枢神经系统（CNS）的不同区域，因此是携带药物和治疗脑部疾病的潜在工具。体外系统和动物模型表明，某些NP类型可促进神经毒性作用，例如中枢神经系统的神经炎症和神经退行性变。因此，需要对NP进行风险评估，但是当前的2D细胞培养无法模仿复杂的体内细胞相互作用，而动物模型由于生理和物种差异而不一定能反映人类的影响。我们评估了模仿人类中枢神经系统生理学的体外模型的适用性，研究用柠檬酸钠（Au-SC）或聚乙二醇（Au-PEG）和聚合聚乳酸NP（PLA-NP）功能化的金属金NP（AuNP）的影响。使用了两种不同的3D神经模型（i）从LUHMES细胞系（3D LUHMES）分化出来的人多巴胺能神经元，以及（ii）从人iPSC衍生的脑球体（BrainSpheres）。我们评估了NP摄取，线粒体膜电位，生存力，形态，细胞因子，趋化因子和生长因子的分泌，以及暴露24和72小时后与ROS调节相关的基因的表达。NP有效地被球体吸收，尤其是在聚乙二醇化且存在神经胶质的情况下。AuNP，特别是PEG化的AuNP，可影响线粒体和抗氧化防御。PLA-NP对3D LUHMES略有细胞毒性，对BrainSpheres无影响。3D脑模型