To address the nanomaterial exposure threat, it is imperative to understand how nanomaterials are recognized, internalized, and distributed within diverse cell systems. Targeting of nanomaterials to a specific cell type is generally attained through the modification of the nanoparticle (NP) surface leading to required cellular uptake. The enhanced cellular uptake to normal cells can direct to the higher interaction of NPs with subcellular organelles resulting the provocation of various signaling pathways. The successes of NPs rely on the prospect for the synthesis of functionalized NPs with necessary properties and their enhanced potential for cellular uptake for specific targeting. In the present study, we have modeled the cellular uptake of 109 surface modifiers of metal oxide nanoparticles (MNPs) for three different cell lines: HUVEC (Human endothelial cells), U937 (human macrophage cells), and PaCa2 (cancer cell lines). Along with the quantitative structure-activity relationship (QSAR) models, for the very first time we have developed and performed quantitative inter cell line uptake specificity (QICLUS) modeling to identify the physicochemical properties, as well as majorly structural fragments responsible for cellular uptake differences between two specific cell lines. The present work provides a comprehensive understanding of the cellular uptake of MNPs and the underlying structural parameters controlling the nano-cellular interactions. This phenomenon has also been analyzed from the QSAR and QICLUS models that concluded the functional groups of surface modifiers like amine, anhydride, halogen atoms, nitro group, acids have the dominating roles for the uptake of MNPs into the cell lines. Thus, the developed models may be used for designing of novel surface modifiers of MNPs of desired characteristics for proper cell-NPs interactions, as well as in the context of virtual screening aspect. Moreover, the MNP-cell interactions can give some idea about the toxicity for target-specific drug delivery treatment as higher cellular uptake is required for specific cells to treat the disease and lower uptake to the neighboring cells for lower toxicity.

中文翻译：

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对多种人类细胞对工程纳米金属氧化物摄取的理解：定量细胞间摄取特异性（QICLUS）模型。

为了解决纳米材料暴露的威胁，必须了解如何在各种细胞系统中识别，内化和分布纳米材料。通常通过修饰纳米颗粒（NP）表面导致所需的细胞摄取来实现将纳米材料靶向特定细胞类型。增强的细胞对正常细胞的摄取可以指导NP与亚细胞器的更高相互作用，从而激发各种信号通路。NP的成功依赖于合成具有必要特性的功能化NP的前景及其增强的针对特定靶标的细胞摄取潜力。在本研究中，我们为三种不同的细胞系模拟了109种金属氧化物纳米颗粒（MNP）表面改性剂对细胞的摄取：HUVEC（人类内皮细胞），U937（人类巨噬细胞）和PaCa2（癌细胞系）。连同定量结构-活性关系（QSAR）模型一起，我们首次开发并进行了定量细胞间摄取特异性（QICLUS）模型，以鉴定理化特性以及负责细胞摄取差异的主要结构片段在两个特定的细胞系之间。本工作提供了对MNPs的细胞摄取和控制纳米细胞相互作用的潜在结构参数的全面理解。还从QSAR和QICLUS模型中分析了这种现象，得出了表面改性剂的官能团，例如胺，酸酐，卤素原子，硝基，酸对于MNP进入细胞系的吸收起主要作用。因此，开发的模型可用于设计具有适当特性的MNP的新型表面修饰剂，以实现适当的细胞-NP相互作用，以及用于虚拟筛选方面。而且，MNP-细胞相互作用可以为靶标特异性药物递送治疗的毒性提供一些思路，因为特定细胞需要更高的细胞摄取来治疗疾病，而对相邻细胞的摄取则需要更低的毒性。