a Drug Theoretics and Cheminformatics Laboratory, Department of Pharmaceutical Technology , Jadavpur University , Kolkata , India.
b Interdisciplinary Nanotoxicity Center, Department of Chemistry, Physics and Atmospheric Sciences , Jackson State University , Jackson , MS , USA.
Nanotoxicology. 2019 Feb;13(1):14-34. doi: 10.1080/17435390.2018.1529836. Epub 2018 Oct 25.
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.
为了应对纳米材料暴露的威胁，必须了解纳米材料在不同细胞系统中是如何被识别、内化和分布的。通过对纳米颗粒（NP）表面的修饰来实现纳米材料对特定细胞类型的靶向，通常会导致所需的细胞摄取。正常细胞摄取的增强可能会导致 NP 与亚细胞细胞器的更高相互作用，从而引发各种信号通路。NP 的成功依赖于合成具有必要性质的功能化 NP 的前景，以及它们增强的特定靶向细胞摄取的潜力。在本研究中，我们模拟了 109 种金属氧化物纳米颗粒（MNPs）表面修饰剂在三种不同细胞系中的细胞摄取：HUVEC（人内皮细胞）、U937（人巨噬细胞）和 PaCa2（癌细胞系）。除了定量构效关系（QSAR）模型外，我们还首次开发并进行了定量细胞间摄取特异性（QICLUS）建模，以确定负责两个特定细胞系之间细胞摄取差异的物理化学性质以及主要结构片段。本工作提供了对 MNPs 细胞摄取以及控制纳米细胞相互作用的潜在结构参数的全面了解。还从 QSAR 和 QICLUS 模型分析了这一现象，得出表面修饰剂的功能团，如胺、酸酐、卤素原子、硝基、酸，对 MNPs 进入细胞系的摄取具有主导作用。因此，所开发的模型可用于设计具有所需特性的 MNPs 的新型表面修饰剂，以实现适当的细胞-NP 相互作用，以及在虚拟筛选方面。此外，MNP-细胞相互作用可以为针对特定细胞的药物输送治疗的毒性提供一些思路，因为需要更高的细胞摄取来治疗疾病，而对相邻细胞的摄取较低，以降低毒性。
