缺乏关于生物细胞摄取NP的知识对药物递送造成重大问题。出于这个原因,设计一个合适的模型是建模者面临的主要挑战。为了解决这个问题,近几十年来,已经进行了可以描述载药纳米颗粒细胞摄取机制的分子建模研究。在这种情况下,我们开发了三种不同的两亲性模型载药纳米粒子(MTX-SS-γ-PGA),通过分子动力学研究预测了其细胞摄取机制。许多因素影响纳米粒子的摄取,包括纳米粒子的物理化学性质,蛋白质-颗粒相互作用,以及随后的聚集,扩散,和沉降。因此,科学界需要了解如何控制这些因素以及纳米粒子的NP摄取。基于这些考虑,在这项研究中,我们首次研究了在不同pH值下接枝亲水性γ-聚谷氨酸(MTX-SS-γ-PGA)的抗癌药物甲氨蝶呤(MTX)的选定理化性质对其细胞摄取的影响。为了回答这个问题,我们开发了三种理论模型,描述了在三种不同pH值下的载药纳米颗粒(MTX-SS-γ-PGA),例如(1)pH7.0(所谓的中性pH模型),(2)pH6.4(所谓的肿瘤pH模型),和(3)pH2.0(所谓的胃pH模型)。例外地,电子密度曲线表明,由于电荷波动,肿瘤模型与脂质双层的头部基团的相互作用比其他模型更强。氢键和RDF分析提供了有关NP与水的溶液及其与脂质双层的相互作用的信息。最后,偶极矩和HOMO-LUMO分析显示了水相中溶液的自由能和化学反应性,这对于确定NP的细胞摄取特别有用。拟议的研究提供了对分子动力学(MD)的基本见解,这将使研究人员能够确定pH值的影响,结构,charge,和NPs对抗癌药物细胞摄取的影响。我们相信,我们目前的研究将有助于开发一种更有效,更耗时的模型将药物输送到癌细胞的新模型。
The lack of knowledge about the uptake of NPs by biological cells poses a significant problem for drug delivery. For this reason, designing an appropriate model is the main challenge for modelers. To address this problem, molecular modeling studies that can describe the mechanism of cellular uptake of drug-loaded nanoparticles have been conducted in recent decades. In this context, we developed three different models for the amphipathic nature of drug-loaded nanoparticles (MTX-SS-γ-PGA), whose cellular uptake mechanism was predicted by molecular dynamics studies. Many factors affect nanoparticle uptake, including nanoparticle physicochemical properties, protein-particle interactions, and subsequent agglomeration, diffusion, and sedimentation. Therefore, the scientific community needs to understand how these factors can be controlled and the NP uptake of nanoparticles. Based on these considerations, in this
study, we investigated for the first time the effects of the selected physicochemical properties of the anticancer drug methotrexate (MTX) grafted with hydrophilic-γ-polyglutamic acid (MTX-SS-γ-PGA) on its cellular uptake at different pH values. To answer this question, we developed three theoretical models describing drug-loaded nanoparticles (MTX-SS-γ-PGA) at three different pH values, such as (1) pH 7.0 (the so-called neutral pH model), (2) pH 6.4 (the so-called tumor pH model), and (3) pH 2.0 (the so-called stomach pH model). Exceptionally, the electron density profile shows that the tumor model interacts more strongly with the head groups of the lipid bilayer than the other models due to charge fluctuations. Hydrogen bonding and RDF analyses provide information about the solution of the NPs with water and their interaction with the lipid bilayer. Finally, dipole moment and HOMO-LUMO analysis showed the free energy of the solution in the water phase and chemical reactivity, which are particularly useful for determining the cellular uptake of the NPs. The proposed
study provides fundamental insights into molecular dynamics (MD) that will allow researchers to determine the influence of pH, structure, charge, and energetics of NPs on the cellular uptake of anticancer drugs. We believe that our current
study will be useful in developing a new model for drug delivery to cancer cells with a much more efficient and less time-consuming model.