论文标题
叶酸功能化TiO $ _ {2} $纳米颗粒的多尺度建模用于主动靶向肿瘤细胞
Multi-scale modeling of folic acid-functionalized TiO$_{2}$ nanoparticles for active targeting of tumor cells
论文作者
论文摘要
基于肿瘤细胞的主动靶向的策略正在成为智能有效的纳米医师程序。叶酸（FA）是一种维生素，是一种已建立的肿瘤靶向剂，因为它对叶酸受体（FR）具有很强的亲和力，叶酸受体（FR）是肿瘤细胞细胞膜上过表达的蛋白质。 FA可以成功锚定在几个纳米载体上，包括基于过渡金属氧化物的无机纳米颗粒（NP）。其中，Tio $ _ {2} $非常有趣，因为它具有出色的光吸附和光催化特性，可以在光动力疗法中利用。但是，尚不清楚基于聚乙二醇（PEG）链的FA直接锚定向NP的直接锚定或使用垫片有所不同，而一种方法是不同的，并且一种方法是否比另一种方法更好。在这项工作中，我们将量子力学（QM）和经典分子动力学（MD）组合在一起，以设计和优化裸露和pegy的Tio $ _ {2} $模型上的FA功能化，并研究在纯水环境和生理条件下导致纳米轭物的动力学行为。我们观察到它们在化学上是化学稳定的，即使在温度升高（最高500 K）的作用下也是如此。使用长MD模拟（100 ns）和自由能计算中的结果，我们确定FA分子在Tio $ _ {2} $ np上的密度以及PEG间隔者的存在如何影响配体的实际暴露，尤其是通过影响FA Intermolecular互动的程度来影响FA的受体，而FA依靠FA的能力，而FA会涉及FA的范围。该分析为实验者提供了坚实而合理的基础，以根据纳米轭的最终目的定义最佳的FA密度和更合适的锚定模式。
Strategies based on the active targeting of tumor cells are emerging as smart and efficient nanomedical procedures. Folic acid (FA) is a vitamin and a well-established tumor targeting agent because of its strong affinity for the folate receptor (FR), which is an overexpressed protein on the cell membranes of the tumor cells. FA can be successfully anchored to several nanocarriers, including inorganic nanoparticles (NPs) based on transition metal oxides. Among them, TiO$_{2}$ is extremely interesting because of its excellent photoabsorption and photocatalytic properties, which can be exploited in photodynamic therapy. However, it is not yet clear in which respects direct anchoring of FA to the NP or the use of spacers, based on polyethylene glycol (PEG) chains, are different and whether one approach is better than the other. In this work, we combine Quantum Mechanics (QM) and Classical Molecular Dynamics (MD) to design and optimize the FA functionalization on bare and PEGylated TiO$_{2}$ models and to study the dynamical behavior of the resulting nanoconjugates in pure water environment and in physiological conditions. We observe that they are chemically stable, even under the effect of increasing temperature (up to 500 K). Using the results from long MD simulations (100 ns) and from free energy calculations, we determine how the density of FA molecules on the TiO$_{2}$ NP and the presence of PEG spacers impact on the actual exposure of the ligands, especially by affecting the extent of FA-FA intermolecular interactions, which are detrimental for the targeting ability of FA towards the folate receptor. This analysis provides a solid and rational basis for experimentalists to define the optimal FA density and the more appropriate mode of anchoring to the carrier, according to the final purpose of the nanoconjugate.
