Physical Science Research Area, Tata Research Development and Design Centre, TCS Research, Tata Consultancy Services, 54B, Hadapsar Industrial Estate, Pune 411013, India.
Nanoscale. 2020 Mar 21;12(11):6318-6333. doi: 10.1039/c9nr09947f. Epub 2020 Mar 5.
Nanoparticles are being explored for topical and oral drug delivery applications as they can cross various biological barriers, for example, the intestinal epithelium. The ability of nanoparticles to cross barriers depends on their morphological and surface properties such as size, surface chemistry and shape, among others. The effect of nanoparticle size on their membrane permeability has been well studied both experimentally and theoretically. However, less attention has been given to understand the role of nanoparticle shape in their translocation across biological barrier membranes. Here, we report on the influence of the nanoparticle's shape, surface chemistry and concentration on their permeation across a human intestinal apical cell membrane model. A representative multicomponent lipid bilayer model of the human intestinal apical membrane was built. The free energy of permeation of nanoparticles across the model lipid bilayer was calculated using multiple umbrella sampling simulations. The interaction of these nanoparticles with the model lipid bilayer was captured using extensive microsecond unrestrained molecular dynamics simulations. We observed that: (a) irrespective of the surface chemistry, the efficacy of nanoparticle penetration across the lipid layer was in the order of rod > disc > sphere; (b) irrespective of the shape, apolar and nonpolar nanoparticles were found to locate in the interior of the lipid bilayer, whereas charged and polar nanoparticles were either adsorbed on the lipid headgroups or remained in the water layer; (c) apolar and nonpolar disc shaped nanoparticles had higher efficacy in permeation across the lipid bilayer as compared to disc and sphere shaped nanoparticles; and (d) at a higher concentration of nanoparticles, sphere and disc shaped nanoparticles exhibited more agglomeration as compared to rod shaped nanoparticles. Based on these outcomes, a few nanoparticles were designed which penetrated readily into the lipid layer and these nanoparticles were also able to co-deliver a therapeutic protein inside the lipid layer. The apical model lipid membrane and protocols used in this study can thus be utilized for the in silico design of nanoparticles for the oral delivery of therapeutics.
纳米颗粒正被探索用于局部和口服药物递送应用，因为它们可以跨越各种生物屏障，例如肠道上皮。纳米颗粒跨越屏障的能力取决于它们的形态和表面特性，例如大小、表面化学和形状等。纳米颗粒大小对其膜通透性的影响已经在实验和理论上得到了很好的研究。然而，对于理解纳米颗粒形状在其穿过生物屏障膜的转位中的作用，关注较少。在这里，我们报告了纳米颗粒的形状、表面化学和浓度对其穿过人肠顶端细胞膜模型的渗透的影响。构建了人肠顶端膜的代表性多组分脂质双层模型。使用多个伞状采样模拟计算了纳米颗粒穿过模型脂质双层的渗透自由能。使用广泛的微秒无约束分子动力学模拟捕获了这些纳米颗粒与模型脂质双层的相互作用。我们观察到：(a) 无论表面化学如何，纳米颗粒穿过脂质层的渗透效果顺序为棒>盘>球；(b) 无论形状如何，非极性和非极性纳米颗粒都被发现位于脂质双层的内部，而带电和极性纳米颗粒要么吸附在脂质头基上，要么留在水层中；(c) 与盘和球形纳米颗粒相比，非极性和非极性盘形纳米颗粒在穿过脂质双层时具有更高的渗透效率；(d) 在较高浓度的纳米颗粒下，与棒状纳米颗粒相比，球形和盘形纳米颗粒表现出更多的聚集。基于这些结果，设计了一些容易穿透脂质层的纳米颗粒，这些纳米颗粒也能够在脂质层内共递送治疗蛋白。因此，该研究中使用的顶端模型脂质膜和方案可用于经口递药治疗的纳米颗粒的计算机设计。
