Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
J Mol Model. 2011 Nov;17(11):2973-87. doi: 10.1007/s00894-011-0989-4. Epub 2011 Mar 1.
Molecular shape, flexibility, and surface hydrophilicity are thought to influence the ability of nanoparticles to cross biological barriers during drug delivery. In this study, coarse-grained (CG) molecular dynamics (MD) simulations were used to study these properties of a polymer-drug construct in potential clinical development: poly(γ-glutamyl-glutamate)-paclitaxel-poly(ethylene glycol) nonpeptide RGD (PGG-PTX-PEG-npRGD), a linear glutamyl-glutamate polymer with paclitaxel and poly(ethylene glycol)-nonpeptide RGD side groups. It was hypothesized that the PEG molecular weight (MW) (500 Da; 1,000 Da; and 2,000 Da) and nonpeptide RGD ligand density (4, 8, 12, and 16 per molecule), respectively, may have advantageous effects on the shape, flexibility, and surface hydrophilicity of PGG-PTX-PEG-npRGD. Circular dichroism spectroscopy was used to suggest initial structures for the all-atom (AA) models of PGG-PTX-PEG-npRGD, which were further converted to CG models using a commercially available mapping algorithm. Due to its semi-flexibility, PGG-PTX-PEG-npRGD is not limited to one specific conformation. Thus, CG MD simulations were run until statistical equilibrium, at which PGG-PTX-PEG-npRGD is represented as an ensemble of statistically similar conformations. The size of a PGG-PTX-PEG-npRGD molecule is not affected by the PEG MW or the nonpeptide RGD density, but higher PEG MW results in increased surface density of a PGG-PTX-PEG-npRGD molecule. Most PGG-PTX-PEG-npRGD shapes are globular, although filamentous shapes were also observed in the PEG500 and PEG1000 molecules. PEG500 and PEG1000 molecules are more flexible than PEG2000 systems. A higher presence of npRGD ligands results in decrease surface hydrophilicity of PGG-PTX-PEG-npRGD. These results indicate that the PGG-PTX-PEG1000-npRGD(4) and PGG-PTX-PEG1000-npRGD(8) molecules are the most efficacious candidates and are further recommended for experimental preclinical studies.
分子形状、柔韧性和表面亲水性被认为会影响纳米粒子在药物传递过程中穿过生物屏障的能力。在这项研究中，使用粗粒（CG）分子动力学（MD）模拟来研究一种具有潜在临床开发前景的聚合物-药物构建体的这些特性：聚（γ-谷氨酸-谷氨酰胺）-紫杉醇-聚（乙二醇）非肽 RGD（PGG-PTX-PEG-npRGD），一种带有紫杉醇和聚（乙二醇）-非肽 RGD 侧基的线性谷氨酸-谷氨酰胺聚合物。假设聚乙二醇分子量（500 Da、1000 Da 和 2000 Da）和非肽 RGD 配体密度（分别为每个分子 4、8、12 和 16）可能对 PGG-PTX-PEG-npRGD 的形状、柔韧性和表面亲水性产生有利影响。圆二色光谱用于为 PGG-PTX-PEG-npRGD 的全原子（AA）模型建议初始结构，然后使用商业可用的映射算法将其进一步转换为 CG 模型。由于其半柔韧性，PGG-PTX-PEG-npRGD 不受一种特定构象的限制。因此，CG MD 模拟一直运行到统计平衡，此时 PGG-PTX-PEG-npRGD 表示为统计上相似构象的集合。PGG-PTX-PEG-npRGD 分子的大小不受 PEG MW 或非肽 RGD 密度的影响，但较高的 PEG MW 会导致 PGG-PTX-PEG-npRGD 分子的表面密度增加。大多数 PGG-PTX-PEG-npRGD 形状为球形，尽管在 PEG500 和 PEG1000 分子中也观察到丝状形状。PEG500 和 PEG1000 分子比 PEG2000 系统更灵活。npRGD 配体的存在量增加会降低 PGG-PTX-PEG-npRGD 的表面亲水性。这些结果表明，PGG-PTX-PEG1000-npRGD(4)和 PGG-PTX-PEG1000-npRGD(8)分子是最有效的候选物，并进一步推荐用于实验前临床研究。
