Chemical and Biomolecular Engineering, University of Pennsylvania, 129 Towne Building, 220 South 33rd St., University of Pennsylvania, Philadelphia, PA 19104, USA.
Adv Mater. 2012 Jul 24;24(28):3823-30. doi: 10.1002/adma.201103192. Epub 2011 Nov 22.
Nanoparticle shape can improve drug delivery, based in part on recent findings that flexible, worm-like nanocarriers (Worms) increase the amount of drug delivered to tumors and shrink the tumors more effectively than spherical micelles (Spheres). Here, all-atom molecular dynamics (MD) simulations are used to build a rational coarse grain (rCG) model that helps clarify shape-dependent effects in delivery of the widely used anticancer drug Taxol by block copolymer micelles. Potentials for rCG-MD were developed to examine the partitioning of this hydrophobic-aromatic drug into Worms and Spheres that self-assemble in water from poly(ethyleneglycol)-poly(caprolactone) (PEG-PCL), a weakly segregating amphiphile. PCL is a biodegradable, hydrophobic polymer widely used in biomaterials and accurately modeled here. Thermodynamic integration of the force to pull a single Taxol molecule from the micelles into solvent shows that twice as much drug loads into Worms than Spheres, fully consistent with experiments. Diffusivity of drug in the hydrated PEG corona is surprisingly slow compared to that in the core, indicative of strong but transient drug-polymer interactions. The distinctly distended corona of the Worms enhances such interactions and reflects the same balance of molecular forces that underlie an experimentally-validated phase diagram for simulated Spheres, Worms, and Bilayers. Moreover, with realistic drug loadings in micro-second simulations, Taxol is seen to draw PEG chains into the PCL core, dispersing the drug while localizing it near the interface—thus providing a molecular explanation for a measurable burst release of drug as well as the enhanced delivery seen with Worms.
纳米颗粒的形状可以改善药物输送，这部分基于最近的发现，即柔性、蠕虫状纳米载体（蠕虫）比球形胶束（球体）增加了递送到肿瘤的药物量，并更有效地缩小了肿瘤。在这里，全原子分子动力学（MD）模拟被用于构建合理的粗粒（rCG）模型，这有助于澄清广泛使用的抗癌药物紫杉醇通过嵌段共聚物胶束输送的形状依赖性效应。开发了 rCG-MD 的势来研究这种疏水性芳香族药物在自组装于水中的聚（乙二醇）-聚（己内酯）（PEG-PCL）中，Worms 和 Spheres 中的分配情况，这是一种弱分离的两亲物。PCL 是一种生物可降解的疏水性聚合物，广泛用于生物材料，并且在此处进行了准确建模。将单个紫杉醇分子从胶束中拉到溶剂中的力的热力学积分表明，药物负载到蠕虫中的量是球体的两倍，这与实验完全一致。药物在水合 PEG 冠中的扩散率与在核中的扩散率相比非常缓慢，表明药物与聚合物之间存在强烈但瞬态的相互作用。蠕虫明显膨胀的冠增强了这种相互作用，并反映了分子力的相同平衡，这种平衡是模拟球体、蠕虫和双层实验验证的相图的基础。此外，在微秒模拟中具有现实的药物负载，紫杉醇被看到将 PEG 链拉入 PCL 核，分散药物，同时将其定位在界面附近 - 从而为药物的可测量爆发释放以及与蠕虫一起看到的增强输送提供了分子解释。
