Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
Patent Examination Cooperation Jiangsu Center of The Patent Office. Sipo, Suzhou 215010, China.
Mol Pharm. 2021 Apr 5;18(4):1643-1655. doi: 10.1021/acs.molpharmaceut.0c01095. Epub 2021 Mar 24.
To better promote the application of polymeric mixed micelles (PMMs), a coarse-grained molecular dynamics simulation (CGMD) has been employed to investigate the factors controlling the spatial distribution within the PMMs and predict their drug-loading properties, meanwhile, combined with experimental methods to validate and examine it. In this study, the snapshots obtained from CGMD and the results of proton nuclear magnetic resonance (H NMR) and transmission electron microscopy (TEM) provide new insights into the distribution principle that the spatial distribution depends on the hydrophobic compatibility of drugs with the regions within PMMs. Docetaxel (DTX) is located within the interior or near the core-corona interface of the HS15 hydrophobic core inside FS/PMMs (PMMs fabricated from a nonionic triblock copolymer (F127)) and a nonionic surfactant (HS15), and therefore, the system with a high HS15 ratio, such as system I, is more suitable for loading DTX. In contrast, the more water-soluble puerarin (PUE) is more likely to be solubilized in the "secondary hydrophobic area," mainly formed by the hydrophobic part of F127 within FS/PMMs. However, when the initial feeding concentration of the drug is increased or the FS mixing ratios are changed, an inappropriate distribution would occur and hence influence the drug-loading stability. Also, this impact was further elucidated by the calculated parameters (solvent-accessible surface area (SASA), the radius of gyration (), and energy landscape), and the analysis of the drug leakage, concluding that inappropriate distribution of the drug would lower the stability of the drug in the PMMs. These results combined together provide new insights into the distribution principle that the spatial distribution of drugs within PMMs depends on the hydrophobic compatibility of drugs with the regions formed by micellar materials. Additionally, drug release yielded a consistent picture with the above conclusions and provides evidence that both the location of the drug within the systems and the stability of the drug-loading system have a great influence on the drug release behavior. Accordingly, this work demonstrates that we can tune the drug-loading stability and drug release behavior the drug-PMM interaction and drug location study, and CGMD technology would be a step forward in the search for suitable drug-delivery PMMs.
为了更好地推广聚合物胶束（PMMs）的应用，采用粗粒化分子动力学模拟（CGMD）研究了控制 PMMs 内空间分布的因素，并预测其载药性能，同时结合实验方法进行验证和检验。在这项研究中，从 CGMD 获得的快照以及质子核磁共振（H NMR）和透射电子显微镜（TEM）的结果为药物在 PMMs 中的空间分布取决于药物与 PMMs 内部区域的疏水性相容性这一分布原理提供了新的见解。多西他赛（DTX）位于疏水核内的 HS15 内部的 FS/PMMs（由非离子型三嵌段共聚物（F127）和非离子型表面活性剂（HS15）制成的 PMMs）的内部或靠近核-冠界面，因此，HS15 比例较高的系统，如系统 I，更适合装载 DTX。相比之下，水溶性更高的葛根素（PUE）更有可能溶解在“次级疏水区”中，主要由 FS/PMMs 中 F127 的疏水部分形成。然而，当药物的初始进料浓度增加或 FS 混合比改变时，会发生不合适的分布，从而影响载药稳定性。此外，通过计算参数（可及表面积（SASA）、回转半径（）和能量景观）和药物泄漏分析进一步阐明了这一影响，得出药物的不合适分布会降低药物在 PMMs 中的稳定性的结论。这些结果结合在一起，提供了新的见解，即药物在 PMMs 内的空间分布取决于药物与胶束材料形成的区域的疏水性相容性。此外，药物释放与上述结论一致，表明药物在系统中的位置和载药系统的稳定性对药物释放行为有很大影响。因此，这项工作表明，我们可以通过药物-PMM 相互作用和药物位置研究来调节载药稳定性和药物释放行为，CGMD 技术将是寻找合适的药物递送 PMMs 的一个进步。
