Shah Tejas, Polara Himanshu, Babanyinah Godwin, Bhadran Abhi, Wang Hanghang, Castillo Cristina Cu, Grabowski Gerik, Biewer Michael C, Torabifard Hedieh, Stefan Mihaela C
Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA.
J Mater Chem B. 2025 Mar 26;13(13):4166-4178. doi: 10.1039/d4tb02789b.
Amphiphilic diblock copolymers are used in drug delivery systems for cancer treatments. However, these carriers suffer from lower drug loading capacity, poor water solubility, and non-targeted drug release. Here, we utilized a computational approach to analyze the effect of the functional groups of the hydrophobic block on the drug-polymer interactions. To design effective drug carriers, four different amphiphilic block copolymer micelles with distinct aromatic and heteroaromatic groups at the hydrophobic core were subjected to molecular dynamics simulations. The solvent-accessible surface area, water shell, hydrogen bonding, and radius of gyration of the simulated micelles were determined. Further, we assessed the interactions between the hydrophobic block and drug molecules using linear interaction energy and non-covalent interactions. The computational studies revealed that the micelles containing a novel poly(γ-2-methoxyfuran-ε-caprolactone) (PFuCL) hydrophobic block have the highest polymer-drug interactions. From these findings, we synthesized a novel amphiphilic poly(ethylene glycol)--poly(γ-2-methoxyfuran(ε-caprolactone)) (PEG--PFuCL) block copolymer using ring-opening polymerization of FuCL monomer. The polymer was self-assembled in aqueous media to form micelles. The aromatic segment of PEG--PFuCL micelles enhanced the doxorubicin (DOX) loading through non-covalent interactions, resulting in a 4.25 wt% drug-loading capacity. We also showed that the hydrolysis of the ester bond allowed a faster drug release at pH 5.0 compared to pH 7.4. Cell viability experiments revealed that DOX-loaded PEG--PFuCL micelles show that micelles are cytotoxic and readily uptaken into MDA-MB-231 cells. Therefore, furan-substituted micelles will be an ideal drug carrier with higher polymer-to-drug interactions, enhanced drug loading, and lower premature leakage.
两亲性二嵌段共聚物用于癌症治疗的药物递送系统。然而，这些载体存在载药量低、水溶性差和药物非靶向释放等问题。在此，我们采用计算方法分析疏水嵌段官能团对药物 - 聚合物相互作用的影响。为了设计有效的药物载体，对四种在疏水核心具有不同芳香族和杂芳香族基团的两亲性嵌段共聚物胶束进行了分子动力学模拟。测定了模拟胶束的溶剂可及表面积、水壳、氢键和回转半径。此外，我们使用线性相互作用能和非共价相互作用评估了疏水嵌段与药物分子之间的相互作用。计算研究表明，含有新型聚（γ - 2 - 甲氧基呋喃 - ε - 己内酯）（PFuCL）疏水嵌段的胶束具有最高的聚合物 - 药物相互作用。基于这些发现，我们通过FuCL单体的开环聚合合成了一种新型两亲性聚（乙二醇） - 聚（γ - 2 - 甲氧基呋喃（ε - 己内酯））（PEG - PFuCL）嵌段共聚物。该聚合物在水性介质中自组装形成胶束。PEG - PFuCL胶束的芳香段通过非共价相互作用提高了阿霉素（DOX）的负载量，载药量达到4.25 wt%。我们还表明，与pH 7.4相比，酯键的水解使得在pH 5.0时药物释放更快。细胞活力实验表明载有DOX的PEG - PFuCL胶束具有细胞毒性，并且易于被MDA - MB - 231细胞摄取。因此，呋喃取代的胶束将是一种理想的药物载体，具有更高的聚合物 - 药物相互作用、增强的载药量和更低的过早泄漏。
