Therapeutic efficiency of amphiphilic methotrexate–camptothecin (MTX‐CPT) prodrug compared to free drug mixture (MTX/CPT) has been investigated using all‐atom molecular dynamics simulation and first principles density functional theory calculations. This comparison revealed that MTX–CPT prodrug tends to form spherical self‐assembled nanoparticle (NP), while free MTX/CPT mixture forms rod‐shape NP. These observations are attributed to a structural defect in the MTX–CPT prodrug and solvation free energies of MTX, CPT and MTX‐CPT molecules. The results provided evidence that noncovalent interactions (NCIs) among the pharmaceutical drugs play a very important role in anticancer agents aggregation process, leading to enhanced stability of the self‐assembled NPs. It is found that the stability of MTX–CPT self‐assembled NP is greater than the MTX/CPT NP due to the synergistic effect of hydrogen bonding between monomers and solvent (water). Moreover, the noncatalyzed as well as catalyzed hydrolysis reactions of MTX–CPT prodrug are theoretically studied at the PCM(water)//M06‐2X/6−31G(d,p) computational level to shed additional light on the role of acidic condition in tumor tissues. We found that the ester hydrolysis in mild acidic solutions is a concerted reaction. In an agreement between theory and experiment, we also confirmed that the activation energies of the catalyzed‐hydrolysis steps are much lower than the activation energies of the corresponding steps in the noncatalyzed reaction. Thus, the MTX–CPT prodrug reveals very promising properties as a pH‐controlled drug delivery system.

中文翻译：

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评价甲氨蝶呤-喜树碱共递送前药从自组装过程到酸催化两种药物释放的协同抗肿瘤作用：综合理论研究

已使用全原子分子动力学模拟和第一原理密度泛函理论计算研究了两亲性甲氨蝶呤-喜树碱 (MTX-CPT) 前药与游离药物混合物 (MTX/CPT) 相比的治疗效率。该比较表明 MTX-CPT 前药倾向于形成球形自组装纳米颗粒 (NP)，而游离的 MTX/CPT 混合物形成棒状 NP。这些观察结果归因于 MTX-CPT 前药的结构缺陷和 MTX、CPT 和 MTX-CPT 分子的溶剂化自由能。结果表明，药物之间的非共价相互作用（NCI）在抗癌药物聚集过程中起着非常重要的作用，从而增强了自组装纳米颗粒的稳定性。发现由于单体和溶剂（水）之间氢键的协同作用，MTX-CPT自组装NP的稳定性大于MTX/CPT NP。此外，在 PCM(water)//M06-2X/6-31G(d,p) 计算水平上对 MTX-CPT 前药的非催化和催化水解反应进行了理论上的研究，以进一步阐明酸性条件的作用在肿瘤组织中。我们发现在弱酸性溶液中的酯水解是一个协同反应。理论与实验一致，我们还证实催化水解步骤的活化能远低于非催化反应中相应步骤的活化能。因此，MTX-CPT 前药作为 pH 控制的药物递送系统显示出非常有前景的特性。