Background: Chemoresistance continues to limit the recovery of patients with cancer. New strategies, such as combination therapy or nanotechnology can be further improved. Objective: In this study, we applied the computational strategy by exploiting two databases (CellMiner and Prism) to sort out the cell lines sensitive to both anti-cancer drugs, paclitaxel (PTX) and dihydroartemisinin (DHA); both of which are potentially synergistic in several cell lines. Methods: The combination of PTX and DHA was screened at different ratios to select the optimal ratio that could inhibit lung adenocarcinoma NCI-H23 the most. To further enhance therapeutic efficacy, these combinations of drugs were incorporated into a nanosystem. Results: At a PTX:DHA ratio of 1:2 (w/w), the combined drugs obtained the best combination index (0.84), indicating a synergistic effect. The drug-loaded nanoparticles sized at 135 nm with the drug loading capacity of 15.5 ± 1.34 and 13.8 ± 0.56 corresponding to DHA and PTX, respectively were used. The nano-sized particles improved drug internalization into the cells, resulting in the significant inhibition of cell growth at all tested concentrations (p < 0.001). Additionally, α-tubulin aggregation, DNA damage suggested the molecular mechanism behind cell death upon PTX-DHA-loaded nanoparticle treatment. Moreover, the rate of apoptosis increased from approximately 5% to more than 20%, and the expression of apoptotic proteins changed 4 and 3 folds corresponding to p-53 and Bcl-2, respectively. Conclusion: This study was designed thoroughly by screening cell lines for the optimization of formulations. This novel approach could pave the way for the selection of combined drugs for precise cancer treatment.

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计算筛选工具和纳米技术在癌症治疗中增强药物协同作用的应用

背景：化疗耐药继续限制癌症患者的康复。可以进一步改进新策略，例如联合疗法或纳米技术。目标：在本研究中，我们通过利用两个数据库（CellMiner 和 Prism）应用计算策略来筛选对两种抗癌药物紫杉醇 (PTX) 和双氢青蒿素 (DHA) 敏感的细胞系；两者在几种细胞系中都具有潜在的协同作用。方法：筛选不同比例的PTX和DHA组合，选择最能抑制肺腺癌NCI-H23的最佳比例。为了进一步提高治疗效果，这些药物组合被纳入纳米系统。结果：在 PTX:DHA 比例为 1:2 (w/w) 时，组合药物获得最佳组合指数 (0.84)，说明有协同作用。使用粒径为 135 nm 的载药纳米颗粒，载药量分别为 15.5 ± 1.34 和 13.8 ± 0.56，对应于 DHA 和 PTX。纳米尺寸的颗粒改善了药物在细胞中的内化，导致在所有测试浓度下显着抑制细胞生长 (p < 0.001)。此外，α-微管蛋白聚集、DNA 损伤表明了载有 PTX-DHA 的纳米颗粒处理后细胞死亡的分子机制。此外，细胞凋亡率从大约 5% 增加到超过 20%，并且凋亡蛋白的表达分别对应于 p-53 和 Bcl-2 改变了 4 倍和 3 倍。结论：本研究是通过筛选细胞系以优化制剂而彻底设计的。