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Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and pH Sensitive Nanocarriers
Drug Design, Development and Therapy ( IF 4.8 ) Pub Date : 2020-11-25 , DOI: 10.2147/dddt.s260253
Yonglong Jin 1 , Yi Wang 2 , Xiguang Liu 1 , Jing Zhou 1 , Xintong Wang 1 , Hui Feng 1 , Hong Liu 2
Affiliation  

Purpose: Prodrug technology-based combination drug therapy has been exploited as a promising treatment strategy to achieve synergistic lung cancer therapy, reduce drug dose, and decrease side effects. In the present study, we synthesized a pH and glutathione (GSH) sensitive prodrug, cisplatin (CIS) and doxorubicin (DOX) conjugates (CIS-DOXp). CIS-DOXp was loaded by nanocarriers and delivered into the tumor site.
Methods: pH and GSH sensitive CIS-DOX prodrug (CIS-DOXp) was synthesized by conjugating GSH responsive CIS prodrug with pH sensitive DOX prodrug. CIS-DOXp-loaded nanocarriers (CIS-DOXp NC) were prepared using emulsification and solvent evaporation method. The morphology, particle size, polydispersity index (PDI) and zeta potential of nanocarriers were measured. In vitro cytotoxicity of nanocarriers and the corresponding free drugs was examined using the MTT assay. In vivo anti-tumor efficiency and biodistribution behaviors were evaluated on lung cancer mice models.
Results: The size, PDI, zeta potential, CIS loading efficiency, and DOX loading efficiency of CIS-DOXp NC were 128.6 ± 3.2 nm, 0.196 ± 0.021, 15.7 ± 1.7 mV, 92.1 ± 2.1%, and 90.4 ± 1.8%, respectively. The best cell killing ability (the lowest combination index of 0.57) was found at the combination ratio of 1:3 (CIS:DOX, w/w) in the drugs co-loaded formulations, indicating the strongest synergism effect. CIS-DOXp NC showed the best tumor inhibition efficiency (79.9%) in mice with negligible body weight lost.
Conclusion: CIS-DOXp NC could be applied as a promising system for the synergistic chemotherapy of lung cancer.

Keywords: lung cancer, combination therapy, prodrug, pH responsive, GSH responsive


中文翻译:

肺癌的协同联合化疗:顺铂和阿霉素共轭前药负载,谷胱甘肽和 pH 敏感纳米载体

目的:基于前药技术的联合药物治疗已被开发为一种有前景的治疗策略,以实现协同肺癌治疗、减少药物剂量和减少副作用。在本研究中,我们合成了一种对 pH 和谷胱甘肽 (GSH) 敏感的前药,顺铂 (CIS) 和阿霉素 (DOX) 偶联物​​ (CIS-DOXp)。CIS-DOXp 由纳米载体装载并递送到肿瘤部位。
方法:pH 和 GSH 敏感的 CIS-DOX 前药 (CIS-DOXp) 是通过将 GSH 响应性 CIS 前药与 pH 敏感的 DOX 前药结合来合成的。使用乳化和溶剂蒸发法制备载有 CIS-DOXp 的纳米载体 (CIS-DOXp NC)。测量了纳米载体的形态、粒径、多分散指数(PDI)和zeta电位。使用 MTT 法检测纳米载体和相应游离药物的体外细胞毒性。在肺癌小鼠模型上评估体内抗肿瘤效率和生物分布行为。
结果:CIS-DOXp NC 的尺寸、PDI、zeta 电位、CIS 加载效率和 DOX 加载效率分别为 128.6 ± 3.2 nm、0.196 ± 0.021、15.7 ± 1.7 mV、92.1 ± 2.1% 和 90.4 ± 1.8%。在药物共载制剂中,以1:3(CIS:DOX,w/w)的组合比例发现细胞杀伤能力最好(最低组合指数为0.57),表明协同作用最强。CIS-DOXp NC 在体重减轻可忽略不计的小鼠中显示出最佳的肿瘤抑制效率 (79.9%)。
结论: CIS-DOXp NC可作为肺癌协同化疗的一个有前景的系统。

关键词:肺癌,联合治疗,前药,pH 反应性,GSH 反应性
更新日期:2020-11-25
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