Department of Radiotherapy, Affiliated Hospital of Qingdao University, Qingdao 266000, People's Republic of China.
Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan 250012, People's Republic of China.
Drug Des Devel Ther. 2020 Nov 25;14:5205-5215. doi: 10.2147/DDDT.S260253. eCollection 2020.
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.
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.
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.
CIS-DOXp NC could be applied as a promising system for the synergistic chemotherapy of lung cancer.
基于前药技术的联合药物疗法已被开发为一种有前途的治疗策略，以实现协同肺癌治疗、降低药物剂量和减少副作用。在本研究中，我们合成了一种 pH 值和谷胱甘肽 (GSH) 敏感的前药，顺铂 (CIS) 和阿霉素 (DOX) 缀合物 (CIS-DOXp)。CIS-DOXp 通过纳米载体装载并递送到肿瘤部位。
通过将 GSH 响应 CIS 前药与 pH 敏感 DOX 前药缀合，合成 pH 值和 GSH 敏感的 CIS-DOX 前药 (CIS-DOXp)。采用乳化溶剂挥发法制备 CIS-DOXp 载纳米载体 (CIS-DOXp NC)。测量纳米载体的形态、粒径、多分散指数 (PDI) 和 Zeta 电位。采用 MTT 法检测纳米载体及其相应游离药物的体外细胞毒性。在肺癌小鼠模型上评估载药纳米载体的体内抗肿瘤效率和生物分布行为。
CIS-DOXp NC 的粒径、PDI、Zeta 电位、CIS 载药量和 DOX 载药量分别为 128.6 ± 3.2nm、0.196 ± 0.021、15.7 ± 1.7mV、92.1 ± 2.1%和 90.4 ± 1.8%。在共载药物制剂中，CIS:DOX（w/w）的最佳配比为 1:3 时，具有最佳的细胞杀伤能力（最低联合指数为 0.57），表明具有最强的协同作用。CIS-DOXp NC 在小鼠中表现出最佳的肿瘤抑制效率（79.9%），且体重损失可忽略不计。
CIS-DOXp NC 可作为一种有前途的肺癌协同化疗系统。
