Synergistic Combination Chemotherapy of Lung Cancer: Cisplatin and Doxorubicin Conjugated Prodrug Loaded, Glutathione and pH Sensitive Nanocarriers

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.