Wang Xin-Shuai, Kong De-Jiu, Lin Tzu-Yin, Li Xiao-Cen, Izumiya Yoshihiro, Ding Xue-Zhen, Zhang Li, Hu Xiao-Chen, Yang Jun-Qiang, Gao She-Gan, Lam Kit S, Li Yuan-Pei
Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang 471003, China.
Department of Internal Medicine, Division of Hematology/Oncology, University of California Davis, Sacramento, CA 95817, USA.
Acta Pharmacol Sin. 2017 Jun;38(6):931-942. doi: 10.1038/aps.2017.43. Epub 2017 May 29.
One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.
精准肿瘤学的主要目标之一是基于抗癌药物的分子机制促进联合治疗，以提高疗效并减少副作用。在本研究中，我们旨在开发并验证多西他赛（DTX）和硼替佐米（BTZ）的新型纳米制剂，用于靶向联合治疗人类食管癌。通过利用我们通用的二硫键交联胶束（DCMs）平台，我们开发了DTX和BTZ的纳米制剂（分别命名为DTX-DCMs和BTZ-DCMs）。对其物理性质进行了表征；在体外人食管癌细胞系中研究了它们的抗癌疗效及作用机制。此外，与单药治疗和游离药物策略相比，检测了联合治疗（同时给药、序贯给药以及使用不同药物比例的治疗）的体外抗肿瘤活性。这些载药纳米颗粒呈球形，尺寸相对较小，约为20 - 22 nm。DTX和BTZ在纳米颗粒中的包封率分别为82.4%和84.1%。DTX-DCMs和BTZ-DCMs的药物释放速率是持续的，并且在谷胱甘肽（GSH）存在的情况下显著增加。这些纳米药物被KYSE30食管癌细胞有效内化，并剂量依赖性地诱导细胞凋亡。我们进一步揭示了DTX-DCMs和BTZ-DCMs对KYSE30食管癌细胞具有强大的协同作用。先使用DTX-DCMs然后使用BTZ-DCMs的序贯联合治疗在体外表现出最佳的抗肿瘤疗效。本研究表明DTX和BTZ可以成功地纳米化制成二硫键交联胶束。DTX和BTZ的纳米制剂在协同联合治疗人类食管癌方面显示出巨大潜力。
