Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer  

作　　者：Wen Chen Kun Shi Jie Liu Peipei Yang Ruxia Han Meng Pan Liping Yuan Chao Fang Yongyang Yu Zhiyong Qian 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University and Collaborative Innovation Center,Chengdu,610041,PR China [2]Department of Gastrointestinal Surgery,West China Hospital,Sichuan University,Chengdu,610041,PR China

出　　处：《Bioactive Materials》2023年第5期1-15,共15页生物活性材料（英文）

基　　金：We gratefully acknowledge financial support from the National Natural Science Foundation of China(U21A20417,31930067,and 31800797);the Sichuan Science and Technology Program(2022YFS0333,2022YFS0203);1⋅3⋅5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18002);the Post-Doctor Research Project,West China Hospital,Sichuan University(2018HXBH066).

摘　　要：Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide,posing a severe threat to human health.Surgical resection remains the most preferred option for gastric cancer treatment.However,for advanced gastric cancer,the curative effect of surgical resection is usually limited by the local recurrence,peritoneal carcinomatosis,or distal metastasis.Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection.Here,we designed a 5-fluorouracil(5-FU)and cis-platinum(DDP)co-delivery system based on a biodegradable temperature-sensitive hydrogel(PDLLA-PEG-PDLLA,PLEL)for intraoperative adjuvant combination chemotherapy of gastric cancer.This 5-FU+DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo.A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU+DDP/PLEL were observed against gastric cancer MKN45-luc cells.After intraperitoneal injection,the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model.The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well.What’s more,we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer,in which the intraoperative administration of 5-FU+DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors,resulting in an extended lifetime.Hence,this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer,that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

关 键 词：Thermo-sensitive hydrogel Localized drug delivery Sustained release Intraoperative chemotherapy Gastric cancer 

分 类 号：TQ427.26[化学工程] R730.5[医药卫生—肿瘤]