目的 制备用于治疗膀胱癌、可经膀胱灌注给药的白藜芦醇温敏型凝胶剂。方法 以最低胶凝温度、溶蚀时间为指标，筛选凝胶处方；通过扫描电镜（SEM）观察凝胶的微观结构，通过傅里叶变换红外光谱（FTIR）观察凝胶基质与药物的相容性，溶出度测定仪考察凝胶的体外释放行为；体外培养小鼠膀胱癌细胞（MB49-LUC），划痕实验和MTT实验考察白藜芦醇浓度、作用时间对膀胱癌细胞迁移和增殖的影响。结果 凝胶的最优处方为白藜芦醇30%、泊洛沙姆407 19%、泊洛沙姆188 7%、海藻酸钠 0.3%、碳酸钙 0.06%、NH₄HCO₃ 0.2%；SEM显示凝胶呈疏松多孔的三维网状结构，FTIR显示凝胶材料官能团结构无明显改变，相容性良好；药物从漂浮凝胶中缓慢释放，80 d 内累积释放 50.37%，药物释放量达 135.58 mg。划痕实验显示，与对照组相比，白藜芦醇≥60 μmol·L^-1可显著抑制MB49-LUC细胞的迁移（P＜0.05）；MTT实验显示，与对照组比较，白藜芦醇作用24 h 的 120、150 μmol·L^-1 组 ，48 h 的 60、90、120、150 μmol·L^-1 组 ，72 h 的 30、60、90、120、150 μmol·L^-1组，96、120 h的15、30、60、90、120、150 μmol·L^-1组细胞存活率显著下降（P＜0.01、0.001）。结论 白藜芦醇对膀胱癌细胞的抑制作用呈浓度、时间相关性，其温敏型凝胶剂能够长时间持续释放药物。

Objective To prepare resveratrol temperature-sensitive gel for the treatment of bladder cancer, which can be administered by bladder perfusion. Methods Using the lowest gelation temperature and dissolution time as indicators, the optimal gel formula was selected, the microscopic structure of the gel was observed by scanning electron microscope (SEM), and the compatibility of the gel matrix with the drug was observed by Fourier transform infrared spectroscopy (FTIR), the in vitro release behavior of the gel was examined by dissolution tester, the migration and proliferation of MB49-LUC mouse bladder cancer cells were examined by scratch test and MTT assay with resveratrol concentration and action time as variables. Results The optimal gel formula was resveratrol 30%, polyoxyethylene sorbitan monolaurate 407 19%, polyoxyethylene sorbitan monooleate 188 7%, alginic acid 0.3%, calcium carbonate 0.06%, and ammonium bicarbonate 0.2%, SEM results showed that the gel had a loose and porous three-dimensional network structure, FTIR showed no significant change in the functional group structure of the gel material, indicating good compatibility, the drug was slowly released from the floating gel, with a cumulative release of 50.37% within 80 days, and a total drug release of 135.58 mg. The scratch test showed that compared with the control group, resveratrol concentrations of ≥ 60 μmol·L^-1 could significantly inhibit the migration of MB49-LUC cells (P <0.05), the MTT assay showed that compared with the control group, the 120, 150 μmol·L^-1 groups at 24 h of resveratrol action, the 60, 90, 120, 150 μmol·L^-1 groups at 48 h, the 30, 60, 90, 120, 150 μmol·L^-1 groups at 72 h, and the 15, 30, 60, 90, 120, 150 μmol·L^-1 groups at 96, 120 h had significantly lower cell viability (P <0.01, 0.001). Conclusion The inhibitory effect of resveratrol on bladder cancer cells is dose-dependent and time-dependent. With the long-lasting drug release capacity of temperature-sensitive gel, resveratrol temperature-sensitive gel has obvious inhibitory effect on bladder cancer cells.

R945

贵州省基础研究计划（黔科合基础—ZK［2021］一般524）；贵州省卫健委科学技术基金项目（gzwkj2022—233）