目的 制備用于治療膀胱癌、可經(jīng)膀胱灌注給藥的白藜蘆醇溫敏型凝膠劑。方法 以最低膠凝溫度、溶蝕時(shí)間為指標(biāo)，篩選凝膠處方；通過(guò)掃描電鏡（SEM）觀察凝膠的微觀結(jié)構(gòu)，通過(guò)傅里葉變換紅外光譜（FTIR）觀察凝膠基質(zhì)與藥物的相容性，溶出度測(cè)定儀考察凝膠的體外釋放行為；體外培養(yǎng)小鼠膀胱癌細(xì)胞（MB49-LUC），劃痕實(shí)驗(yàn)和MTT實(shí)驗(yàn)考察白藜蘆醇濃度、作用時(shí)間對(duì)膀胱癌細(xì)胞遷移和增殖的影響。結(jié)果 凝膠的最優(yōu)處方為白藜蘆醇30%、泊洛沙姆407 19%、泊洛沙姆188 7%、海藻酸鈉 0.3%、碳酸鈣 0.06%、NH₄HCO₃ 0.2%；SEM顯示凝膠呈疏松多孔的三維網(wǎng)狀結(jié)構(gòu)，F(xiàn)TIR顯示凝膠材料官能團(tuán)結(jié)構(gòu)無(wú)明顯改變，相容性良好；藥物從漂浮凝膠中緩慢釋放，80 d 內(nèi)累積釋放 50.37%，藥物釋放量達(dá) 135.58 mg。劃痕實(shí)驗(yàn)顯示，與對(duì)照組相比，白藜蘆醇≥60 μmol·L^-1可顯著抑制MB49-LUC細(xì)胞的遷移（P＜0.05）；MTT實(shí)驗(yàn)顯示，與對(duì)照組比較，白藜蘆醇作用24 h 的 120、150 μmol·L^-1 組 ，48 h 的 60、90、120、150 μmol·L^-1 組 ，72 h 的 30、60、90、120、150 μmol·L^-1組，96、120 h的15、30、60、90、120、150 μmol·L^-1組細(xì)胞存活率顯著下降（P＜0.01、0.001）。結(jié)論 白藜蘆醇對(duì)膀胱癌細(xì)胞的抑制作用呈濃度、時(shí)間相關(guān)性，其溫敏型凝膠劑能夠長(zhǎng)時(shí)間持續(xù)釋放藥物。

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

貴州省基礎(chǔ)研究計(jì)劃（黔科合基礎(chǔ)—ZK［2021］一般524）；貴州省衛(wèi)健委科學(xué)技術(shù)基金項(xiàng)目（gzwkj2022—233）