生物黏附型结肠靶向5-FU/癸酸钠微球用于门脉缓释化疗的研究

Intraportal venous chemotherapy (IPVC) probably leads to multiple catheter-related complications. Recent efforts, including ours, suggest that the colon has the characteristic of homogenous drug reservoir and colon-targeted drugs exhibit systemic sustained release at a low level. Moreover, we found the certain sustained release in portal venous system by the administration of oral colon-specific drug delivery system (OCDDS), but it should be further improved. Based on the former researches, incorporated with the colonic absorption enhancer sodium caprate, this study will be undertaken to synthesize and screen out carboxymethyl chitosan/sodium alginate microspheres loaded with 5-fluorouracil (5-FU) and sodium caprate characterized by certain potential colon-specific delivery in vitro, and then evaluate the property of colon-specific delivery and sustained release in portal venous system in rats. Considering the recent work that the incorporation of colonic mucoadhesion allows more consistent colonic mucosal uptake of colon-targeted drugs, the study will further synthesize wheat germ agglutinin-conjugated carboxymethyl chitosan/sodium alginate microspheres for local colon delivery of 5-FU and sodium caprate, and evaluate whether sustained-release profile in portal venous system could be further optimized in rats. The present investigation will offer new ideas for the sustained-release chemotherapy in portal venous system by oral administration and thus provide an alternative route of administration to conventional IPVC (or as a beneficial supplement to it), and meanwhile bring about new clinical implications for OCDDS.

门静脉置管化疗存在与导管相关的诸多问题。近年研究（包括我们）提示结肠具有类似于"均质储药库"的特征，靶向结肠的药物呈现低水平的全身缓释性；而我们还发现，经口服结肠靶向释药系统给药也具有一定的门脉缓释性，但仍须大力优化。本项目拟在以往研究基础上，添加结肠粘膜促吸收剂癸酸钠，构建并筛选具有结肠靶向释药潜能的负载5-FU及癸酸钠的羧甲基壳聚糖/海藻酸钠微球，大鼠体内实验考察其结肠靶向性同时重点观察能否优化其门脉缓释性。鉴于新近研究提示生物粘附性修饰有利于其靶向药物更为恒定的结肠吸收，本项目拟进一步构建麦胚凝集素介导的粘附型结肠靶向5-FU/癸酸钠微球，大鼠体内观察能否进一步优化其门脉缓释性。本项目的成功实施，预期将为经口服途径给药进行门脉缓释化疗提供新思路，从而为常规"门脉化疗"提供另一可供选择的给药途径（或者成为它的有益补充）；同时也拓宽"结肠靶向系统"的应用范畴。

门静脉置管化疗存在与导管相关的诸多问题。近年研究提示结肠具有类似于“均质储药库”的特征，靶向结肠的药物呈现低水平的全身缓释性；而我们还发现，经口服结肠靶向释药系统给药也具有一定的门脉缓释性，但仍须大力优化。本项目在前期研究基础上，构建并筛选具有结肠靶向释药潜能的5-FU微囊包衣片。用正交试验摸索获得5-FU缓释微囊的最佳制备工艺，微囊的载药率为16.03%，微囊外观圆整，83%粒径在100~136μm。微囊通过压片制备5-FU微囊片，体外模拟结肠溶出度实验显示其有一定的缓释效果：在0.5h、1h、2h、4h、6h、8h、10h、12h、24h的释放度分别为17.9%、18.2%、19.7%、24.7%、36.5%、42.6%、48.8%、59.5%、81.2%，但是微囊片的结肠靶向性差。微囊片结肠靶向通过包衣获得，证实包衣增重14%（记为A）体外有较好的结肠靶向性，其在模拟胃酸和小肠液累计的释放率为3.5%。用A片剂进一步做大鼠体内药代动力学实验,动物为SD大鼠，灌胃给药，剂量为25mg/kg,分别于灌胃后0.5h, 1h,2h,4h,8h,12h,16h,23h,26h,30h行眼球和门静脉取血2mL，高效液相测定5-FU血药浓度。结果显示：口服A后8h门脉达到最大血药浓度（980±16ng/mL），且在6-20h内能保持较高的门脉血药浓度（>650ng/mL），证实了其有结肠靶向及门脉缓释性。而外周血8h也达到最大血药浓度(453±31ng/mL)，但是在整个体内过程始终保持较低且比较均衡的浓度(～400ng/mL)，这在用于口服门脉缓释化疗时可大大降低外周的毒性。本项目的成功实施，预期将为经口服途径给药进行门脉缓释化疗提供新思路，从而为门静脉置管化疗IPVC提供另一可供选择的给药途径（或者成为它的有益补充）；同时也拓宽OCDDS的临床应用范畴。