仿生纳米乳调控肿瘤hedgehog通路治疗胰腺癌的研究

Extensive extracellular matrix fibrosis of pancreatic cancer has seriously hindered the application of nano-drug delivery system in the treatment of pancreatic cancer, and it is urgent to establish a more rational and effective pancreatic cancer drug delivery system. In this project, cyclopamine, the inhibitor of Hedgehog pathway of Pancreatic fibrosis, and gemcitabine，an angent for pancreatic cancer therapy, are encapsulated in erythrocyte membrane-camouflaged nanoemulsions to combine biomimetic nano-drug delivery system and pancreatic cancer microenvironment regulation for the treatment of pancreatic cancer. Compared with traditional nano-drug delivery system, this new system achieved much longer blood circulation time. By inhibiting desmoplastic stroma formation, large amounts of biomimetic nanoemulsions could enter tumor blood vessles, penetrate the extracellular matrix, and finally reach the tumor cells, accomplishing more effective tumor drug delivery. This therapeutic strategy and the constructing mode of biomimetic nanoemulsions system have never been reported in domestic and abroad, which present high-level research value and innovation significance.The results of this project can also provide relevant research methods and experimental reference for the treatment of other cancers, with high significance and social benefits.

胰腺癌的基质广泛纤维化严重阻碍了纳米递药系统在胰腺癌治疗中的应用，设计更为合理、有效的胰腺癌递药系统具有重要的研究价值和应用前景。本项目将针对胰腺癌纤维化的Hedgehog通路抑制剂环巴胺和抗胰腺癌药物吉西他滨包载在红细胞膜包被的纳米乳剂中，将仿生纳米递药系统与胰腺癌的微环境调控巧妙地结合起来。与传统的纳米递药系统相比，该系统具有更长的血液循环时间，通过抑制肿瘤的纤维化，仿生纳米乳大量到达肿瘤血管内并穿过基质到达肿瘤细胞，实现更为有效的肿瘤细胞递药。该治疗策略及仿生纳米递药系统的构建模式目前国内外未见报道，具有较高的创新意义。本项目的研究结果也可为其它肿瘤治疗提供相关的研究方法和实验参考，具有较高的研究意义和社会效益。

胰腺癌的基质广泛纤维化严重阻碍了纳米递药系统在胰腺癌治疗中的应用，设计更为合理、有效的胰腺癌递药系统具有重要的研究价值和应用前景。本项目将针对胰腺癌纤维化的特异性Hedgehog通路抑制剂环巴胺和抗胰腺癌药物吉西他滨包载在红细胞膜包被的纳米乳剂中，将仿生纳米递药系统与胰腺癌的微环境调控巧妙地结合起来。与传统的纳米递药系统（4 h-24 h）相比，该仿生纳米乳的血中平均滞留时间长达2天以上。将环巴胺载入仿生纳米乳，可显著抑制肿瘤内hedgehog信号通路关键蛋白GLI-1基因mRNA和蛋白的表达，使肿瘤内纤维化基质表达下降50%以上。通过抑制肿瘤的纤维化，不仅解除了纤维化基质对肿瘤血管的挤压，显著增加了瘤内的血流灌注（1.8倍）和仿生纳米乳的瘤内蓄积（2.5倍），而且显著增加了载药仿生纳米乳的瘤内穿透深度，实现更为有效的肿瘤细胞递药。药效学实验表明，在所有治疗组中，载环巴胺仿生纳米乳联合载吉西他滨仿生纳米乳组具有最小的肿瘤体积和最长的生存期。上述结果表明，采用仿生纳米乳递送肿瘤微环境调控药物和抗肿瘤药物的策略，可以很好地调控胰腺癌微环境，提高抗肿瘤药物的瘤内递送和治疗效果。该研究结果也为其它肿瘤治疗提供相关的研究方法和实验参考，具有较高的研究意义和社会效益。