姜黄素多肽小分子水凝胶的制备及性能研究

Curcumin, a kind of liposoluble phenolic pigments that extracted from Traditional Chinese Medicine turmeric rhizome, possesses the properties of broad anti-cancer spectrum and high anti-cancer activity, which has been included in the third generation of cancer prevention drugs by the U.S. National Cancer Institute. But some limitations such as poor water solubility, easy oxidation in vitro, and low bioavailability etc. severely hinder the clinical application of curcumin. Our previous work have found that anti-cancer drugs based molecular hydrogel not only has versatile property of high loading weight percentages of drug molecules (>60wt%), no needing drug carrier, good water solubility for hydrophobic drugs, but also could be sustained release without rapid degradation. And in view of the multi-target and multi-effect characteristics of curcumin, in this proposal, we will prepare a novel self-delivery system based on the curcumin peptide molecular hydrogel which expect to hold the properties of good stability, high loading weight percentages of drug molecules, long detention time in vivo and excellent targeting and specificity for the tumor tissue. We then test the chemical structure, assembled morphology, drug release properties and tissue distribution of the novel curcumin delivery systems, so as to optimize for the best formulations. After this, we will then carry out the vitro and in vivo experiments to observe the therapeutic effect on the tumor. This project is expected to provide new ideas for the design and development of the novel curcumin based anti-tumor drug delivery system.

姜黄素是从中药姜黄的根茎中提取出来的一种脂溶性酚类色素，抗癌谱广，抗肿瘤活性明确，已被美国国立肿瘤所列入第三代癌化学预防药物。但因难溶于水，在体外容易被氧化，生物利用度低等缺陷，严重限制了姜黄素的临床应用。课题组前期工作发现，由抗癌药物衍生物自组装而成的小分子水凝胶具有不需要载体、药物包载率高（大于60 wt%）、能提高疏水药物水溶性、防止药物体内的快速降解、药物释放过程是一种缓释不易出现突释等优点和特点。基于姜黄素增敏剂的多靶点和多效能特性，本课题拟发展一类载药量高、体内驻留时间长、稳定性好、对肿瘤组织具有靶向特异性的新型姜黄素小分子水凝胶传输体系，并对该药物体系的成胶因子化学结构、组装体形貌、释放性能及组织分布等方面进行测试，不断优化以获得最佳新剂型；通过体外细胞实验和在体动物实验等观察其对肿瘤的治疗效果，从而为姜黄素新型高效低毒抗肿瘤给药系统的设计和开发提供新思路。

本项目研究主要针对抗肿瘤候选药物姜黄素现有剂型的缺陷及在临床应用中受到的限制，拟开发出毒副作用较小的新剂型，获得新型姜黄素药物分子组成的缓释体系，然后通过体内、外实验对该体系进行全面的毒理和药效学评估。该体系既能克服目前姜黄素水溶性差、在体外易被氧化及生物利用度低等缺陷，同时还可作为药物载体结合其它化疗药物（姜黄素和紫杉醇共自组装的小分子水凝胶，Curcumin-紫杉醇-SMHs），提供联合用药便利以提高化疗疗效，在各种晚期癌症的治疗具有潜在应用价值。. 在项目资助下，课题组通过二硫键还原酶促成胶法制备了姜黄素水凝胶、Curcumin-紫杉醇-水凝胶。体外抗癌细胞活性研究证实，姜黄素水凝胶更有利于细胞摄取、细胞毒性小；酶促成胶法的实验结果进一步证实我们设计的紫杉醇两亲性药物前体分子在癌细胞周围原位自组装形成纳米纤维比相应的药物水凝胶因子能够更加有效的抑制癌细胞生长。我们还发展了姜黄素-紫杉醇复合水凝胶，一种新型的基于两种抗癌药物的水凝胶药物传输体系，这种双抗癌药物传输体系表现出了更加优异的癌细胞抑制效果，实现了协同抗癌作用。. 发表了4篇SCI，最高影响因子12.12分，同时申请了2项中国发明专利，培养了1名硕士，2名博士毕业。