基于葛根素小分子水凝胶眼部给药体系的构建及其性能研究

Natural drugs such as puerarin in the treatment of ocular diseases have received extensive attentions recently. The application of traditional eye drops is limited due to their low bioavailability, short retaining time, and poor targeting performance. In-situ injectable hydrogel, as a kind of novel drug administration, have shown great scientific research value and application prospect in recent years. Compared with polymers, injectable self-assembling molecule hydrogels have shown a lot of advantages, including biocompatibility, facile synthesis and easy modification etc. Our previous work have found that the drug-peptide conjugation forming hydrogel precursors possess the characteristics of high drug loading, carrier-free and syringeability, and therefore having shown excellent results for the antineoplastic and glucocorticoids based molecular hydrogel drug delivery systems in the treatment of animal disease models. Combined with the good effect of the puerarin on the eye disease and our intensive study of the pharmacology, pharmacokinetics, and dosage forms of puerarin, this project plan to build novel puerarin molecule hydrogel drug delivery systems, and then to evaluate their biocompatibility and pharmacokinetics, and sequently to observe their effect on the treatment of glaucoma, retinal disease and other animal disease models. We imagine that the puerarin molecular hydrogel delivery systems could provide us another choice when treating ophthalmic diseases.

葛根素作为治疗眼科疾病的天然药物近年来受到广泛关注，传统的溶液滴眼剂给药方式往往存在药物滞留时间短、生物利用度低及难以到达靶治疗区等缺点。水凝胶因与角膜组织亲和性强，滞留时间长而成为极具应用前景的眼部缓释载体。自组装多肽小分子水凝胶以其优良的生物相容性、合成简便、易于修饰等优点而备受青睐。课题组在前期研发了一系列小分子水凝胶并发现该体系药物连接短肽形成的成胶前体因子具有载药高、无需载体、水溶性好、可控缓释等特点，已在抗肿瘤、糖皮质激素类等药物控释方面取得了良好效果。结合我们前期在传统中药葛根素的药理、药代动力学和其剂型改造等方面的研究基础，本课题组拟构建基于多肽小分子水凝胶的葛根素眼部递送体系，研究该体系的成胶因子化学结构、组装体形貌、释放性能、离体角膜渗透及其在体眼部组织分布等性能，并在青光眼、视网膜血管病等动物疾病模型上验证其疗效，为葛根素小分子水凝胶给药体系在眼科疾病的应用拓展思路。

传统的溶液滴眼剂存在的共性问题是在结膜囊内滞留时间很短、药物难透过角膜、眼内生物利用度很低等问题。所以增加药物与角膜的接触时间以及改善角膜通透性十分重要。近年来，葛根素作为治疗眼科疾病的天然药物受到广泛关注。课题组在前期研发了一系列小分子水凝胶并发现该体系药物连接短肽形成的成胶前体因子具有载药高、无需载体、水溶性好、可控缓释等特点。结合我们前期在传统中药葛根素的药理、药代动力学和其剂型改造等方面的研究基础，课题组拟构建基于多肽小分子水凝胶的葛根素眼部递送体系，研究该体系的成胶因子化学结构、组装体形貌、释放性能等性能，并在葡萄膜炎、视网膜炎的疾病模型上验证其疗效。结果表明，葛根素水凝胶的载药率为100%，在体内外均保持稳定，体外显示葛根素水凝胶无明显的细胞毒性，体内显示葛根素水凝胶较葛根素单体提高3 倍。结果显示，葛根素水凝胶有效改善家兔的葡萄膜炎反应，以及通过激活Wnt 信号通路减轻视网膜色素上皮细胞炎症。本课题为葛根素小分子水凝胶的开发和临床应用提供理论依据，又可望为传统中药眼部给药方式拓展思路。