载药量精准可控的双药物小分子水凝胶在眼底疾病治疗中的应用

Up to now, the anti-angiogenesis drugs (avastin, etc) and anti-inflammatory drugs (diclofenac, etc) were still very important strategies for the clinical treatment of posterior neovascular diseases. Based on our previous studies, we attempted to develop a dual-drugs supramolecular hydrogel based on anti-angiogenesis drugs (avastin, etc) and anti-inflammatory drugs (diclofenac, etc). In this project, the precise and controllable drug loading was achieved by the number of drug molecules grafting onto the peptide. The mechanical property of supramolecular hydrogel was tailored by the self-assembly ability of peptide, yet resulting in the control release of its payload drug. The enhanced in vivo stability was achieved by using unnatural amino acids (D-amino acides) in the supramolecular hydrogel. We believed that the developed dual-drug supramolecular hydrogel could be sustained release of its payload drug realizing both two drugs synergy for treatment of posterior disease via intravitreal administration. The ocular biocompatibility after intravitreal injection of dual-drugs supramolecular hydrogel were systemically studied by ophthalmic examination technologies such as optical coherence tomography (OCT), electroretinography (ERG) and etc. The effect of dual-drugs supramolecular hydrogel on the suppression of posterior neovascular diseases was studied on the rat choroidal neovascularization disease model. We believed that the developed supramolecular hydrogel could provide us another strategy in the treatment of posterior diseases.

抗新生血管药物（阿瓦斯汀等）和抗炎类药物（双氯芬酸等）治疗是目前临床治疗眼底新生血管性疾病的关键策略。本研究基于前期研究结果，拟发展一类基于抗炎类药物（双氯芬酸等）和抗新生血管活性短肽（GNQWFI六肽等）的双药物小分子水凝胶。项目拟通过改变与多肽键合的抗炎类药物分子的个数来实现药物的精确可控定量装载；通过调整多肽的自组装能力调控小分子水凝胶的力学性能进而实现药物的可控释放；采用非天然氨基酸（D构型）调控小分子水凝胶的体内稳定性。期望在玻璃体腔给药之后，能长效缓控释药物作用于病变部位，发挥药物的相互协同作用达到治疗眼底新生血管性疾病的目的。课题组将采用光学相干断层扫描、视网膜电图等眼科技术手段从影像学、组织学以及视觉功能角度系统性评价大鼠玻璃体腔注射双药物小分子水凝胶后的眼组织相容性，测定药物代谢动力学，并在大鼠脉络膜新生血管疾病模型中验证其疗效，为小分子水凝胶最终的眼内应用奠定前期基础。

慢性炎症损伤是众多眼科疾病（包括糖尿病视网膜病变、青光眼、葡萄膜炎等）的常见病因之一。本课题基于前期研究工作基础，拟构建一类基于非甾体抗炎药物（布洛芬）的多功能药物小分子水凝胶体系，期望通过合理的化学结构设计，引入抗氧化化学桥接基团（对羟基苯甲酸、3,5-二羟基苯甲酸）构筑多功能药物小分子水凝胶体系，实现抗炎和抗氧化治疗的协同效应，以增强疾病治疗效果，为眼科相关疾病临床治疗提供新的策略与方法。通过筛选与优化化学桥接基团，我们将抗氧化剂（3,5-二羟基苯甲酸）作为桥接基团，通过生物可降解酯键将甾体抗炎药物与自组装多肽序列（GFFYD）进行化学键合，获得一类多功能药物小分子水凝胶体系。并通过透射电镜、圆二色谱仪、流变仪等完成药物小分子水凝胶的理化性能表征。在脂多糖（LPS）诱导RAW264.7巨噬细胞系的非特异性炎症模型中，我们发现相比于布洛芬原药，所构建的药物小分子水凝胶能通过NF-кB、炎症小体等通路显著抑制相关炎症因子的转录、表达与释放；同时引入的抗氧化结构单元可以提高自由基清除效率和促进抗氧化相关蛋白（Nrf2、HO-1等）表达进一步提高其抗炎疗效。通过眼表给药后，我们发现所构建的药物小分子水凝胶无明显眼刺激性以及具有良好的眼组织相容性，且能够显著延长药物眼表滞留时间，以提高药物生物利用度。采用脂多糖（LPS）诱导兔急性葡萄膜炎模型，我们发现所构建的药物小分子水凝胶能够有效抑制炎症损伤（白细胞/巨噬细胞浸润、血-房水屏障破坏等），且治疗效果优于目前临床常用的0.1%双氯芬酸钠滴眼液。综述，我们所构建的药物小分子水凝胶具有强大的抗炎疗效和良好的眼组织相容性，对于慢性炎症损伤相关的眼科疾病治疗具有重要临床价值。