Hydrogels for Periocular Drug Delivery to Treat Diabetic Retinopathy

描述（由申请人提供）：糖尿病视网膜病变的特征在于血-视网膜屏障的渗透性增加和通过凋亡性细胞死亡加速视网膜神经元的损失。胰岛素是已知的内皮细胞和神经细胞的存活因子，并且在视网膜功能中起重要作用。我们的初步工作表明，胰岛素拯救视网膜神经元细胞凋亡细胞死亡，全身，玻璃体内，和结膜下注射胰岛素激活促生存胰岛素受体和Akt激酶的糖尿病大鼠。然而，注射的胰岛素只有暂时的活性，低血糖限制了患者服用足够胰岛素的能力，以最大限度地降低视网膜病变的风险。在设计糖尿病视网膜病变的临床治疗时，持续释放胰岛素至视网膜可以增强全身胰岛素的作用而不会有低血糖的风险。本项目的总体目标是开发新型药物递送系统，用于长期释放治疗药物，以预防和治疗糖尿病视网膜病变。本项目的目的是开发结膜下可植入的、可生物降解的水凝胶，用于持续释放完整的胰岛素至少两个月，以延缓早期实验性糖尿病视网膜病变的发展和进展。该项目的核心假设是，结膜下可植入的可生物降解的水凝胶可以作为持续递送胰岛素的新型递送系统，以保护糖尿病患者的视网膜细胞。这两个具体目标是：1）用于持续释放胰岛素的热响应性和可生物降解的水凝胶的体外优化和表征;和2）负载胰岛素的结膜下植入的水凝胶对视网膜的毒性和功效的体外和体内评价。该项目具有创新性，将提供临床相关数据，说明如何生成用于控制释放治疗药物（包括胰岛素）的先进生物材料，以治疗糖尿病视网膜病变和其他视网膜疾病。它也将帮助我们获得重要的见解，糖尿病细胞凋亡和血管通透性增加的机制。糖尿病视网膜病变是糖尿病的一种潜在的致盲并发症，会损害视网膜。该转化研究的眼部药物递送发明将提供有效且微创的眼部治疗，以预防或治疗1型糖尿病中的早期糖尿病视网膜病变。

DESCRIPTION (provided by applicant): Diabetic retinopathy is characterized by increased permeability of the blood-retinal barrier and accelerated loss of retinal neurons through apoptotic cell death. Insulin is a known survival factor for endothelial and neural cells, and plays an important role in retinal function. Our preliminary work has demonstrated that insulin rescues retinal neuronal cells from apoptotic cell death, and systemic, intravitreal, and subconjunctival injections of insulin activate pro-survival insulin receptor and Akt kinases of diabetic rats. However, injected insulin has only temporary activities, and hypoglycemia limits the ability of patients to take enough insulin to minimize the risk of retinopathy. In designing clinical treatment for diabetic retinopathy, sustained release of insulin to the retina may augment effects of systemic insulin without risking hypoglycemia. The overall goal of this project is to develop novel drug delivery systems for long-term release of therapeutic agents for the prevention and treatment of diabetic retinopathy. The objective of this project is to develop subconjunctivally implantable, biodegradable hydrogels for sustained release of intact insulin for at least two months to retard the development and progression of early experimental diabetic retinopathy. The central hypothesis underlying this project is that subconjunctivally implantable, biodegradable hydrogels can act as novel delivery systems for sustained delivery of insulin to protect retinal cells in diabetes. The two specific aims are: 1) In vitro optimization and characterization of thermo-responsive and biodegradable hydrogels for sustained release of insulin; and 2) In vitro and in vivo evaluation of the toxicity and efficacy of insulin-loaded, subconjunctivally implanted hydrogels on the retinal. This project is innovative, and will provide clinically relevant data on how to generate advanced biomaterials for controlled release of therapeutics including insulin, for treating diabetic retinopathy and other retinal disorders. It will also help us gain important insights into the mechanism of apoptotic cell death and increased vascular permeability in diabetes. Diabetic retinopathy is a potentially blinding complication of diabetes that damages the retina. The ocular drug delivery inventions of this translational research will provide effective and minimally invasive ocular therapy to prevent or treat early stages of diabetic retinopathy in Type 1 diabetes.