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是血视网膜屏障通透性增加，细胞凋亡导致视网膜神经元加速损失。胰岛素是已知的内皮细胞和神经细胞的存活因子，在视网膜功能中起重要作用。我们的初步研究表明，胰岛素可使视网膜神经元细胞免于凋亡，并且全身、玻璃体内和结膜下注射胰岛素可激活促存活胰岛素受体和Akt激酶。然而，注射胰岛素只有暂时的活性，低血糖限制了患者服用足够的胰岛素以减少视网膜病变风险的能力。在设计糖尿病视网膜病变的临床治疗时，持续向视网膜释放胰岛素可以增强全身胰岛素的作用，而不会有低血糖的风险。该项目的总体目标是开发新的药物输送系统，用于长期释放治疗药物，以预防和治疗糖尿病视网膜病变。该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一种新的递送系统，用于持续递送胰岛素，以保护糖尿病患者的视网膜细胞。两个具体目标是：1)体外优化和表征热响应和可生物降解的胰岛素缓释水凝胶；2)体外和体内评价载胰岛素结膜下植入水凝胶对视网膜的毒性和疗效。该项目具有创新性，将为如何生成先进的生物材料以控制胰岛素等治疗药物的释放提供临床相关数据，用于治疗糖尿病视网膜病变和其他视网膜疾病。这也将帮助我们对糖尿病中凋亡细胞死亡和血管通透性增加的机制获得重要的见解。糖尿病视网膜病变是糖尿病损害视网膜的潜在致盲并发症。本转化研究的眼部给药发明将为预防或治疗1型糖尿病早期糖尿病视网膜病变提供有效和微创的眼部治疗。

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.