Hydrogels for Periocular Drug Delivery to Treat Diabetic Retinopathy

描述(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，并通过细胞凋亡加速视网膜神经元的丧失。胰岛素是一种已知的内皮细胞和神经细胞的生存因子，在视网膜功能中起着重要作用。我们的初步工作表明，胰岛素可使视网膜神经细胞免于细胞凋亡，全身注射、玻璃体内注射和结膜下注射胰岛素可激活糖尿病大鼠的促生存胰岛素受体和Akt激酶。然而，注射的胰岛素只是暂时的活动，低血糖限制了患者摄取足够的胰岛素以将视网膜病变的风险降至最低的能力。在设计糖尿病视网膜病变的临床治疗时，将胰岛素持续释放到视网膜可能会增强全身胰岛素的效果，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，用于长期释放用于预防和治疗糖尿病视网膜病变的治疗剂。本项目的目标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生和发展。该项目的中心假设是，结膜下可植入的、可生物降解的水凝胶可以作为新型的胰岛素持续输送系统，以保护糖尿病患者的视网膜细胞。这两个具体目标是：1)体外优化和表征用于胰岛素持续释放的温度响应性和生物可降解性水凝胶；以及2)体外和体内评估胰岛素负载的结膜下植入视网膜的水凝胶的毒性和有效性。该项目具有创新性，将提供有关如何产生先进生物材料的临床相关数据，这些材料用于控制释放包括胰岛素在内的治疗药物，用于治疗糖尿病视网膜病变和其他视网膜疾病。这也将有助于我们对糖尿病中细胞凋亡和血管通透性增加的机制有重要的了解。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。这项转化研究的眼部给药发明将提供有效和微创的眼科治疗，以预防或治疗1型糖尿病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.