Hydrogels for Periocular Drug Delivery to Treat Diabetic Retinopathy

用于眼周药物递送的水凝胶治疗糖尿病视网膜病

• 批准号: 7472429
• 负责人: Tao L Lowe
• 金额: $ 1.98万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472429
• 关键词: 2-hydroxyethyl methacrylate; Affect; Albumins; Apoptotic; Biochemical; Biocompatible Materials; Biological; Biological Assay; Biotechnology; Blindness; Blood-Retinal Barrier; Cell Death; Cells; Chemical Structure; Clinical Treatment; Complications of Diabetes Mellitus; Data; Development; Dextrans; Diabetes Mellitus; Diabetic Retinopathy; Diffuse; Doctor of Medicine; Drug Delivery Systems; Drug Kinetics; Electroretinography; Encapsulated; Endothelial Cells; Environment; Evaluation; Eye; Goals; Hematoxylin and Eosin Staining Method; Histology; Hormones; Hydrogels; Hypoglycemia; Impairment; Implant; In Vitro; Injection of therapeutic agent; Insulin; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Invasive; Kinetics; N-isopropylacrylamide; Neuroglia; Neurons; Patients; Permeability; Phosphotransferases; Physiological; Play; Polymers; Prevention; Process; Property; Rate; Rattus; Receptor Signaling; Research; Retina; Retinal; Retinal Diseases; Risk; Role; Sclera; Signal Pathway; Solutions; Sprague-Dawley Rats; Staging; Support System; System; TdT-Mediated dUTP Nick End Labeling Assay; Technology; Testing; Therapeutic; Therapeutic Agents; Tissue Engineering; Tissues; Toxic effect; Translational Research; Vascular Permeabilities; Vision; Water; Work; aqueous; caspase-3; clinically relevant; conjunctiva; controlled release; day; design; desire; dextran; diabetic rat; experience; implantation; improved; in vivo; innovation; insight; mathematical model; neuron apoptosis; novel; prevent; research study; retinal apoptosis; retinal neuron

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.

描述（由申请人提供）：糖尿病视网膜病的特征是血-视网膜屏障的通透性增加以及通过细胞凋亡加速视网膜神经元的损失。胰岛素是内皮细胞和神经细胞的已知生存因子，在视网膜功能中发挥重要作用。我们的初步工作表明，胰岛素可挽救视网膜神经元细胞免于凋亡细胞死亡，并且全身、玻璃体内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，注射胰岛素仅具有暂时的作用，低血糖限制了患者服用足够胰岛素以最大程度降低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，向视网膜持续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。该项目的目标是开发结膜下可植入、可生物降解的水凝胶，用于持续释放完整胰岛素至少两个月，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输送胰岛素的新型输送系统，以保护糖尿病患者的视网膜细胞。这两个具体目标是：1）用于持续释放胰岛素的热响应性和可生物降解水凝胶的体外优化和表征； 2) 结膜下植入的负载胰岛素的水凝胶在视网膜上的毒性和功效的体外和体内评价。该项目具有创新性，将提供有关如何生成先进生物材料用于控制释放治疗药物（包括胰岛素）以治疗糖尿病视网膜病变和其他视网膜疾病的临床相关数据。它还将帮助我们深入了解糖尿病中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致盲并发症，会损害视网膜。这项转化研究的眼部药物递送发明将提供有效的微创眼部治疗，以预防或治疗 1 型糖尿病的早期糖尿病视网膜病变。