Nanogels for Drug Delivery across the BRB to Treat Diabetic Retinopathy

纳米凝胶通过 BRB 输送药物治疗糖尿病视网膜病变

• 批准号: 9329464
• 负责人: Tao L Lowe
• 金额: $ 38万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329464
• 关键词: Adverse effects; Animals; Apoptosis; Avastin; Biochemical; Biological; Biological Assay; Biological Availability; Blood Vessels; Blood-Retinal Barrier; CASP3 gene; Cell membrane; Cells; Charge; Choroid; Clinical; Crosslinker; DNA Fragmentation; Data; Diabetes Mellitus; Diabetic Retinopathy; Dose; Drug Delivery Systems; Drug Kinetics; Drug Transport; Encapsulated; Endothelial Cells; Equilibrium; Evaluation; Extravasation; Face; Family suidae; Goals; Growth Factor; Histology; Human; Hydrogels; Hydrophobicity; Implant; In Vitro; Injectable; Injection of therapeutic agent; Insulin; Insulin, Lispro, Human; Kinetics; Length; Lucentis; Macular degeneration; Measures; Methods; Microglia; Modeling; NanoGel; Nanotechnology; Neurons; Particle Size; Permeability; Pharmaceutical Preparations; Physiological; Play; Polyesters; Process; Property; Proteins; Rattus; Retina; Retinal; Retinal Diseases; Role; Sclera; Series; Structure of retinal pigment epithelium; Surface; System; Technology; Therapeutic; Therapeutic Uses; Tight Junctions; Tissues; Toxic effect; Toxicology; Translating; Translational Research; Water; Work; aqueous; bench to bedside; diabetic rat; drug clearance; drug development; fetal; glial activation; hydrophilicity; improved; in vivo; innovation; mathematical model; minimally invasive; nanoparticle; neuron apoptosis; novel; novel therapeutics; occludin; retinal neuron

While new therapeutics, especially protein drugs such as Avastin, Lucentis and growth factors, are being developed for treating retinal diseases, such as diabetic retinopathy and macular degeneration, the use of these therapeutics is still hampered by the need for more effective method of delivery. The reason is that these therapeutics have short half-lives, do not or hardly cross the blood retinal barrier (BRB), and can cause toxicity and side effects at high dose. Nanoparticles show great promise for transporting drugs across biological barriers, reducing drug clearance, and improving the bioavailability of drugs at targets. However, no nanoparticles have been developed to effectively deliver drugs across the BRB yet. The long-range goal of this project is to develop novel nanoparticles for long-term release of therapeutics across the BRB to treat retinal diseases. The immediate objective is to develop unique subconjunctivally injectable, thermoresponsive and biodegradable nanogels for aqueous loading, enhanced stability and BRB permeability, and sustained release of protein drugs to treat early diabetic retinopathy. For this specific objective, we will use insulin as a model protein drug for the development of the nanogel drug delivery platform because insulin is a survival factor for endothelial and neural cells, and plays an important role in retinal function. The hypothesis of the proposal is that subconjunctivally injectable nanogels with tailored balance of hydrophilicity, hydrophobicity, charge content and hydrolytic degradation properties, can act as an effective local delivery system platform for sustained release of therapeutics such as insulin across the BRB to protect retinal cells from apoptosis and improve vascular leakage in diabetes. Three specific aims are: 1) in vitro optimization and characterization of nanogels for aqueous loading, enhanced stability, and sustained release of insulin; 2) in vitro and ex vivo optimization and characterization of nanogels for enhanced insulin permeability across the sclera and the BRB; and 3) in vitro bioeffect, and in vivo pharmacokinetics and bioeffect evaluations of subconjunctivally injected insulin-loaded nanogels. The proposed nanogels are physicochemically, biologically, clinically and collaboratively innovative, and will provide a novel periocular drug delivery platform for enhancing drug permeability across the BRB and achieving long-term drug bioavailability in the retina to treat diabetic retinopathy and other retinal diseases.

与此同时，新的治疗方法，特别是蛋白质药物，如阿瓦斯丁、Lucentis和生长因子，正在被 开发用于治疗视网膜疾病，如糖尿病视网膜病变和黄斑变性，使用这些 治疗仍然受到需要更有效的递送方法的阻碍。原因是这些 治疗药物的半衰期很短，不会或几乎不会穿过血视网膜屏障(BRB)，并且可能会引起毒性 以及高剂量时的副作用。纳米颗粒在跨越生物屏障运送药物方面显示出巨大的前景， 减少药物清除，提高药物在靶点的生物利用度。然而，没有纳米颗粒具有 已经被开发出来，可以有效地在整个BRB中运送药物。这个项目的长远目标是发展 新的纳米颗粒用于在整个BRB治疗视网膜疾病的治疗药物的长期释放。最直接的 目的是开发独特的结膜下注射、热响应性和可生物降解的纳米凝胶 水负载、增强的稳定性和BRB通透性，以及用于早期治疗的蛋白质药物的持续释放 糖尿病视网膜病变。为了这个特定的目标，我们将胰岛素作为蛋白质药物的模型进行开发 由于胰岛素是内皮细胞和神经细胞的生存因素，所以纳米凝胶药物传递平台的重要性 在视网膜功能中起着重要作用。该建议的假设是结膜下注射 具有亲水性、疏水性、电荷含量和水解性平衡的纳米凝胶 性质，可作为有效的局部递送系统平台，用于治疗药物的持续释放，如 胰岛素通过BRB保护视网膜细胞免受凋亡，并改善糖尿病患者的血管渗漏。三 具体目标是：1)用于水负载的纳米凝胶的体外优化和表征，增强的 胰岛素的稳定性和缓释；2)纳米凝胶的体内外优化和表征 用于增强胰岛素通过巩膜和BRB的渗透性；以及3)体外生物效应和体内 胰岛素纳米凝胶结膜下注射的药代动力学及生物效应评价。建议数 纳米凝胶在物理化学、生物、临床和协作方面都是创新的，并将提供一种新颖的 增强药物透过BRB并实现长期给药的眼周给药平台 用于治疗糖尿病视网膜病变和其他视网膜疾病的视网膜生物利用度。