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: 9197096
• 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/9197096
• 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; 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; Hematoxylin and Eosin Staining Method; 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.

虽然新的治疗方法，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，这些药物的用途 治疗仍然受到需要更有效的递送方法的阻碍。原因是这些 治疗剂具有短的半衰期，不或几乎不穿过血视网膜屏障（BRB），并且可引起毒性 以及高剂量的副作用纳米颗粒在跨生物屏障运输药物方面显示出巨大的前景， 降低药物清除率，提高靶点药物的生物利用度。然而，没有纳米颗粒具有 已经被开发出来可以有效地将药物输送到整个BRB。该项目的长期目标是开发 新型纳米颗粒，用于长期释放治疗剂穿过BRB以治疗视网膜疾病。立即 目的是开发独特的结膜下可注射的、温敏的和可生物降解的纳米凝胶， 水负载，增强稳定性和BRB渗透性，并持续释放蛋白质药物，以治疗早期 糖尿病视网膜病变为了这个特定的目标，我们将使用胰岛素作为模型蛋白质药物进行开发 因为胰岛素是内皮细胞和神经细胞的存活因子， 在视网膜功能中起着重要作用。该提案的假设是，结膜下注射 具有亲水性、疏水性、电荷含量和水解降解的定制平衡的纳米凝胶 性质，可以作为有效的局部递送系统平台，用于持续释放治疗剂， 胰岛素穿过BRB以保护视网膜细胞免于凋亡并改善糖尿病中的血管渗漏。三 具体的目的是：1）用于水负载的纳米凝胶的体外优化和表征，增强 稳定性和胰岛素的持续释放; 2）纳米凝胶的体外和离体优化和表征 用于增强胰岛素穿过巩膜和BRB的渗透性;和3）体外生物效应，和体内生物效应， 结膜下注射的负载胰岛素的纳米凝胶的药代动力学和生物效应评价。拟议 纳米凝胶在物理化学、生物学、临床和合作方面具有创新性， 眼周药物递送平台，其用于增强药物穿过BRB的渗透性并实现长期给药 本发明提供了一种用于治疗糖尿病视网膜病变和其它视网膜疾病的药物组合物。