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

基本信息

批准号：
10000203
负责人：
Tao L Lowe
金额：
$ 38.63万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000203
关键词：
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 Injections 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 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 side effect

项目摘要

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（Avastin）、雷珠单抗（Lucentis）和生长因子，正在被开发出来。开发用于治疗视网膜疾病，例如糖尿病视网膜病变和黄斑变性，使用这些由于需要更有效的递送方法，治疗仍然受到阻碍。原因就在于这些治疗药物半衰期短，不能或几乎不能穿过血视网膜屏障（BRB），并且可能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输药物方面显示出巨大的前景，降低药物清除率，提高药物在靶标处的生物利用度。然而，没有纳米粒子尚未开发出能够有效地跨 BRB 输送药物的药物。该项目的长期目标是开发新型纳米粒子，用于通过 BRB 长期释放治疗药物来治疗视网膜疾病。即时的目标是开发独特的结膜下注射、热响应和可生物降解的纳米凝胶水载量、增强稳定性和 BRB 通透性、持续释放蛋白药物以治疗早期糖尿病视网膜病变。为了这个具体目标，我们将使用胰岛素作为模型蛋白药物来进行开发纳米凝胶药物递送平台，因为胰岛素是内皮细胞和神经细胞的生存因子，并且在视网膜功能中发挥重要作用。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平衡的纳米凝胶特性，可以作为持续释放治疗药物的有效局部递送系统平台，例如胰岛素穿过 BRB 可保护视网膜细胞免于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，增强胰岛素的稳定性和持续释放； 2）纳米凝胶的体外和离体优化和表征增强胰岛素在巩膜和 BRB 的渗透性； 3) 体外生物效应和体内生物效应结膜下注射胰岛素纳米凝胶的药代动力学和生物效应评价。拟议的纳米凝胶在物理化学、生物学、临床和协作方面都具有创新性，并将提供一种新颖的眼周药物递送平台，用于增强BRB的药物渗透性并实现长期药物视网膜中的生物利用度可治疗糖尿病性视网膜病和其他视网膜疾病。