Sustained Ocular Drug Delivery System for Anti-VEGF Agents

抗 VEGF 药物持续眼部给药系统

基本信息

批准号：
10307325
负责人：
JENNIFER J Kang-Mieler
金额：
$ 5.23万
依托单位：
ILLINOIS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307325
关键词：
Age related macular degeneration Animals Aqueous Humor Biocompatible Materials Biodegradable microsphere Blood Vessels Blood flow Bolus Infusion Cataract Choroidal Neovascularization Clinical Clinical Research Data Dexamethasone Diabetic Retinopathy Disease Drug Delivery Systems Drug Kinetics Drug Side Effects Electroretinography Emulsions Endophthalmitis Endothelial Cells Enzyme-Linked Immunosorbent Assay Exposure to Eye Family member Fluorescein Angiography Fundus photography Goals Gold Healthcare Systems Hemorrhage Histologic Histology Hydrogels Image Inflammation Injectable Injection of therapeutic agent Injections Kinetics Knowledge Lasers Macaca mulatta Measurement Measures Methods Microspheres Mitogens Modeling Monitor Morphology Needles Ophthalmic examination and evaluation Ophthalmoscopes Optical Coherence Tomography Patients Pharmaceutical Preparations Pharmacology Posterior eyeball segment structure Primates Regimen Retina Retinal Detachment Retinal Perforations Rodent Rodent Model Safety Scanning Site Sterility Techniques Technology Therapeutic Effect Time Translations VEGFA gene Vascular Endothelial Growth Factors Vascular Permeabilities angiogenesis base bevacizumab biomaterial compatibility clinical practice comparative efficacy conventional therapy drug release kinetics imaging modality in vitro Model intravitreal injection nonhuman primate ranibizumab release factor response sample collection side effect slit lamp imaging standard care

项目摘要

Project Summary Recently employed intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is a promising treatment for the wet form of age-related macular degeneration with choroidal neovascularization (CNV) and diabetic retinopathy. In fact, the anti-VEGF therapy has become a gold standard for these diseases. While the therapeutic effects are positive, a major drawback is that this treatment must be repeated every four to six weeks. The repetitive treatment burden on the patients, family members, and clinicians is substantial. Recently, we have developed a biodegradable microspheres, thermo-responsive hydrogel ocular drug delivery system (DDS). Biodegradable microspheres are produced using our modified double emulsion technique providing a better microenvironment for pharmacological agents. The biodegradable thermo-responsive hydrogel is a safe, effective, and injectable biomaterial that is used to confine the microspheres to a specific delivery site. We have previously demonstrated a controlled sustained release of anti-VEGF for a period of 6 months with excellent safety profiles. The overall goal of this proposal is to quantitatively evaluate the safety and efficacy of our proposed DDS in a non-human primate model and compare to the conventional therapy. Our hypothesis is that a sustained controlled anti-VEGF release over a prolong period of ~6 months, will be as effective, if not more effective, as the conventional therapy. The Specific Aim 1 is to determine ocular pharmacokinetics (PK) of aflibercept released from DDS in a non-human primate (NHP) model. The Specific Aim 2 to determine biocompatibility of DDS in a NHP model. The Specific Aim 3 is to quantitatively compare the efficacy and bioactivity of the proposed DDS to the conventional therapy in its ability to suppress angiogenic responses in CNV model. The Specific Aim 4 is to measure long-term potential side effects, if any, of the proposed DDS and exposure of anti-VEGF in a rodent model. The Specific Aim 5 is to quantitatively evaluate the drug release kinetics and bioactivity of the dual-drug release DDS. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment of the eye. We believe that our drug delivery system will fill this critical clinical need. The knowledge gained in this proposal will bring this technology one step closer to translation into the clinical practice and will have a significant impact on the current healthcare system.

项目概要最近采用的玻璃体内抗血管内皮生长因子（抗 VEGF）疗法是一种有前途的疗法治疗伴有脉络膜新生血管（CNV）的湿性年龄相关性黄斑变性和糖尿病视网膜病变。事实上，抗VEGF疗法已成为这些疾病的金标准。虽然治疗效果是积极的，一个主要缺点是这种治疗必须每四到六次重复一次几周。患者、家属和临床医生的重复治疗负担是巨大的。最近，我们开发了一种可生物降解的微球、热响应水凝胶眼部药物递送系统（DDS）。可生物降解的微球是使用我们改良的双乳液技术生产的为药物制剂提供更好的微环境。可生物降解的热响应水凝胶是一种安全、有效、可注射的生物材料，用于将微球限制在特定的范围内。交货地点。我们之前已经证明了抗 VEGF 的受控缓释时间为 6 小时。几个月的时间，具有出色的安全性。该提案的总体目标是定量评估安全性以及我们提出的 DDS 在非人类灵长类动物模型中的疗效，并与传统疗法进行比较。我们的假设是，在约 6 个月的较长时间内持续受控的抗 VEGF 释放将与与传统疗法一样有效，甚至更有效。具体目标 1 是确定眼部在非人灵长类动物 (NHP) 模型中从 DDS 释放的阿柏西普的药代动力学 (PK)。具体目标 2 确定 DDS 在 NHP 模型中的生物相容性。具体目标 3 是定量比较所提出的 DDS 相对于传统疗法的功效和生物活性，能够抑制 CNV 模型中的血管生成反应。具体目标 4 是衡量长期潜在副作用（如果有），所提出的 DDS 和在啮齿动物模型中暴露抗 VEGF 的结果。具体目标 5 是定量评估双药物释放 DDS 的药物释放动力学和生物活性。临床广泛使用抗 VEGF 药物需要一种实用且有效的递送方法至眼后段。我们相信我们的药物输送系统将满足这一关键的临床需求。通过本提案获得的知识将使这项技术更接近转化为临床实践，并将具有重大意义对当前医疗体系的影响。