Sustained Ocular Drug Delivery System for Anti-VEGF Agents

抗 VEGF 药物持续眼部给药系统

• 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
• 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

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.

项目摘要 最近使用玻璃体内抗血管内皮生长因子（抗VEGF）治疗是一种有前途的 与脉络膜新生血管形成（CNV）和 糖尿病性视网膜病。实际上，抗VEGF疗法已成为这些疾病的黄金标准。而 治疗作用是积极的，一个主要的缺点是，必须每四到六次重复一次这种治疗 几周。对患者，家庭成员和临床医生的重复治疗负担很大。 最近，我们开发了可生物降解的微球，热响应水凝胶眼药递送 系统（DDS）。可生物降解的微球是使用我们改良的双乳液技术产生的 为药理学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，有效且可注射的生物材料，用于将微球局限于特定 送货网站。我们以前已经证明了抗VEGF的受控持续释放，为6个。 具有出色的安全概况的月份。该提案的总体目标是定量评估安全性 我们提出的DD在非人类灵长类动物模型中的功效，并与常规疗法进行比较。 我们的假设是，持续受控的抗VEGF释放在大约6个月的时间内将是 作为常规疗法，有效，即使不是更有效。具体目的1是确定眼 Afibercept的药代动力学（PK）从非人类灵长类动物（NHP）模型中释放出来。具体 目标2确定在NHP模型中DDS的生物相容性。特定目的3是定量比较 提出的DDS对传统疗法的疗效和生物活性在抑制其能力方面 CNV模型中的血管生成反应。具体目的4是测量长期潜在副作用（如果有） 在啮齿动物模型中提出的DDS和抗VEGF的暴露。具体目标5是定量 评估双重药物释放DDS的药物释放动力学和生物活性。广泛的临床用途 抗VEGF需要对眼后部分进行实际有效的递送方法。我们 相信我们的药物输送系统将满足这种关键的临床需求。该提议中获得的知识 将使这项技术更接近转化为临床实践，并将具有重要的 对当前医疗保健系统的影响。