Sustained Ocular Drug Delivery System for Anti-VEGF Agents

抗 VEGF 药物持续眼部给药系统

• 批准号: 10645936
• 负责人: JENNIFER J Kang-Mieler
• 金额: $ 56.13万
• 依托单位: STEVENS 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/10645936
• 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，但一个主要缺点是这种治疗必须每四到六周重复一次。 患者、家属和临床医生的重复治疗负担是巨大的。最近，我们有 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进的双乳液技术生产的，提供了更好的 药物的微环境。可生物降解的热响应水凝胶是一种安全、 有效的、可注射的生物材料，用于将微球限制在特定的递送部位。我们有 此前已证明抗 VEGF 药物的受控缓释效果长达 6 个月，具有优异的效果 安全概况。该提案的总体目标是定量评估我们的安全性和有效性 提出了在非人类灵长类动物模型中进行 DDS 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控制抗 VEGF 释放，即使不是更有效，也将同样有效 与常规疗法一样有效。具体目标 1 是确定眼部药代动力学 (PK) 在非人类灵长类动物 (NHP) 模型中从 DDS 释放阿柏西普。具体目标2确定 NHP 模型中 DDS 的生物相容性。具体目标 3 是定量比较功效和 所提出的 DDS 相对于常规疗法的生物活性在于其抑制血管生成反应的能力 CNV 模型。具体目标 4 是衡量所提议的 DDS 的长期潜在副作用（如果有）和 在啮齿动物模型中暴露抗 VEGF 药物。具体目标 5 是定量评估药物释放 双药物释放 DDS 的动力学和生物活性。抗 VEGF 药物的广泛临床应用需要 实用且有效的眼后段输送方法。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。在该提案中获得的知识将使该技术更进一步 更接近转化为临床实践，将对当前的医疗保健系统产生重大影响。