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 治疗作用是阳性的，一个主要的缺点是必须每四到六周重复一次这种治疗方法。 对患者，家庭成员和临床医生的重复治疗负担很大。最近，我们有 开发了可生物降解的微球，热响应水凝胶眼药输送系统（DDS）。 可生物降解的微球是使用我们改良的双重乳液技术生产的 药理剂的微环境。可生物降解的热响应水凝胶是安全的， 有效且可注射的生物材料，用于将微球局限于特定的递送位点。我们有 先前证明了抗VEGF的受控持续释放6个月，非常出色 安全概况。该提案的总体目标是定量评估我们的安全性和功效 在非人类灵长类动物模型中提出的DDS，并与常规疗法进行比较。我们的假设是 持续受控的抗VEGF释放延长了6个月，即使不是更多，甚至更多 有效，作为常规疗法。具体目的1是确定眼科药代动力学（PK） Aflibercept以非人类灵长类动物（NHP）模型从DDS释放。确定的特定目标2 DDS在NHP模型中的生物相容性。特定目的3是定量比较功效和 拟议的DDS对常规疗法的生物活性抑制其血管生成反应的能力 CNV模型。特定目的4是衡量拟议DDS的长期潜在副作用（如果有的话）和 在啮齿动物模型中暴露抗VEGF。具体目的5是定量评估药物释放 双毒释放DDS的动力学和生物活性。抗VEGF的广泛临床使用需要 实际有效的递送方法到眼后部分。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。该提案中获得的知识将使这项技术一步 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。