Sustained Ocular Drug Delivery System for Anti-VEGF Agents

项目摘要 最近采用的玻璃体内抗血管内皮生长因子（抗VEGF）治疗是一种有前途的治疗方法。 治疗湿性年龄相关性黄斑变性伴脉络膜新生血管形成（CNV）， 糖尿病视网膜病变。事实上，抗VEGF治疗已成为这些疾病的金标准。而 虽然治疗效果是积极的，但主要缺点是这种治疗必须每四至六周重复一次。 患者、家属和临床医生的重复治疗负担是巨大的。最近我们 开发了一种可生物降解的微球、温敏性水凝胶眼部给药系统（DDS）。 可生物降解的微球是使用我们改进的复乳技术生产的， 药物的微环境。该生物可降解热响应水凝胶是一种安全， 有效且可注射的生物材料，其用于将微球限制在特定的递送部位。我们有 先前证实了抗VEGF的受控持续释放持续6个月， 安全配置文件。本提案的总体目标是定量评估我们的 在非人灵长类动物模型中提出DDS，并与传统疗法进行比较。我们的假设是 在约6个月的延长期内持续控制抗VEGF释放将同样有效，如果不是更多的话。 与传统疗法一样有效。具体目的1是确定以下药物的眼部药代动力学（PK）： 在非人灵长类动物（NHP）模型中从DDS释放的阿柏西普。第二个目标是确定 DDS在NHP模型中的生物相容性。具体目标3是定量比较疗效， 与常规治疗相比，所提出的DDS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是测量拟定DDS的长期潜在副作用（如有）， 在啮齿动物模型中暴露抗VEGF。具体目标5是定量评价药物释放 双药释放DDS的动力学和生物活性。抗VEGF的广泛临床应用需要 提供了一种实用且有效的眼后段递送方法。我们相信我们的药物输送 该系统将满足这一关键的临床需求。本提案中获得的知识将使这项技术更上一层楼 更接近于转化为临床实践，并将对当前的医疗保健系统产生重大影响。

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.