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 治疗效果是积极的，一个主要的缺点是，这种治疗必须重复每四到六个 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，热响应水凝胶眼部给药 系统（DDS）。生物可降解微球是用我们改进的复乳技术生产的 为药物提供更好的微环境。可生物降解的热响应 水凝胶是一种安全、有效和可注射的生物材料，用于将微球限制在特定的 交货地点。我们先前已经证明了抗VEGF的控制持续释放持续6个月。 几个月来，安全性很好。该提案的总体目标是定量评估安全性 和我们提出的DDS在非人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个月的延长期内持续控制的抗VEGF释放将是如 有效，如果不是更有效，作为常规疗法。具体目标1是确定眼 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 目的2在NHP模型中测定DDS的生物相容性。具体目标3是定量比较 所提出的DDS的有效性和生物活性与常规治疗相比，其抑制 CNV模型中的血管生成反应。具体目标4是测量长期潜在副作用（如有）， 在啮齿类动物模型中的拟定DDS和抗VEGF暴露。具体目标5是定量地 评价双释药DDS的释药动力学和生物活性。广泛的临床应用 抗VEGF需要一种实用和有效的递送方法到眼后段。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。在这份提案中获得的知识 将使这项技术更接近于转化为临床实践，并将有重大意义。 对当前医疗体系的影响。

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.