Sustained Ocular Drug Delivery System for Anti-VEGF Agents

项目摘要 新近采用的玻璃体内抗血管内皮生长因子(anti-VEGF)疗法是一种很有前途的治疗方法 湿性老年性黄斑变性合并脉络膜新生血管的治疗 糖尿病视网膜病变。事实上，抗血管内皮生长因子治疗已经成为这些疾病的金标准。而当 治疗效果是肯定的，一个主要缺点是这种治疗必须每四到六次重复一次 几周。重复治疗给患者、家庭成员和临床医生带来了沉重的负担。 最近，我们开发了一种可生物降解的微球，温度响应性水凝胶眼部给药 系统(DDS)。利用我们改进的复乳技术制备了可生物降解的微球 为药理药剂提供更好的微环境。可生物降解的热响应性材料 水凝胶是一种安全、有效、可注射的生物材料，用于将微球限制在特定的 送货地点。我们之前已经证明了抗血管内皮生长因子的受控持续释放6 安全状况极佳的几个月。这项建议的总体目标是对安全进行量化评估 以及我们建议的DDS在非人灵长类动物模型中的有效性，并与传统疗法进行比较。 我们的假设是，在延长~6个月的时间内持续控制释放抗血管内皮生长因子将是AS 有效的，如果不是更有效的，就像传统疗法一样。具体目标1是确定眼睛 非人灵长类动物模型中从DDS释放的阿普利塞的药代动力学(PK)。具体的 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 DDS与传统疗法相比的疗效和生物活性 新生血管模型的血管生成反应。具体目标4是衡量长期潜在的副作用，如果有的话， 在啮齿动物模型中应用DDS和暴露抗血管内皮生长因子。具体目标5是定量地 评价双药物释放DDS的释药动力学和生物活性。广泛的临床应用 抗血管内皮生长因子抗体需要一种实用有效的眼后段给药方法。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。从这项建议中获得的知识 将使这项技术离转化为临床实践更近一步，并将具有重要的 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.