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 治疗效果是积极的，一个主要缺点是这种治疗必须每四到六周重复一次。 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，我们有 开发了一种可生物降解的温度响应性水凝胶眼部给药系统(DDS)。 可生物降解的微球使用我们改进的复乳技术生产，提供了更好的 药理制剂的微环境。可生物降解的热响应水凝胶是一种安全的， 有效的、可注射的生物材料，用于将微球限制在特定的传递位置。我们有 先前证实了抗血管内皮生长因子的受控缓释，为期6个月，具有极好的 安全配置文件。该提案的总体目标是定量评估我们的安全性和有效性 在非人类灵长类动物模型中提出DDS，并与传统治疗方法进行比较。我们的假设是 在长达6个月的时间内持续控制释放抗血管内皮生长因子，即使不是更有效，也是同样有效的 有效，与常规疗法一样。具体目的1是测定阿司匹林的眼内药代动力学(PK)。 在非人类灵长类动物(NHP)模型中，afLibercept从DDS中释放。确定的具体目标2 DDS在NHP模型中的生物相容性。具体目标3是定量比较疗效和 DDS抑制血管生成反应的生物活性优于传统疗法 CNV模型。具体目标4是衡量拟议的DDS的长期潜在副作用，如果有的话，以及 在啮齿动物模型中暴露抗血管内皮生长因子。具体目的5是定量评价药物释放 双药缓释药物DDS的动力学和生物活性。抗血管内皮生长因子抗体的广泛临床应用需要一种 实用有效的眼球后段给药方法。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。从这项提议中获得的知识将使这项技术向前迈进一步 更接近于转化为临床实践，并将对当前的医疗体系产生重大影响。

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.