Efficacy of the Microsphere-Thermo-Responsive Hydrogel Ocular Drug Delivery System

 描述(申请人提供)：最近使用的玻璃体内抗血管内皮生长因子(抗血管内皮生长因子)疗法是一种非常有前途的湿性老年性黄斑变性和糖尿病视网膜病变的治疗方法。虽然治疗效果是积极的，但一个主要缺点是这种治疗必须每四到六周重复一次。这不是一个理想的治疗方法，因为它与几个固有的并发症有关。目前还没有可用的设备可以持续地输送抗血管内皮生长因子。因此，迫切需要一种相对非侵入性的、比目前临床上更有效的递送系统。 养生法。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。采用改进的复乳技术制备了可生物降解的聚乳酸-乙醇酸共聚物(PLGA)微球，为蛋白质类药物提供了更好的微环境。温度响应性水凝胶是一种安全、有效、可注射的生物材料，用于包裹和释放各种药物。这种水凝胶将被用来将微球限制在特定的传递位置。我们已经建立了为期6个月的抗血管内皮生长因子的受控缓释和所建议的药物传递系统的良好的生物相容性。这项建议的总体目标是通过与传统疗法的比较来证明我们所建议的药物在体外和体内系统中的有效性。假说是，持续控制释放抗血管内皮生长因子，持续6个月，将与传统疗法一样有效，如果不是更有效的话。具体目标1的目的是在体外和体内模型中定量比较所建议的药物递送系统与传统疗法在抑制血管生成反应方面的有效性和生物活性。具体目标1将分两部分完成：1在体外模型中检测释放的抗血管内皮生长因子药物的生物活性；1b在激光诱导的脉络膜新生血管(CNV)啮齿动物模型中，比较时间释放的抗血管内皮生长因子药物与常规治疗方法的生物活性和治疗效果。具体目标2的目标是在活体模型中测量长期疗效并监测拟议药物传递系统的潜在副作用(如果有)。在对照组和治疗组中，将通过视网膜电图(ERG)反应、扫描激光眼底镜(SLO)血管成像血流测量、光谱域光学相干断层扫描(SD-OCT)和组织学检查(终点)来监测长期疗效和潜在的副作用。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后段给药方法。从这项提案中获得的知识将使这项技术离转化为临床实践更近一步。我们相信，我们的药物输送系统将提供一种实用而有效的方法来输送抗病毒药物 血管内皮生长因子试剂。该系统将通过减少注射频率和提供持续治疗的好处，对当前的医疗体系产生重大影响。

 DESCRIPTION (provided by applicant): Recently employed intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is a very promising treatment for the wet form of age-related macular degeneration and diabetic retinopathy. While the therapeutic effects are positive, a major drawback is that this treatment must be repeated every four to six weeks. This is not a desirable treatment method as it is associated with several inherent complications. No currently available device can deliver anti-VEGF in a sustained manner. Hence, there is a great need for a relatively non-invasive delivery system that is more effective than the current clinical regimen. Recently, we have developed a biodegradable microspheres, thermo-responsive hydrogel ocular drug delivery system. Biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres are produced using our modified double emulsion technique providing a better microenvironment for protein-based pharmacological agents. The thermo-responsive hydrogel is a safe, effective, and injectable biomaterial that is used to encapsulate and release various agents. The hydrogel will be used to confine the microspheres to a specific delivery site. We have established both a controlled sustained release of anti-VEGF for a period of 6 months and excellent biocompatibility of the proposed drug delivery system. The overall goal of this proposal is to demonstrate the efficacy of our proposed drug delivery in both in vitro and in vivo systems and by comparing to the conventional therapy. The 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 goal of Specific Aim 1 is to quantitatively compare the efficacy and bioactivity of the proposed drug delivery system to the conventional therapy in its ability to suppress angiogenic responses in both in vitro and in vivo models. Specific Aim 1 will be accomplished in two parts: 1a testing bioactivity of released anti-VEGF agent in an in vitro model and 1b comparing the bioactivity and treatment efficacy via time-released anti-VEGF agents to conventional treatment in a laser-induced choroidal neovascularization (CNV) rodent model. The goal of Specific Aim 2 is to measure long-term efficacy and monitor for potential side effects, if any, of the proposed drug delivery system in an in vivo model. Long-term efficacy and potential side effects will be monitored through electroretinogram (ERG) responses, scanning laser ophthalmoscope (SLO)-vascular imaging blood flow measurements, spectral- domain optical coherence tomography (SD-OCT) and histological examination (at endpoint) in both control and treated groups. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment of the eye. The knowledge gained in this proposal will bring this technology one step closer to translation into the clinical practice. We believe that our drug delivery system will provide a practical and effective method to deliver anti VEGF agents. The system will have a significant impact on the current healthcare system by reducing the frequency of injections and providing benefits of sustained treatment.