Biocompatibility of thermo-responsive hydrogel ocular drug delivery system

描述(申请人提供)：最近使用的抗血管内皮生长因子(VEGF)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。为了有效，每四到六周需要多次玻璃体内注射。这不是一个可取的方法，因为它与几个固有的并发症有关。目前，还没有替代的方法，因此，非常需要开发一种相对非侵入性的、比目前的临床方案更有效的给药方法。建议的药物输送系统使用温度响应性水凝胶，它将优化抗血管生成的效果，同时将大剂量输送的异位效应的可能性降至最低。由于其新颖的温度响应特性，水凝胶可通过小口径针以液体形式注射到巩膜旁区域或玻璃体腔。一旦暴露在体温下，溶液就会变成固体凝胶，释放出抗血管内皮生长因子的试剂。体外研究表明，温度响应型水凝胶可以包裹和释放活性蛋白。本研究的目的是探讨温敏性水凝胶作为眼部给药系统的可行性和生物相容性。具体目标1将在活体啮齿动物模型中研究温度响应型植入物在玻璃体腔或巩膜旁区域的生物相容性。为了评估生物相容性，植入后的不同时间点将进行视网膜电信号(ERG)反应、扫描激光眼底镜(SLO)成像血流测量、光谱域光学相干断层扫描(SD-OCT)成像以及视网膜毒性和炎症的组织学检查。特定目的2将确定从水凝胶中释放的抗血管内皮生长因子抑制激光诱导的脉络膜新生血管啮齿动物模型中血管生成反应的有效性。ERG反应、SLO成像血流测量、OCT成像和组织学将用于评估疗效。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后节段给药方法。该项目的创新之处在于，将使用一种新型生物材料来最大限度地减少反复玻璃体内注射的需要，并提高药物的疗效。拟议的药物输送系统将对目前的治疗方案产生重大影响。 公共卫生相关性：抗血管内皮生长因子(VEGF)疗法在临床上的广泛应用需要一种实用而有效的眼后段给药方法。最近开发的可生物降解的热响应水凝胶系统已经证明可以包裹和释放活性蛋白。该提案的总体目标是研究温度响应性水凝胶作为眼部给药系统的可行性和生物相容性，这将对目前老年性黄斑变性和糖尿病视网膜病变的治疗产生重大影响。

DESCRIPTION (provided by applicant): Recently employed anti-vascular endothelial growth factor (VEGF) therapy is a very promising treatment for the wet form of age-related macular degeneration and diabetic retinopathy. To be effective, multiple intravitreal injections are needed every four to six weeks. This is not a desirable method as it is associated with several inherent complications. Currently, there is no alternative method; hence, there is a great need to develop a relatively non-invasive delivery method that is more effective than the current clinical regimen. The proposed drug delivery system uses thermo-responsive hydrogel that would optimize the anti-angiogenic effects but minimize the potential for ectopic effects of a large bolus delivery. Due to its novel thermo-responsive characteristic, the hydrogel can be injected as a liquid form to the juxtascleral region or vitreous cavity via a small gauge needle. Once exposed to the body temperature, the solution will become a solid gel that will release the anti-VEGF agents. In vitro studies have demonstrated that thermo-responsive hydrogels can encapsulate and release active protein. The goal of this proposal is to investigate the feasibility and biocompatibility of thermo-responsive hydrogel as an ocular drug delivery system in vivo. Specific Aim 1 will investigate the biocompatibility of the thermo-responsive implant in either the vitreous cavity or juxtascleral region in an in vivo rodent model. To evaluate biocompatibility, electroretinogram (ERG) responses, scanning laser ophthalmoscope (SLO)-imaging blood flow measurements, spectral domain optical coherence tomography (SD-OCT) imaging and histological examination of retinal toxicity and inflammation will be performed at various time points after the implantation. Specific Aim 2 will determine the efficacy of released anti-VEGF from the hydrogels to suppress angiogenic responses in a laser-induced choroidal neovascularization rodent model. ERG responses, SLO-imaging blood flow measurements, OCT imaging and histology will be used to evaluate the efficacy. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment. The innovation of this project is that a novel biomaterial will be used to minimize the need for repeated intravitreal injections and improve the efficacy of the drug. The proposed drug delivery system will have a great impact on the current treatment regimen. PUBLIC HEALTH RELEVANCE: Widespread clinical use of anti-vascular endothelial growth factor (VEGF) therapy necessitates a practical and effective delivery method to the posterior segment of the eye. Recently developed biodegradable thermo- responsive hydrogel system has demonstrated to encapsulate and release active protein. The overall goal of this proposal is to investigate the feasibility and biocompatibility of thermo-responsive hydrogel as an ocular drug delivery system which can have a significant impact on the current treatment of age-related macular degeneration and diabetic retinopathy.