Predictive Drug Release from a Tunable Injectable Capsule

项目总结 数以百万计的人受到慢性病的影响，由于寿命的增加，这个数字还会继续上升 期望值。这些疾病，包括湿性老年性黄斑变性(AMD)，依赖于频繁的局部 用于疾病管理的注射。需要频繁注射才能达到最大的治疗效果 与护理障碍相关，包括患者不适、高昂的治疗成本和并发症风险。 临床上需要减少注射频率，同时保持对这些慢性疾病的治疗效果 以改善这些患者的治疗结果和生活质量。这个项目的总体目标是 是开发一种可调的、可注射的、可生物降解的微胶囊递送装置，它具有维持 释放不同分子量的治疗药物至少12个月。理论模型将是 结合体内外实验研究优化微胶囊体系及预测 治疗性的释放。在目标1中，微囊孔隙率将使用两种方法来调整治疗 放手。释放不同分子量的治疗药物，包括抗血管内皮细胞生长 因素)和曲安奈德(TA)，将进行至少12个月的评估。治疗释放率和 生物活性将在体外通过使用超性能液体--ELISA法评估样本来进行评估 层析(UPLC)、内皮细胞管形成试验和视网膜炎症标志物的抑制 细胞。依赖于孔隙率和药物尺寸的药物释放的电子计算机模型将得到改进。在目标2中， 微囊外聚合物层厚度将被调节以调节治疗释放。长期释放 抗血管内皮生长因子和TA的比率和生物活性将在体外进行评估。In Silico模式将得到改进，并 根据胶囊层厚度验证药物释放。在目标3中，微胶囊的生物兼容性和 治疗药物的药代动力学分布将在体内进行评估。首先将对微胶囊进行评估 短期生物相容性为1个月。然后，荧光标记的治疗药物将被加载到优化 并与空白胶囊和仅治疗12个月的对照组进行比较。荧光光度法 将用于定量评估随时间释放的治疗浓度，并将与 在研究结束时对提取的眼组织进行分析。研究结果将与已发表的研究进行比较。 有效的治疗浓度。这项研究还将提供12个月的体内安全性数据。In Silico 模型将被改进，以包括玻璃体和视网膜中治疗浓度的测量，以预测 体内分布与胶囊药物释放相结合。此外，还将开发一个计算工具 为了在指定的释放时间内优化胶囊层厚度和孔隙率，药动学组织 分布和治疗大小。该项目的目标是开发一种可调的药物输送装置， 有可能将注射次数减少到每年一次，提高AMD或其他疾病患者的生活质量 依靠局部注射治疗的慢性病。

PROJECT SUMMARY Millions of people are affected by chronic conditions, and the number will continue to rise due to increased life expectancy. These diseases, including wet age-related macular degeneration (AMD), rely on frequent local injections for disease management. Frequent injections required for maximum therapeutic efficacy are associated with barriers to care including patient discomfort, high treatment costs, and risk of complications. There is a clinical need to reduce injection frequency while maintaining treatment efficacy for these chronic diseases to improve treatment outcomes and quality of life for these patients. The overall objective of this project is to develop a tunable, injectable, biodegradable microcapsule delivery device that has the potential to sustain release of therapeutics of varying molecular weights for at least 12 months. Theoretical modeling will be combined with in vitro and in vivo experimental studies to optimize the microcapsule system and predict therapeutic release. In Aim 1, microcapsule porosity will be modulated using two methods to tune therapeutic release. Release of therapeutics of varying molecular weights, including anti-VEGF (vascular endothelial growth factor) and triamcinolone acetonide (TA), will be evaluated at least 12 months. Therapeutic release rates and bioactivity will be assessed in vitro by evaluating samples using ELISA, Ultra Performance Liquid Chromatography (UPLC), endothelial cell tube formation assays, and inhibition of inflammatory markers in retinal cells. An in silico model for drug release dependent on porosity and drug size will be refined. In Aim 2, microcapsule outer polymer layer thickness will be modulated to tune therapeutic release. Long-term release rates and bioactivity of anti-VEGF and TA will be evaluated in vitro. The in silico model will be refined and validated for drug release dependent on capsule layer thickness. In Aim 3, microcapsule biocompatibility and pharmacokinetic distribution of the therapeutics will be evaluated in vivo. The microcapsule will first be evaluated for 1 month for short-term biocompatibility. Then, fluorescently labeled therapeutics will be loaded into optimized microcapsules and compared to blank capsules and therapeutic only controls for 12 months. Fluorophotometry will be used to quantitatively assess therapeutic concentrations released over time and will be compared to assays conducted on extracted ocular tissues at study termination. Results will be compared to published studies for effective therapeutic concentrations. This study will also provide 12 month in vivo safety data. The in silico model will be refined to include measurements of therapeutic concentrations in the vitreous and retina to predict in vivo distribution coupled to drug release from a capsule. Additionally, a computational tool will be developed for optimizing capsule layer thickness and porosity for specified release duration, pharmacokinetic tissue distribution, and therapeutic size. The goal of this project is to develop a tunable drug delivery device with the potential to reduce injections to one time per year, improving the quality of life for patients with AMD or other chronic diseases that rely on local injections for treatment.