Manufacture of Self-Reporting, Drug Loaded Porous Silicon Nanomaterials for Treat

项目总结/摘要 视力障碍是一种全球流行病，目前影响着数百万人。很大一部分 这些个体中的10%患有慢性年龄相关性黄斑变性（AMD），其特征在于 通过进行性新生血管形成和血管渗漏，靠近黄斑中心区（黄斑）， 视网膜。目前对AMD的治疗，包括激光光凝，光动力疗法， 和手术，只能使晚期患者受益，并暂时缓解 疾病的进展。对更有效疗法的需求促进了 开发抗血管内皮生长因子（VEGF）治疗。虽然反- 增殖剂显示出改善的功效，以6-8周的间隔重复注射 通常需要维持这些药物的疗效，导致不便， 成本较高，注射相关并发症（如眼内炎和视网膜病变）的风险较高 支队本项目的总体目标是开发一种每年或每两年注射一次的眼用药物， 具有延长活性药物释放和自我报告释放的能力的递送系统 同时减少了系统中药物残留量，减少了注射相关的发生 并发症以及频繁复诊和注射后检查的费用。Spinnaker Biosciences已经授权了这项技术，该技术基于利用光子微粒， 电化学制备的多孔硅或氧化的多孔硅（多孔二氧化硅）， 眼内药物输送，来自圣地亚哥的加州大学。在这个系统中，反 增殖性药物被容纳在精心设计的和生物惰性的多孔材料内， 保护药物免受不必要的酶消化。多孔颗粒还 由一个或多个不同的层制备，这些层反射不同的光谱，这些光谱随着 颗粒溶解并释放它们的药物有效载荷。我们的UCSD合作者有 证明了眼科应用的重要关键特征;特别是， 以递送基于活性抗体的药物的恒定释放曲线达数月， 通过检眼镜非侵入性地观察微粒的剩余容量的能力。 然而，颗粒还没有被配制用于最佳注射、药物递送方案， 和治疗水平。此外，UCSD研究中使用的生产方法 实验室的规模、可重复性、无菌性或一致性不足以支持我们的 计划的临床试验。这个STTR第一阶段项目将过渡和扩大颗粒 生产和载药技术，它将确定最佳配方， 给药方法，以便能够转化为临床试验。除了AMD之外， 递送系统可以被配制成容纳广泛的药物（例如非甾体类药物 抗炎药、阿霉素等）用于治疗严重的眼部疾病，如黄斑 水肿、葡萄膜炎和增生性玻璃体视网膜病变（PVR）。这项研究的结果可以 外推至用于治疗其它眼部疾病的其它治疗剂。

PROJECT SUMMARY/ABSTRACT Visual impairment is a global epidemic affecting millions of individuals currently. A large portion of these individuals suffer from chronic age-related macular degeneration (AMD), characterized by progressive neovascularization and vascular leakage near the central region (macula) of the retina. Current treatments for AMD, including laser photocoagulation, photodynamic therapy, and surgery, only benefit patients in the advanced stages and temporarily alleviate the progression of the disease. The need for more effective therapies has fostered the development of anti-vascular endothelial growth factor (VEGF) treatments. Although anti- proliferative agents have shown improved efficacy, repeated injections with 6-8 week intervals are often required to maintain therapeutic efficacy of these drugs, leading to inconvenience, higher cost and risk of injection-related complications such as endophthalmitis and retinal detachment. The overall goal of this project is to develop a yearly or bi-yearly injectable ocular delivery system with the ability to prolong the release of active drug and to self-report the amount of drug left in the system simultaneously, reducing the occurrence of injection-related complications and the cost of frequent re-visitations and post-injection examinations. Spinnaker Biosciences has licensed this technology, which is based on utilizing photonic microparticles of electrochemically prepared porous silicon or oxidized porous silicon (porous silica) for intraocular drug delivery, from the University of California, San Diego. In this system, anti- proliferative drugs are hosted inside the carefully devised and biologically inert porous material, protecting the drugs from unwanted enzymatic digestions. The porous particles are also prepared with one or more distinct layers, which reflect distinctive optical spectra that change as the particles dissolve and release their drug payload. Our UCSD collaborators have demonstrated the key features important for the ophthalmic application; in particular, the ability to deliver a constant release profile of active antibody-based drug for several months, and the ability to non-invasively observe the residual capacity of the microparticles via ophthalmoscope. However, the particles have not been formulated for the optimal injection, drug delivery regimen, and therapeutic levels. In addition, the production methods used in the UCSD research laboratories are not of the scale, reproducibility, sterility, or consistency needed to support our planned clinical trials. This STTR Phase I project will transition and scale up the particle production and drug loading technology, and it will determine the optimal formulation and administration method to enable translation to clinical trials. Besides AMD, the proposed ocular delivery system can be formulated to accommodate a wide range of drugs (e.g. non-steroidal anti-inflammatory drugs, doxorubicin, etc.) used to treat serious eye diseases such as macular edema, uveitis and proliferative vitreoretinopathy (PVR). The findings in this study can be extrapolated to other therapeutic agents intended for treating other ocular disorders.