Porous Silicon Particles for Sustained Intravitreal Drug Delivery

描述（由申请人提供）：对于治疗后眼疾病的微创、长效、可监测的药物输送系统，有一个重要的未满足的需求。由于难以通过血视网膜屏障，玻璃体内给药已成为治疗后眼疾病的主要方法。目前可用的药物需要频繁的玻璃体内注射或侵入性手术眼内植入。本应用旨在开发和评估基于多孔硅（Psi）的玻璃体内给药系统。三种候选药物：贝伐单抗、柔红霉素和地塞米松，将被用作模型药物来研究这一新颖独特的系统。贝伐单抗代表大分子，如蛋白质；柔红霉素和地塞米松是针对绒毛膜视网膜疾病的两个主要组成部分的小分子：不必要的增殖和炎症。我们假设Psi颗粒在玻璃体内注射后是无毒的，可生物降解的，它们的孔隙度可以用来承载治疗药物，它们的光学特性可以用来远程报告药物释放。我们的初步数据表明，通过氧化或硅氢化修饰Psi的表面化学性质，Psi颗粒在玻璃体中停留的能力可以从1周延长到16周，而不会产生眼毒性。我们的体外数据表明，柔红霉素的加载和去除改变了Psi颗粒的光谱，Psi颗粒作为药物监测的条形码，可以通过数码相机捕获，从而允许在临床环境中对药物释放进行无创监测。我们还发现，柔红霉素与硅氢化或氧化Psi颗粒的共价附着将药物半衰期从几个小时延长到23天（硅氢化）甚至更长（氧化）。我们已经通过细胞培养和MTT试验证实释放的柔红霉素是完全有效的。我们将首先通过氧化、硅氢化和有机卤化物的电化学接枝来优化Psi玻璃体的稳定性。具有良好玻璃体稳定性的Psi将通过物理捕获、静电吸附、共价附着或逐层方法来优化候选药物的装载。我们将评估体外和体内药物释放的无创监测方法。优化后的载药Psi颗粒及其无创传感能力将在动物眼和动物模型上进一步评价其药代动力学和疗效。我们还将通过注射两种Psi颗粒的混合物（每种类型装载一种药物）来评估该系统对黄斑变性CNV动物模型提供协同作用的能力。预期所提出的基于Psi的眼部给药系统将减轻频繁的玻璃体内注射或眼内手术植入药物装置的需要，显著提高患者的生活质量。

DESCRIPTION (provided by applicant): There is an important unmet need for a minimally invasive long acting, and monitorable drug delivery system for the treatment of posterior eye diseases. Due to the difficulty of crossing the blood-retinal barrier, intravitreal drug delivery has become the mainstay to treat posterior eye diseases. The current available medications require frequent intravitreal injection or invasive surgical intraocular implant. This application seeks to develop and evaluate a porous silicon (Psi) based intravitreal drug delivery system. Three candidate drugs: bevacizumab, daunorubicin, and dexamethasone, will be used as model drugs to investigate this novel and unique system. Bevacizumab represents large molecule such as protein; daunorubicin and dexamethasone represent small molecules which target two major components of chorioretinal diseases: unwanted proliferation and inflammation. We hypothesize that Psi particles are non-toxic and biodegradable after intravitreal injection, that their porosity can be used for hosting therapeutics, and that their optical property can be harnessed to report drug release from remote. Our preliminary data have shown that by modifying the surface chemistry of Psi via oxidation or hydrosilylation, the Psi particle's ability to remain in the vitreous can be extended from 1 week to 16 weeks without ocular toxicity. Our in vitro data demonstrated that the loading and removal of daunorubicin changed the spectrum of Psi particles which served as a barcode for drug monitoring and could be captured by a digital camera, allowing for non-invasive monitoring of drug release in the clinical setting. We also showed that covalent attachment of daunorubicin to either hydrosilylated or oxidized Psi particles extended the drug half-life from a few hours to 23 days (hydrosilylated) or even longer (oxidized). We have confirmed that released daunorubicin is fully functional through the cell culture and MTT assays. We will first optimize the Psi vitreous stability by oxidations, hydrosilylations, and electrochemical grafting of organohalides. Psi with a good vitreous stability will be optimized for loading of the candidate drugs using physical trapping, electrostatic adsorption, covalent attachment, or layer by layer approaches. We will evaluate non-invasive monitoring of drug release in vitro and in vivo approaches. The optimized drug loaded Psi particles and its non-invasive sensing ability will be further evaluated in animal eyes and animal models for its pharmacokinetics and efficacy. We will also evaluate the ability of this system to offer synergistic effect on macular degeneration CNV animal model by injection of a mixture of two types of Psi particles (each type loaded with one drug). It is expected that the proposed Psi based ocular drug delivery systems will alleviate the need for frequent intravitreal injections or intraocular surgery for drug device planting, significantly improving the quality of life of patients.