Porous Silicon Particles for Sustained Intravitreal Drug Delivery

用于持续玻璃体内药物输送的多孔硅颗粒

• 批准号: 8316278
• 负责人: LINGYUN CHENG
• 金额: $ 51.13万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316278
• 关键词: Address; Adsorption; Age related macular degeneration; Animal Model; Animals; Avastin; Biological Assay; Blood-Retinal Barrier; Cell Culture Techniques; Cellular Assay; Chemistry; Chronic; Cicatrix; Clinical; Data; Daunorubicin; Development; Devices; Dexamethasone; Dimensions; Disease; Disease model; Drug Controls; Drug Delivery Systems; Drug Kinetics; Drug Monitoring; Drug usage; Electrostatics; Engineering; Enzyme-Linked Immunosorbent Assay; Evaluation; Excision; Eye; Eye diseases; Goals; Half-Life; Hour; Implant; In Vitro; Inflammation; Injection of therapeutic agent; Lasers; Macular degeneration; Methods; Modality; Modeling; Modification; Monitor; Nanostructures; Operative Surgical Procedures; Optics; Patients; Pharmaceutical Preparations; Plants; Porosity; Prevention; Process; Proliferative Vitreoretinopathy; Property; Proteins; Pupil; Quality of life; Refractory; Reporting; Retinal; Safety; Scanning; Series; Silicon; Surface; System; Testing; Therapeutic; Tissues; Toxic effect; Trauma; Uveitis; base; bevacizumab; diabetic; digital; digital imaging; drug candidate; improved; in vivo; intravitreal injection; minimally invasive; nanostructured; non-invasive monitor; novel; oxidation; particle; research study; small molecule; treatment strategy

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.

描述(由申请人提供)：有一个重要的未得到满足的需求，一个微创，长效，可监测的药物输送系统，用于治疗眼后部疾病。由于难以跨越血-视网膜屏障，玻璃体内给药已成为治疗眼后部疾病的中流砥柱。目前可用的药物需要频繁地玻璃体内注射或侵入性手术眼内植入。本申请旨在开发和评估一种基于多孔硅(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而独特的系统。贝伐单抗代表大分子，如蛋白质；柔红霉素和地塞米松代表小分子，针对脉络膜视网膜疾病的两个主要成分：不想要的增殖和炎症。我们假设Psi颗粒在玻璃体内注射后是无毒和可生物降解的，它们的孔隙度可以用来容纳治疗药物，它们的光学性质可以被利用来报告药物的远程释放。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，Psi颗粒在玻璃体中的停留能力可以从1周延长到16周，而不会对眼睛产生毒性。我们的体外数据表明，柔红霉素的加载和移除改变了Psi颗粒的光谱，Psi颗粒作为药物监测的条形码，可以被数码相机捕获，从而能够在临床环境中对药物释放进行非侵入性监测。我们还发现柔红霉素与硅氢化或氧化的Psi颗粒的共价结合将药物的半衰期从几小时延长到23天(硅氢化)，甚至更长(氧化)。我们通过细胞培养和四甲基偶氮唑盐试验证实了释放的柔红霉素具有完全的功能。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、共价吸附或逐层方法进行优化，以装载候选药物。我们将评估体外和体内药物释放的非侵入性监测方法。优化的载药Psi颗粒及其非侵入性传感能力将在动物眼睛和动物模型中进一步评估其药代动力学和疗效。我们还将评估该系统通过注射两种类型的Psi颗粒(每种类型加载一种药物)的混合物对黄斑变性CNV动物模型提供协同效应的能力。预计基于PSI的眼部给药系统将减少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。