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）：对最低侵入性的长作用和可监测的药物输送系统的重要需求，用于治疗后眼疾病。由于难以越过血视网膜屏障，玻璃体内药物的输送已成为治疗后眼病的中流型。当前可用的药物需要频繁的玻璃体内注射或侵入性手术内植入物。该应用程序旨在开发和评估基于多孔硅（PSI）的玻璃体内药物输送系统。三种候选药物：贝伐单抗，杜申umubicin和地塞米松将被用作模型药物，以研究这种新颖而独特的系统。贝伐单抗代表大分子，例如蛋白质。 daunorubicin和地塞米松代表小分子，这些分子针对脉络膜视网膜疾病的两个主要成分：不良的增殖和炎症。我们假设PSI颗粒在玻璃室内注射后是无毒的，可生物降解，它们的孔隙率可用于托管治疗剂，并且可以利用其光学特性报告从远程释放药物。我们的初步数据表明，通过通过氧化或氢硅烷化修改PSI的表面化学，PSI颗粒保持在玻璃体中的能力可以从1周延长至16周而没有眼毒性。我们的体外数据表明，daunorubicin的负载和去除改变了PSI颗粒的光谱，PSI颗粒用作药物监测的条形码，可以通过数码相机捕获，从而可以在临床环境中对药物释放进行非侵入性监测。我们还表明，对氢氨基甲基甲硅烷基镀膜或氧化的PSI颗粒的共价附着将药物半衰期从几个小时延长到23天（氢硅烷基）甚至更长（氧化）。我们已经证实，通过细胞培养和MTT测定法，释放的daunorubicin具有完全功能性。我们将首先通过氧化，氢化硅烷化和有机甲藻的电化学嫁接来优化PSI玻璃体稳定性。具有良好玻璃体稳定性的PSI将被优化，以使用物理捕获，静电吸附，共价附着或按层进近的方法加载候选药物。我们将在体外和体内方法评估对药物释放的非侵入性监测。在动物眼和动物模型中，将进一步评估优化的药物负载的PSI颗粒及其非侵入性传感能力的药代动力学和功效。我们还将评估该系统通过注入两种类型的PSI颗粒（每种装有一种药物）的混合物来评估该系统对黄斑变性CNV动物模型的协同作用的能力。预计拟议的基于PSI的眼药输送系统将减轻对药物设备种植的频繁注射或眼内手术的需求，从而显着改善患者的生活质量。