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: 8105835
• 负责人: LINGYUN CHENG
• 金额: $ 53.46万
• 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/8105835
• 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; 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. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop and evaluate a porous silicon based eye drug delivery system which is minimally invasive, slow releasing and long-lasting. The system could eliminate the need for frequent intravitreal injections or invasive intraocular implant surgeries for many of the refractory eye diseases such as macular degeneration, diabetic or trauma induced retinal scarring, and chronic uveitis.

描述（由申请人提供）：对于用于治疗眼后部疾病的微创长效且可监测的药物递送系统存在重要的未满足的需求。由于药物难以穿过血-视网膜屏障，玻璃体内给药已成为治疗后眼部疾病的主要方法。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物。本申请寻求开发和评估基于多孔硅（Psi）的玻璃体内药物递送系统。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，以研究这种新颖而独特的系统。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，其靶向脉络膜视网膜疾病的两个主要成分：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和可生物降解的，它们的多孔性可用于容纳治疗剂，并且它们的光学性质可用于报告药物从远程释放。我们的初步数据表明，通过氧化或氢化硅烷化修饰Psi的表面化学，Psi颗粒保留在玻璃体中的能力可以从1周至16周延长，而没有眼毒性。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颗粒用作药物监测的条形码，并且可以通过数码相机捕获，从而允许在临床环境中非侵入性监测药物释放。我们还表明，柔红霉素与氢化硅烷化或氧化的Psi颗粒的共价连接将药物半衰期从几小时延长至23天（氢化硅烷化）或甚至更长（氧化）。我们已经通过细胞培养和MTT测定证实释放的柔红霉素是完全功能性的。我们将首先通过有机卤化物的氧化、氢化硅烷化和电化学接枝来优化Psi玻璃体的稳定性。具有良好玻璃体稳定性的Psi将被优化用于使用物理捕获、静电吸附、共价连接或逐层方法来装载候选药物。我们将评估体外和体内方法的药物释放的非侵入性监测。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功效。我们还将通过注射两种类型的Psi颗粒（每种类型装载有一种药物）的混合物来评估该系统对黄斑变性CNV动物模型提供协同效应的能力。预期所提出的基于Psi的眼部药物递送系统将减轻频繁的玻璃体内注射或眼内手术用于药物装置植入的需要，显著改善患者的生活质量。 公共卫生关系：本课题的目的是开发和评价一种具有微创、缓释、长效的多孔硅眼部给药系统。该系统可以消除对许多难治性眼部疾病的频繁玻璃体内注射或侵入性眼内植入手术的需要，所述难治性眼部疾病例如黄斑变性、糖尿病或创伤诱导的视网膜瘢痕形成和慢性葡萄膜炎。