A nanoparticle platform for targeted delivery of therapeutic agents to retinal pigment epithelial or choroidal endothelial cells

用于将治疗剂靶向递送至视网膜色素上皮或脉络膜内皮细胞的纳米颗粒平台

• 批准号: 9195104
• 负责人: Glenn Yiu
• 金额: $ 20.66万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195104
• 关键词: Affect; Affinity; Age related macular degeneration; Angiogenesis Inhibitors; Animals; Anterior; Applications Grants; Area; Binding; Blindness; Cell Culture Techniques; Cells; Cholic Acids; Choroidal Neovascularization; Clinical; Clinical Research; Cultured Cells; Defect; Development; Diagnostic; Doxorubicin; Drug Delivery Systems; Drug Targeting; Drug usage; Elderly; Electron Transport; Encapsulated; Endocytosis; Endophthalmitis; Endothelial Cells; Epithelial; Exudative age-related macular degeneration; Eye; Faculty; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Functional disorder; Goals; Human; Image; Imaging technology; Inflammatory; Injectable; Injection of therapeutic agent; Integrins; Intravenous; Intravenous Drug Delivery Systems; Laboratories; Lasers; Libraries; Ligand Binding; Ligands; Light; Mentors; Metabolic; Monitor; Mus; Neurons; Ophthalmoscopy; Optical Coherence Tomography; PUVA Photochemotherapy; Pathogenesis; Peptide Library; Peptides; Permeability; Pharmaceutical Preparations; Pharmacology; Photosensitization; Play; Porphyrins; Protocols documentation; Regulation; Research; Retinal; Retinal Detachment; Retinal Diseases; Retinal Pigments; Risk; Role; Scanning; Scientist; Singlet Oxygen; Source; Specialist; Specificity; Structure; Structure of retinal pigment epithelium; Surface; System; Tail; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Training; Transducers; Translational Research; Veins; Verteporfin; Viral; Wild Type Mouse; adaptive optics; base; biomaterial compatibility; cancer clinical trial; cancer therapy; cell type; combinatorial; cost; crosslink; fetal; gene therapy; in vivo; interest; intravitreal injection; mouse model; nanoparticle; nanotherapeutic; overexpression; particle; public health relevance; screening; skills; small molecule; subretinal injection; targeted delivery; targeted treatment; tool

 DESCRIPTION (provided by applicant): The retinal pigment epithelium (RPE) and choroidal vasculature play important roles in the pathophysiology of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Current therapeutic strategies rely on intravitreal or subretinal injections to deliver the pharmacologic agents. However, these injections are invasive and costly, and may adversely affect other ocular structures. The goal of this study is to develop a drug delivery system that could be given intravenously, and directly targeted to RPE or choroidal vessels for the treatment of retinal diseases like AMD. Our hypothesis is that nanoporphyrins, a multifunctional porphyrin/cholic acid-based micellar nanoparticle, that can 1) efficiently encapsulate fluorescent dyes or pharmacologic compounds, 2) release the payload when triggered with an external light source, and 3) be decorated with tissue-specific ligands, can be used to provide both diagnostic and therapeutic functions in the eye. Using confocal scanning laser ophthalmoscopy (SLO) technology, nanoporphyrins can be visualized and triggered to release a drug directly to RPE or CECs. The specific aims of this study are to 1) to discover RPE and CEC-specific peptide ligands using combinatorial library screening, 2) to visualize and trigger nanoporphyrins in mouse eyes using SLO imaging, and 3) to test transducers that efficiently convert light to heat for photothermal therapy (PTT) and to singlet oxygen for PDT, similAs an academic clinician-scientist and vitreoretinal specialist, I have both clinical and research interests in As an academic clinician-scientist and vitreoretinal specialist, I have both clinical and research interests in understanding the mechanisms of retinal diseases. With a strong background in neuronal cell culture and clinical ophthalmic imaging, I am well-prepared to pursue translational research to study the pathogenesis and treatment of AMD. UC Davis offers a world-class faculty and facilities that has the potential to facilitate my training in areas of nanotherapeutics, drug delivery, and live animal ocular imaging. The mentoring and skills acquired with this grant proposal will enable me to attain expertise in translational AMD research.

 描述（由申请人提供）：视网膜色素上皮（RPE）和脉络膜血管在老年性黄斑变性（AMD）的病理生理学中起重要作用，AMD是老年人失明的主要原因。目前的治疗策略依赖于玻璃体内或视网膜下注射来递送药理学药剂。然而，这些注射是侵入性的和昂贵的，并且可能不利地影响其他眼部结构。本研究的目的是开发一种药物递送系统，可以静脉内给药，并直接靶向RPE或脉络膜血管，用于治疗视网膜疾病，如AMD。我们的假设是，纳米卟啉，一种多功能卟啉/胆酸基胶束纳米颗粒，可以1）有效地包封荧光染料或药物化合物，2）当用外部光源触发时释放有效载荷，3）用组织特异性配体装饰，可以用于在眼睛中提供诊断和治疗功能。使用共聚焦扫描激光检眼镜（SLO）技术，纳米卟啉可以被可视化并触发直接释放药物到RPE或CEC。本研究的具体目的是1）使用组合文库筛选发现RPE和CEC特异性肽配体，2）使用SLO成像可视化和触发小鼠眼中的纳米卟啉，以及3）测试有效将光转换为光热治疗（PTT）的热和PDT的单线态氧的换能器，类似于学术临床医生-科学家和玻璃体视网膜专家，作为一名学术临床科学家和玻璃体视网膜专家，我对了解视网膜疾病的机制有临床和研究兴趣。凭借在神经元细胞培养和临床眼科成像方面的强大背景，我已经准备好进行转化研究，以研究AMD的发病机制和治疗。加州大学戴维斯分校提供世界一流的教师和设施，有可能促进我在纳米治疗，药物输送和活体动物眼部成像领域的培训。通过这项资助计划获得的指导和技能将使我能够获得翻译AMD研究的专业知识。