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

 描述(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)的病理生理学中起着重要作用，AMD是导致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传递药物。然而，这些注射是侵入性的，成本高昂，可能会对其他眼部结构产生不利影响。这项研究的目标是开发一种可以静脉给药的药物释放系统，并直接针对RPE或脉络膜血管，用于治疗像AMD这样的视网膜疾病。我们的假设是，纳米卟啉是一种基于卟啉/胆酸的多功能胶束纳米颗粒，可以1)有效地包裹荧光染料或药物化合物，2)在外部光源触发时释放有效载荷，以及3)用组织特异性配体修饰，可以用于眼睛的诊断和治疗功能。使用共聚焦扫描激光眼底镜(SLO)技术，纳米卟啉可以被可视化并触发以直接将药物释放到RPE或CEC。本研究的具体目的是1)通过组合文库筛选发现RPE和CEC特异性的多肽配体，2)使用SLO成像显示和触发小鼠眼睛中的纳米卟啉，以及3)测试用于光热治疗(PTT)和PDT的单线态氧高效转化为光-热的转换器，类似地，作为一名学术临床科学家和玻璃体视网膜专家，我对临床和研究都有兴趣，作为一名学术临床科学家和玻璃体视网膜专家，我在了解视网膜疾病的机制方面具有临床和研究兴趣。我在神经细胞培养和临床眼科成像方面有很强的背景，我已经做好了充分的准备，可以从事翻译研究，研究AMD的发病机制和治疗。加州大学戴维斯分校拥有世界一流的师资和设施，有可能促进我在纳米疗法、药物输送和活体动物眼部成像领域的培训。通过这项拨款计划获得的指导和技能将使我能够在翻译AMD研究方面获得专业知识。

 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.