Exosome based intraocular therapy combined with active targeting of ocular neovascularization

基于外泌体的眼内治疗联合主动靶向眼部新生血管

基本信息

批准号：
10690935
负责人：
Sun Young Lee
金额：
$ 41.74万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2024-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10690935
关键词：
Acids Area Binding Blindness Bypass Cell Communication Cell Line Cells Characteristics Choroidal Neovascularization Clinical Data Development Diabetic Retinopathy Diffusion Drug Delivery Systems Elderly Endocytosis Endothelial Cells Exudative age-related macular degeneration Eye diseases Formulation Gliosis Goals Hela Cells Histologic Human Hypoxia Immune response Infection Inflammation Inflammatory Response Injections Integrin Binding Integrins Lasers Lesion Ligand Binding Ligands Lipids Malignant Neoplasms Mediating MicroRNAs Modification Mus Pathologic Patients Pharmaceutical Preparations Physiological Proteins Public Health RGD (sequence)Research Retina Retinal Degeneration Retinal Neovascularization Retinal Vein Occlusion Savings Signal Transduction Site Testing Therapeutic Effect Time Toxic effect Treatment Efficacy Tropism Vascular Diseases Vascular Endothelial Growth Factors Vision Work angiogenesis antagonist base delivery vehicle exosome extracellular extracellular vesicles in vivo inhibitor innovation intravitreal injection mouse model nanoparticle nanosized neovascularization novel novel strategies ocular neovascularization overexpression receptor socioeconomics treatment strategy uptake

项目摘要

Abstract Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent monotherapy is the current mainstay for treating neovascular age-related macular degeneration (NVAMD). However, despite its vision saving benefit, some patients fail to respond to the treatment because of insufficient therapeutic effect and/or the socioeconomic burden of frequently required repeat injection. Therefore, the long-term goal of our studies is to develop superior or adjunctive approaches to the current anti-VEGF therapy that can provide active targeting of NVAMD, have the capacity to deliver multiple drugs, and maintain long-term efficacy. Exosomes are naturally occurring, cell- secreted, and nano-sized extracellular vesicles capable of carrying various cargos including microRNAs, proteins, and lipids for cell-to-cell communications. Based on these characteristics, exosomes have great potential to be used as novel carriers for intraocular drug delivery. Recently, we have shown that ASL-exosomes composed of Anchor, Spacer, and Arg-Gly-Asp acid (RGD) Ligand-modification actively target angiogenesis in cancer. However, studies demonstrating the utility of exosomes in intraocular drug delivery systems remains to be explored. The overall objectives of this application are to develop a novel ASL-exosome based intraocular drug delivery system for the treatment of NVAMD that actively targets ocular neovascularization (NV) and can deliver multiple drugs with sustained efficacy. The central hypothesis of the proposal is that ASL-exosomes can co- deliver Eylea and miR-24, a new intracellular target for choroidal NV, and effectively suppress NV by active targeting and sustained drug delivery with minimal immune responses. We hypothesize that localized delivery of ASL-exosomes to NV lesions using RGD-integrin ligand binding mediated active targeting will also increase intracellular uptake of ASL-exosomes by integrin receptor-mediated intracellular endocytosis. The central hypothesis will be tested by pursuing two specific aims. Aim 1 is to determine the mechanism by which ASL- exosomes actively target ocular NV and to evaluate whether RGD mediated active intracellular uptake of ASL- exosomes bypasses ocular cell tropism directed intracellular uptake of exosomes. Aim 2 is to determine sustained multi-drug delivery using ASL-exosomes and related immune response. The research proposed in this application is innovative, because the combination of an exosome-based intraocular drug delivery system with active targeting is a novel strategy that has potential to change the current treatment paradigm from passive targeting-directed monotherapy to active targeting-directed multi-drug delivery with sustained efficacy for the treatment of various retinal and choroidal vascular diseases, such as NVAMD, diabetic retinopathy and retinal vein occlusion.

抽象的玻璃体内注射抗血管内皮生长因子（VEGF）药物单一疗法是目前的主流用于治疗新生血管性年龄相关性黄斑变性（NVAMD）。然而，尽管它有保护视力的好处，一些患者由于治疗效果不足和/或社会经济状况而对治疗没有反应经常需要重复注射的负担。因此，我们研究的长远目标是培养优秀的人才或当前抗 VEGF 疗法的辅助方法，可以主动靶向 NVAMD，输送多种药物并保持长期疗效的能力。外泌体是天然存在的、细胞分泌的纳米级细胞外囊泡，能够携带各种货物，包括 microRNA、蛋白质、和用于细胞间通讯的脂质。基于这些特性，外泌体具有巨大的潜力用作眼内药物输送的新型载体。最近，我们发现 ASL-外泌体由锚定基、间隔基和精氨酸-甘氨酸-天冬氨酸 (RGD) 配体修饰可主动靶向癌症中的血管生成。然而，证明外泌体在眼内药物递送系统中的效用的研究仍有待进一步研究。探索过。本申请的总体目标是开发一种基于 ASL 外泌体的新型眼内药物用于治疗 NVAMD 的输送系统，主动靶向眼部新生血管 (NV)，并可输送多种药物，疗效持续。该提案的中心假设是 ASL-外泌体可以共同递送 Eylea 和 miR-24（脉络膜 NV 的新细胞内靶点），并通过活性有效抑制 NV 以最小的免疫反应进行靶向和持续药物输送。我们假设本地化交付使用RGD-整合素配体结合介导的主动靶向的ASL-外泌体对NV病变的作用也将增加通过整合素受体介导的细胞内内吞作用对 ASL-外泌体进行细胞内摄取。中央假设将通过追求两个具体目标来检验。目标 1 是确定 ASL- 外泌体主动靶向眼部 NV 并评估 RGD 是否介导 ASL-的主动细胞内摄取外泌体绕过了眼部细胞向性引导的外泌体的细胞内摄取。目标 2 是确定使用 ASL-外泌体和相关免疫反应进行持续的多药物递送。该研究提出于该应用具有创新性，因为结合了基于外泌体的眼内药物递送系统主动靶向是一种新颖的策略，有可能改变当前被动治疗模式靶向定向单一疗法到主动靶向定向多药递送，具有持续疗效治疗各种视网膜和脉络膜血管疾病，如NVAMD、糖尿病性视网膜病变和视网膜病变静脉闭塞。