Theranostic Nanovesicles for Ocular Angiogenesis Therapy

湿性老年性黄斑变性(AMD)玻璃体内注射的现行护理标准 血管内皮生长因子(VEGF)抑制剂已经改变了治疗模式。然而，许多人 伴有脉络膜新生血管(CNV)的AMD患者要么对抗血管内皮生长因子治疗无效，要么 避免与反复玻璃体内注射相关的并发症。因此，非常需要 开发替代治疗方式，包括新的治疗剂和给药方法，以 为AMD患者抗击CNV。 某些整合素在脉络膜和视网膜新生血管上的选择性表达使整合素成为 理想的靶点，而整合素拮抗剂的输送可以使用干细胞衍生的纳米微囊来实现 该系统具有生物兼容性，可跨越眼部屏障。我们假设这一修改 从干细胞衍生的超顺磁性氧化铁颗粒(SPIO)标记的外体中传递整合素 拮抗剂将提供一种有效的治疗药物，有效地抑制或消退CNV，具有直接 可视化和定量评估药物在体内的分布。在具体目标1中，我们将发展和充分 表征纳米微囊制剂，并测试其细胞毒性、抗血管生成特性以及 磁粉成像(MPI)灵敏度。在特定的目标2中，我们将检验这样的假设 纳米胶囊系统提高了CNV的体内治疗效果，并使MPI成像成为可能 药品分配的量化。在这个目标中，我们将确定SPIO标记的药物偶联的效果 在激光诱导的CNV上制备纳米微囊，并通过无创MPI成像分析药物分布的动力学。 拟议的研究带来了眼科、药物输送、MPI等方面的独特专业知识组合 成像和视网膜疾病的动物模型，以解决有效地将药物输送到 眼睛的后部。成功完成拟议的活动将产生巨大的影响 为促进干细胞衍生纳米囊作为新型眼科治疗药物的开发 血管疾病和其他与血管生成相关的疾病。

The current standard of care for wet age-related macular degeneration (AMD) with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors has transformed the treatment paradigm. However, many AMD patients with choroidal neovascularization (CNV) either fail to respond to anti-VEGF therapy or suffer from complications associated with repeated intravitreal injections. Therefore, there is great need for developing alternative treatment modalities, including novel therapeutic agents and delivery methods, to combat CNV for patients with AMD. The selective expression of certain integrins on choroidal and retinal neovasculature makes integrin an ideal target, while delivery of integrin antagonists can be engineered using stem cell-derived nanovesicle system that is biocompatible and amenable for crossing the ocular barriers. We hypothesize that modification of the stem cell-derived, superparamagnetic iron oxide particle (SPIO)-labeled exosomes to deliver an integrin antagonist will provide a potent theranostic agent to effectively inhibit or regress CNV with the ability to directly visualize and quantitatively assess drug distribution in vivo. In Specific Aim 1, we will develop and fully characterize the nanovesicle formulations and test their cytotoxicity, antiangiogenic property, as well as magnetic particle imaging (MPI) sensitivity. In Specific Aim 2, we will test the hypothesis that the engineered nanovesicle system improves the therapeutic efficacy of CNV in vivo and enables MPI imaging for longitudinal quantification of drug distribution. In this aim, we will determine the effect of SPIO-labeled, drug-conjugated nanovesicles on Iaser-induced CNV and analyze the kinetics of drug distribution by noninvasive MPI imaging. The proposed study brings a unique combination of expertise in ophthalmology, drug delivery, MPI imaging, and animal model of retinal diseases, to address the critical challenges for efficient drug delivery into the posterior segment of the eye. Successful completion of the proposed activities will have vast ramifications for advancing the development of stem cell-derived nanovesicles as novel theranostic agent for treating ocular vascular diseases and other angiogenesis-related disorders.