Theranostic Nanovesicles for Ocular Angiogenesis Therapy

用于眼部血管生成治疗的治疗诊断纳米囊泡

• 批准号: 10556380
• 负责人: Yingli Fu
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10556380
• 关键词: Address; Advanced Development; Adverse effects; Age related macular degeneration; Angiogenesis Inhibitors; Animal Model; Binding; Biological; Blindness; Cataract; Cells; Choroidal Neovascularization; Deterioration; Developed Countries; Diabetic Retinopathy; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Electroporation; Endophthalmitis; Engineering; Exudative age-related macular degeneration; Eye; Eye diseases; Formulation; Image; In Vitro; Injections; Integrin alpha5beta1; Integrin alphaVbeta3; Integrins; Ionizing radiation; Label; Lasers; Legal Blindness; Lesion; Liquid substance; Magnetism; Malignant Neoplasms; Mediating; Medical; Mesenchymal Stem Cells; Methods; Modality; Modification; Mus; Ophthalmology; PUVA Photochemotherapy; Pathologic Neovascularization; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Posterior eyeball segment structure; Property; Rattus; Recovery; Research; Resolution; Retina; Retinal Detachment; Retinal Diseases; Stem Cell Development; System; Testing; Therapeutic Agents; Time; Tissues; Treatment Efficacy; Vascular Diseases; Vascular Endothelial Growth Factors; Vision; Visualization; aged; alternative treatment; angiogenesis; antagonist; biomaterial compatibility; combat; cytotoxicity; drug distribution; exosome; imaging modality; immunogenicity; immunoregulation; improved; in vivo; inhibitor; intravitreal injection; iron oxide; iron oxide nanoparticle; laminin gamma 1; laser photocoagulation; legally blind; molecular imaging; nanocarrier; nanoengineering; nanoparticle; nanoparticle delivery; nanotechnology platform; nanovesicle; neovascular; neovasculature; non-invasive imaging; novel; novel therapeutics; ocular angiogenesis; ocular neovascularization; particle; quantitative imaging; selective expression; serial imaging; standard of care; stem cell exosomes; stem cells; superparamagnetism; theranostics; therapeutic angiogenesis; tomography; tool; tumor growth

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.

目前治疗湿性年龄相关性黄斑变性（AMD）的标准是玻璃体内注射 血管内皮生长因子（VEGF）抑制剂改变了治疗模式。然而，许多 患有脉络膜新生血管 (CNV) 的 AMD 患者要么对抗 VEGF 治疗无反应，要么遭受痛苦 避免与重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，包括新型治疗剂和递送方法，以 对抗 AMD 患者的 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得整合素成为 理想的靶标，而整合素拮抗剂的递送可以使用干细胞衍生的纳米囊泡进行设计 具有生物相容性且易于跨越眼部屏障的系统。我们假设修改 干细胞来源的超顺磁性氧化铁颗粒 (SPIO) 标记的外泌体可传递整合素 拮抗剂将提供有效的治疗诊断剂，有效抑制或消退 CNV，并能够直接 可视化并定量评估药物在体内的分布。在具体目标 1 中，我们将发展并充分 表征纳米囊泡制剂并测试其细胞毒性、抗血管生成特性以及 磁粒子成像 (MPI) 灵敏度。在具体目标 2 中，我们将检验以下假设： 纳米囊泡系统提高了 CNV 的体内治疗效果，并使纵向 MPI 成像成为可能 药物分布的量化。为此，我们将确定 SPIO 标记的药物缀合的效果 激光诱导的 CNV 上的纳米囊泡，并通过无创 MPI 成像分析药物分布动力学。 拟议的研究将眼科、药物输送、MPI 方面的专业知识独特地结合起来 成像和视网膜疾病动物模型，以解决高效药物输送的关键挑战 眼睛的后段。成功完成拟议活动将产生巨大影响 促进干细胞衍生纳米囊泡作为治疗眼部疾病的新型治疗诊断剂的发展 血管疾病和其他血管生成相关疾病。