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; 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.

当前对湿年龄相关的黄斑变性（AMD）的护理标准，玻璃体内注射 血管内皮生长因子（VEGF）抑制剂已改变了治疗范例。但是，很多 AMD脉络膜新生血管形成（CNV）的患者无法对抗VEGF治疗做出反应或受​​苦 来自与重复玻璃体内注射有关的并发症。因此，非常需要 开发替代治疗方式，包括新型治疗剂和输送方法， AMD患者的CNV战斗CNV。 某些整联蛋白在脉络膜和视网膜新生儿腔内的选择性表达使整联蛋白成为 理想的目标，而整联蛋白拮抗剂的递送可以使用干细胞衍生的纳米层进行设计 具有生物相容性且适合跨越眼屏障的系统。我们假设修改 干细胞衍生的超帕磁铁氧化铁颗粒（SPIO）标记的外泌体以递送整联蛋白 拮抗剂将提供有效的疗法剂，以有效抑制或回归CNV，并直接抑制CNV 可视化和定量评估体内药物分布。在特定目标1中，我们将发展并完全 表征纳米层配方并测试其细胞毒性，抗血管生成特性以及 磁颗粒成像（MPI）灵敏度。在特定目标2中，我们将测试以下假设 纳米层系统提高了CNV在体内的治疗功效，并启用MPI成像进行纵向成像 药物分布的定量。在此目标中，我们将确定SPIO标记的药物偶联的效果 关于IASER诱导的CNV的纳米嵌段，并通过非侵入性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，MPI专业知识的独特组合 成像和视网膜疾病的动物模型，以应对有效输送药物的关键挑战 眼后部分。成功完成拟议活动将产生巨大的影响 为了推进干细胞衍生的纳米层的发展，作为治疗眼的新型治疗剂 血管疾病和其他与血管生成有关的疾病。