Systemic nanotherapies for ocular inflammation and choroidal neovascularization.

用于眼部炎症和脉络膜新生血管形成的全身纳米疗法。

• 批准号: 9052766
• 负责人: Kannan Rangaramanujam
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052766
• 关键词: Adverse effects; Age related macular degeneration; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Attenuated; Biodistribution; Blindness; Blood; Blood Circulation; Cells; Chemistry; Choroid; Choroidal Neovascularization; Clinical; Combined Modality Therapy; Cysteine; Dendrimers; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug usage; Drug vehicle; Early treatment; Exudative age-related macular degeneration; Eye; Fluorescence; Generations; Health; Human; Hydroxyl Radical; Immunohistochemistry; Implant; Inflammation; Interdisciplinary Study; Label; Lipids; Measures; Mediating; Microglia; Mission; Modeling; Nanotechnology; Older Population; Organ; Oxidative Stress; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacotherapy; Play; Public Health; Radiation; Radioactive; Rattus; Research; Retina; Retinal; Role; Staging; Testing; Thick; Time; Toxic effect; Triamcinolone Acetonide; United States National Institutes of Health; Work; attenuation; base; compliance behavior; cost; cyanine dye 5; cytokine; geographic atrophy; improved; insight; macrophage; nanoparticle; nanotherapy; neuroprotection; response; systemic toxicity; targeted treatment; therapy development; time use; uptake

 DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in older people. Inflammation, mediated by activated microglia/macrophages (mi/ma), plays a key role in the pathogenesis of both geographic atrophy and exudative AMD, in humans and in animal models. Development of systemic drug delivery approaches targeting these cells to treat ocular inflammation and choroidal neovascularization (CNV), can have significant benefits, in addition to providing insights on the role of mi/ma on AMD therapy. Such therapies may improve patient compliance, reduce side effects arising from intravitreal implants and free drugs, reduce costs, and allow therapies during early stages of AMD. Understanding and utilizing the transport of nanoparticles from blood to the choroid/retina may provide new avenues for systemic drug delivery. We explored globular, polyamidoamine (PAMAM) dendrimers, with favorable physicochemical attributes. Our preliminary results in a lipid-induced rat dry/wet AMD model demonstrate that systemic hydroxyl-functionalized PAMAM dendrimers: (1) can target activated mi/ma in the areas of choroidal neovascularization and retinal inflammation, and be selectively retained for a sustained period of time; (2) can deliver anti-inflammatory, anti- oxidant N-acetyl cysteine (NAC) to attenuate proinflammatory cytokines, and cause significant CNV suppression, when administered in early stages (day 3 after lipid, `dry' AMD); (3) deliver a combination of NAC and triamcinolone acetonide (TA), to cause CNV regression, when administered in late stages (day 11 after lipid, `wet' AMD); We explore three aims: (1) Determine whether systemic dendrimer-drug conjugates selectively localize and retain in activated microglia/macrophages in the choroid/retina, and whether an increase in dendrimer size improves such localization and retention in the rat AMD model. (2) Determine the ocular toxicity of the systemic dendrimer vehicle in healthy rats, and characterize pharmacokinetics and biodistribution of the conjugated drugs in the rat CNV model. (3) Determine if systemically administered D-NAC and/or D-TA conjugates attenuate inflammation, suppress and cause regression of CNV in the rat AMD model. If successful, these studies offer potential for targeted therapies for dry/wet AMD, and broad clinical adaptation.

 描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是老年人失明的主要原因。在人类和动物模型中，由活化的小胶质细胞/巨噬细胞（mi/ma）介导的炎症在地图状萎缩和渗出性AMD的发病机制中起关键作用。开发靶向这些细胞的全身性药物递送方法以治疗眼部炎症和脉络膜新生血管形成（CNV），除了提供关于mi/ma对AMD治疗的作用的见解之外，还可以具有显著的益处。这样的疗法可以改善患者依从性，减少由玻璃体内植入物和免费药物引起的副作用，降低成本，并且允许在治疗期间进行治疗。 早期AMD理解和利用纳米颗粒从血液到脉络膜/视网膜的运输可以为全身药物递送提供新的途径。我们探讨了球形，聚酰胺胺（PAMAM）树枝状聚合物，具有良好的物理化学属性。我们在脂质诱导的大鼠干/湿AMD模型中的初步结果表明，全身羟基官能化的PAMAM树枝状聚合物：（1）可以靶向脉络膜新生血管和视网膜炎症区域中的活化的mi/ma，并且选择性地持续保留一段时间;（2）可以递送抗炎、抗氧化剂N-乙酰半胱氨酸（NAC）以减弱促炎细胞因子，并引起显著的CNV抑制，当在早期阶段给药时（脂质、“干性”AMD后第3天）;（3）递送NAC和曲安奈德（TA）的组合，以在晚期施用时引起CNV消退（脂质，“湿性”AMD后第11天）;我们探索三个目标：（1）确定全身性树枝状聚合物-药物缀合物是否选择性地定位并保留在脉络膜/视网膜中的活化的小胶质细胞/巨噬细胞中，以及树枝状聚合物尺寸的增加是否改善了大鼠AMD模型中的这种定位和保留。(2)确定全身性树枝状聚合物媒介物在健康大鼠中的眼毒性，并表征缀合药物在大鼠CNV模型中的药代动力学和生物分布。(3)确定在大鼠AMD模型中全身施用D-NAC和/或D-TA缀合物是否减轻炎症、抑制CNV并引起CNV消退。如果成功的话，这些研究为干/湿型AMD的靶向治疗提供了潜力，并具有广泛的临床适应性。