Topical Drug Delivery for Treating Macular Degeneration

治疗黄斑变性的局部给药

• 批准号: 10338098
• 负责人: Nathan RAVI
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10338098
• 关键词: Adult; Affect; Affinity; Age; Age related macular degeneration; Age-Years; Angiogenesis Inhibitors; Anterior; Antibodies; Biological Assay; Blindness; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood-Retinal Barrier; Bypass; Capsid Proteins; Caring; Cell Proliferation; Cell Surface Receptors; Cells; Choroid; Choroid Melanoma; Choroidal Neovascularization; Cicatrix; Citrates; Clinical; Confocal Microscopy; Diabetic Retinopathy; Diagnostic; Disease; Drops; Drug Delivery Systems; Electrons; Electroretinography; Endothelial Cells; Epithelial; Equus caballus; Exhibits; Eye; Eye diseases; Fibroblasts; Fluorescein Angiography; Functional disorder; Funding; Ganglionic Layer; Generations; Glaucoma; Growth; Histologic; Histology; Home; Human; Hyaluronic Acid; Image; In Vitro; Inflammation; Inflammatory; Injections; Lasers; Left; Legal Blindness; Ligands; Liquid substance; Macular degeneration; Malignant Neoplasms; Metals; Methods; Mitochondria; Muller' s cell; Mus; Nanosphere; Neoplasm Metastasis; Neovascular Glaucoma; Nutrient; Ophthalmology; Optical Coherence Tomography; Oxygen; Pathology; Pathway interactions; Patient Noncompliance; Patients; Permeability; Persons; Pharmaceutical Preparations; Prevention; Procedures; Proliferating; Property; Proteins; Protocols documentation; Reaction; Reactive Oxygen Species; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinoblastoma; Route; Shapes; Specificity; Spectrum Analysis; Structure of retinal pigment epithelium; Surface Plasmon Resonance; Surface Properties; Tail; Technology; Testing; Therapeutic; Topical application; Toxic effect; Transmission Electron Microscopy; Treatment Cost; United States Department of Veterans Affairs; United States National Institutes of Health; Vascular Diseases; Vascular Endothelial Growth Factors; Veins; Veterans; Vision; angiogenesis; aqueous; biomaterial compatibility; blood vessel development; cancer cell; cancer therapy; cell growth; clinical translation; combat; compliance behavior; design; effective therapy; electric impedance; ganglion cell; glaucoma surgery; hyaluronate; in vivo; intravenous administration; intravitreal injection; light scattering; macromolecule; macula; mouse model; nano; nanoGold; nanocarrier; nanoparticle; nanoparticle delivery; nanoparticle drug; nanorod; nanotechnology platform; new growth; novel; overexpression; particle; photothermal therapy; prevent; prototype; real time monitoring; receptor; receptor mediated endocytosis; targeted delivery; theranostics; tissue culture; transcytosis; treatment strategy

Many blinding eye diseases, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR), are commonly seen in veterans. If left untreated, both AMD and DR can result in irreversible blindness. Both diseases exhibit increased permeability of blood vessels in the macula (central) portion below the retina, the choroid, leading to abnormal fluid accumulation and vision loss. The dry form of AMD does not cause much vision reduction; however, the wet form (10-15% of AMD) is associated with leaky new blood vessels (angiogenesis) and can destroy the central vision. The wet form of AMD is treated with an intravitreal injection of antibodies, a therapy that has transformed eye care. However, intravitreal injections are associated with complications, and patient compliance is poor. Ideally, topical delivery of large molecules to the retina would be preferable, because patients could administer the drug in the comfort of their home. The over-expression of cluster of differentiation 44 (CD44) cell surface receptors is a common feature of many blinding diseases, which offers a fortunate opportunity for research. Overexpression is frequently observed during disease proliferation and inflammation, as well as in cancer growth and metastasis. Retinal pigment epithelial (RPE) cells, as well as the Müller cells and the ganglion cells in the retina, express CD44 receptors in their normal state and overexpress them in disease states. CD44 receptors have an affinity for hyaluronic acid (HA) that enables cells to internalize large molecules that have HA attached to them. Thus, coating drug nanoparticles (NPs) with HA can deliver more drugs to cells that overexpress CD44 receptors and also enable receptor-mediated endocytosis, providing a transcytosis pathway to bypass the ocular barriers. Although any drug-NP can be coated with HA, in this proposal, we will use gold nanoparticles (AuNPs) because their size, shape, and surface properties can be precisely altered. Further, their unique surface plasmon resonance effect can be used for imaging and photothermal therapy, while their anti-angiogenic properties are useful for therapeutic applications. Au-nanorods, in particular, possesses superior photothermal conversion properties. During choroidal neovascularization (CNV), endothelial cells over-express CD44 and release vascular endothelial growth factors, so the innate antiangiogenic activity of AuNPs can be tested. Our strategically designed nanoplatform will enable us to carry various payloads across the barriers and to effectively treat potentially blinding diseases. The proposed research is expected to assess the two routes of administration (for greater specificity, better efficiency, and higher biocompatibility) of our targeted nanoplatform to the retina. This contribution will be significant, because it will both provide a formula for creating a smart biocompatible nano-core-shell carrier and identify a method for effective delivery of drugs to the eye, particularly to the retina. We will synthesize HA-coated au nanorods. Prior to in-vivo applications, we will test the NPs for biocompatibility in tissue culture on retinal pigment epithelial cells. Next, we will assess the efficacy of the Au- nanorods following topical and intravenous administrations in mice that have CNV in the macular region, induced by laser. We will check for retinal toxicity using electroretinography, optical coherence tomography, fluorescein angiography, and histology analysis. The application of HA-NPs can potentially be extended to treating retinal degeneration, choroidal melanoma, retinoblastoma, neovascular glaucoma, and many anterior segment diseases. Our HA-coated AuNP CD44- targeted delivery platform could also be used for cancer theranostics because cancer cells tend to proliferate and need new blood vessel formation for additional oxygen and nutrient supply. If we observe that HA-coated NPs, in addition to crossing the blood-retinal barrier, also cross the blood-brain barrier, we will explore these possibilities with additional collaborators in subsequent studies. Creating a smart nanocarrier can provide an effective treatment strategy, while also reducing treatment costs and increasing patient compliance.

许多致盲眼病，例如年龄相关性黄斑变性（AMD）和糖尿病性视网膜病变（DR）， 常见于退伍军人。如果不及时治疗，AMD 和 DR 都可能导致不可逆的失明。两个都 疾病表现出视网膜下方黄斑（中央）部分血管的通透性增加， 脉络膜，导致异常液体积聚和视力丧失。干性 AMD 不会造成太大影响 视力下降；然而，湿型（AMD 的 10-15%）与新血管渗漏有关 （血管生成）并且可以破坏中央视力。湿性 AMD 通过玻璃体内注射进行治疗 抗体，一种改变了眼部护理的疗法。然而，玻璃体内注射与 并发症多，患者依从性差。理想情况下，将大分子局部递送至视网膜将是 更好的是，因为患者可以在舒适的家中服用药物。 分化簇 44 (CD44) 细胞表面受体的过度表达是许多细胞的共同特征。 致盲疾病，这为研究提供了一个幸运的机会。经常观察到过度表达 在疾病增殖和炎症以及癌症生长和转移过程中。视网膜色素 上皮 (RPE) 细胞以及视网膜中的 Müller 细胞和神经节细胞表达 CD44 受体 它们在正常状态下表达，并在疾病状态下过度表达。 CD44 受体对透明质酸具有亲和力 (HA) 使细胞能够内化附着有 HA 的大分子。因此，包衣药物 含有 HA 的纳米粒子 (NP) 可以向过度表达 CD44 受体的细胞输送更多药物，并且还可以 受体介导的内吞作用，提供绕过眼屏障的转胞吞途径。虽然任何 drug-NP可以用HA包被，在这个提案中，我们将使用金纳米颗粒（AuNPs），因为它们的尺寸， 形状和表面特性可以精确改变。此外，它们独特的表面等离子共振效应 可用于成像和光热疗法，而它们的抗血管生成特性可用于 治疗应用。特别是金纳米棒具有优异的光热转换性能。 在脉络膜新生血管 (CNV) 过程中，内皮细胞过度表达 CD44 并释放血管 内皮生长因子，因此可以测试 AuNP 的先天抗血管生成活性。我们的战略 设计的纳米平台将使我们能够跨越障碍携带各种有效载荷并有效地处理 潜在的致盲疾病。拟议的研究预计将评估两种给药途径 （为了更大的特异性、更好的效率和更高的生物相容性）我们的目标纳米平台到视网膜。 这一贡献将是重大的，因为它将提供一个创建智能生物相容性的公式 纳米核壳载体并确定了一种将药物有效输送到眼睛，特别是视网膜的方法。 我们将合成HA涂层的金纳米棒。在体内应用之前，我们将测试纳米粒子 视网膜色素上皮细胞组织培养的生物相容性。接下来，我们将评估 Au- 的功效 对黄斑区有 CNV 的小鼠进行局部和静脉注射后的纳米棒， 由激光诱导。我们将使用视网膜电图检查、光学相干断层扫描、 荧光素血管造影和组织学分析。 HA-NPs 的应用有可能扩展到治疗视网膜变性、脉络膜黑色素瘤、 视网膜母细胞瘤、新生血管性青光眼和许多眼前节疾病。我们的 HA 涂层 AuNP CD44- 靶向递送平台也可用于癌症治疗诊断，因为癌细胞倾向于增殖 并且需要新的血管形成来提供额外的氧气和营养。如果我们观察到HA涂层 NPs除了可以穿过血视网膜屏障外，还可以穿过血脑屏障，我们将探讨这些 在后续研究中与其他合作者的可能性。创建智能纳米载体可以提供 有效的治疗策略，同时还可以降低治疗成本并提高患者的依从性。