Topical Drug Delivery for Treating Macular Degeneration

治疗黄斑变性的局部给药

• 批准号: 10058218
• 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/10058218
• 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; 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.

许多盲目的眼部疾病，例如与年龄相关的黄斑变性（AMD）和糖尿病性视网膜病变（DR）， 通常在退伍军人中看到。如果未经治疗，AMD和DR都可能导致不可逆转的失明。两个都 暴露于视网膜以下的黄斑（中心）部分血管渗透性增加的疾病， 脉络膜，导致流体异常的积累和视力丧失。 AMD的干燥形式不会导致太多 降低视觉；但是，湿形式（AMD的10-15％）与泄漏的新血管有关 （血管生成），可以破坏中央视力。 AMD的湿形式用玻璃体内注射治疗 抗体，一种改变了眼部护理的疗法。但是，玻璃体内注射与 并发症和患者依从性很差。理想情况下，将大分子传递到视网膜的局部递送将是 最好，因为患者可以在家里舒适地服用药物。 分化44（CD44）细胞表面受体的过表达是许多人的常见特征 盲目疾​​病，这为研究提供了幸运的机会。经常观察到过表达 在疾病增殖和感染以及癌症生长和转移中。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 它们的正常状态并在疾病状态下过表达。 CD44受体对透明质酸具有亲和力 （HA）使细胞能够内化与它们附着在其上的大分子。那，涂料 带有HA的纳米颗粒（NP）可以向过表达CD44受体的细胞输送更多的药物，并启用 受体介导的内吞作用，提供了绕过眼屏障碍的跨介症途径。虽然有 Drug-np可以用HA涂覆，在此提案中，我们将使用金纳米颗粒（Aunps），因为它们的大小， 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体共振效果 可用于成像和光热疗法，而它们的抗血管生成特性对于 治疗应用。特别是Au纳米棒具有优质的光热转化特性。 在脉络膜新血管形成（CNV）期间，内皮细胞过表达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。我们的战略性 设计的纳米板将使我们能够在障碍物上携带各种有效载荷并有效治疗 潜在的盲目疾病。拟议的研究预计将评估两种管理途径 （为了提高特异性，提高效率和更高的生物相容性）我们对视网膜的纳米植物的纳米植物。 这项贡献将是重要的，因为这两个都将为创建智能生物相容性提供一个公式 纳米核壳载体并确定一种有效将药物递送到眼睛的方法，尤其是向视网膜输送的方法。 我们将合成涂有HA涂层的Au纳米棒。在进行体内应用程序之前，我们将测试NP的 视网膜色素上皮细胞上组织培养的生物相容性。接下来，我们将评估Au-的效率 在黄斑区域具有CNV的小鼠局部和静脉内施用后，纳米棒， 由激光诱导。我们将使用电视图，光学相干断层扫描，检查视网膜毒性， 荧光素血管造影和组织学分析。 HA-NP的应用可能会扩展到处理永久性变性，脉络膜黑色素瘤， 视网膜母细胞瘤，新生血管瘤和许多前部疾病。我们的HA涂层AUNP CD44- 靶向输送平台也可以用于癌症热剂，因为癌细胞倾向于增殖 并需要新的血管形成，以供额外的氧气和养分供应。如果我们观察到那个涂层 NP除了越过血视网膜屏障外，还穿过血脑屏障，我们将探索这些 在随后的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，同时还会降低治疗成本并提高患者依从性。