Identification of eye-homing peptides and their use for targeted liposomal drug delivery in posterior uveitis

眼归巢肽的鉴定及其在后葡萄膜炎靶向脂质体药物递送中的应用

基本信息

批准号：
10612913
负责人：
KAMAL D MOUDGIL
金额：
$ 19.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612913
关键词：
Address Adjuvant Arthritis Adverse effects Affect Alzheimer&apos s Disease Amino Acids Animal Cancer Model Animals Antibodies Antigens Arthritis Attention Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Bacteriophages Binding Biological Availability Biology Blindness Blood Vessels Blood-Retinal Barrier Cells Characteristics Choroid Chronic Disease Collaborations Cyclic Peptides Cysteine Disease Drug Delivery Systems Drug Targeting Encapsulated Endothelium Experimental Autoimmune Encephalomyelitis Eye Eye diseases Gene Expression Profiling Hemorrhage Heterogeneity Home Homing Human Hypoxia Immune Immunization Individual Inflammation Inflammation Mediators Joints Lesion Libraries Ligands Liposomes Lymphoid Tissue Mediator Methodology Methods Methotrexate Modeling Molecular Molecular Profiling Multiple Sclerosis Neural Retina Organ Oxygen Pathogenesis Pathogenicity Pathology Peptide Library Peptide Phage Display Library Peptides Peripheral Pharmaceutical Preparations Pharmacodynamics Posterior Uveitis Procedures Process Proteins Publishing Rattus Reporting Retina Retinal Detachment Retinal Diseases Rheumatoid Arthritis Rodent Site Specificity T-Lymphocyte Testing Tissues Topical application Toxic effect Uvea Uveitis Vascular Endothelium Visual impairment Work anterior chamber autoimmune pathogenesis autoimmune uveitis autoreactive T cell design human model improved in vivo innovation interstitial retinol-binding protein intravitreal injection medication safety migration molecular marker nanoparticle neoplastic cell novel novel therapeutics posterior eyeball chamber protein aminoacid sequence screening systemic toxicity tool trafficking tumor

项目摘要

Human posterior segment uveitis of autoimmune origin is a chronic disease that can impair vision and result in blindness. A variety of autoantigens, including interphotoreceptor retinoid binding protein (IRBP), have been implicated in uveitis pathogenesis. The T cells reactive against these antigens access the eye through the blood-retinal barrier and cause local inflammation and tissue damage. Two of the main challenges in non- infectious posterior uveitis are – 1) to define the molecular changes induced during uveitis in endothelium of the choroidal and retinal vasculature, and 2) to devise novel ways to direct the systemically-administered drugs primarily into the eye to enhance their efficacy but minimize adverse effects. We hypothesize that the vascular endothelium of the eye in uveitis is characterized by unique molecular markers that facilitate both selective migration of the pathogenic T cells into the target organ and cellular interaction with the inducers/ mediators of inflammation and tissue damage. Accordingly, the identification of peptide ligands (by phage peptide library screening) that interact with such markers would be invaluable tools to study disease pathogenesis. Furthermore, these peptide ligands can be exploited for targeted drug delivery to the eye with the objective of enhancing efficacy, but reducing systemic toxicity of those drugs. In collaboration with Dr. Erkki Ruoslahti (Sanford-Burnham, La Jolla), who pioneered the concept of vascular ‘address molecules’ or ‘zip codes’, we published a study on the molecular profiling of the synovial vasculature in adjuvant arthritis in rats (PNAS 2011). We identified unique joint-homing peptide ligands using an innovative approach of ex vivo/ in vivo enrichment of clones from a phage peptide-display library. Recently, we also reported CNS-homing peptides in the EAE model of human multiple sclerosis. The advantage of using phages to detect tissue-specific markers is that there is no a priori bias in predicting the peptide sequences/motifs. And, unlike antibodies, phage peptides interact with functional domains of target molecules. We now plan to apply this methodology to rat experimental autoimmune uveitis (EAU). The aims of our study in collaboration with experts in EAU (Dr. Caspi and Dr. Sun), [in vascular biology (Dr. Teesalu from Ruoslahti group), and in pharmacodynamics (Dr. Swaan)] are: Aim 1. To identify peptide ligands homing to the diseased eye in EAU using the ex vivo/ in vivo screening of phage peptide library. (a) To identify unique peptide-encoding phages that home to the vasculature and retina of the diseased eye; and (b) to determine the relative specificity of select phages/ peptides [for other tissues within the eye as well as other organs in EAU versus control (healthy/EAE) rats.] Aim 2. To use the eye-homing peptides for targeted drug delivery to the diseased sites in EAU. To use a specific peptide to guide liposomes encapsulating a drug (e.g., methotrexate) [to the diseased sites in eyes in EAU, and compare the pharmacodynamics and safety of that drug] with that using plain liposomes or free drug. The results would advance understanding of pathogenesis of human uveitis and designing of novel therapies.

自身免疫性人类后段葡萄膜炎是一种慢性疾病，可损害视力和多种自身抗原，包括光感受器间视黄醇结合蛋白（IRBP），可导致失明。与葡萄膜炎发病机制有关，针对这些抗原的 T 细胞通过眼睛进入眼睛。血视网膜屏障并引起局部炎症和组织损伤是非治疗中的两个主要挑战。传染性后葡萄膜炎是 – 1) 定义葡萄膜炎期间内皮细胞引起的分子变化脉络膜和视网膜脉管系统，2) 设计新的方法来指导全身给药主要进入眼睛以增强其功效，但最大限度地减少不良影响。葡萄膜炎眼内皮的特征是独特的分子标记，可促进选择性致病性 T 细胞迁移至靶器官以及细胞与诱导剂/介质的相互作用相应地，肽配体的鉴定（通过噬菌体肽库）。与这些标记相互作用的筛选）将是研究疾病发病机制的宝贵工具。此外，这些肽配体可用于将药物靶向输送至眼睛，目的是与 Erkki Ruoslahti 博士合作，提高疗效，但降低这些药物的全身毒性。（Sanford-Burnham，La Jolla）率先提出了血管“地址分子”或“邮政编码”的概念，我们发表了一项关于大鼠佐剂性关节炎滑膜血管系统分子谱的研究（PNAS 2011）我们使用离体/体内创新方法鉴定了独特的关节归巢肽配体。最近，我们还报道了噬菌体肽展示文库中的中枢神经系统归巢肽。人类多发性硬化症的EAE模型使用噬菌体检测组织特异性标记物的优势。与抗体、噬菌体不同的是，在预测肽序列/基序时不存在先验偏差。我们现在计划将这种方法应用于大鼠。实验性自身免疫性葡萄膜炎 (EAU) 我们与 EAU 专家（Caspi 博士）合作进行研究的目的。和孙博士），[血管生物学（Ruoslahti 小组的 Teesalu 博士）和药效学（Swaan 博士）] 目标 1. 使用离体/体内鉴定 EAU 中归巢至患病眼睛的肽配体噬菌体肽库的筛选 (a) 鉴定编码噬菌体的独特肽。患病眼睛的脉管系统和视网膜；以及（b）确定选定噬菌体的相对特异性/ 肽[EAU 与对照（健康/EAE）大鼠眼内其他组织以及其他器官的比较。] 目标 2. 使用眼归巢肽将药物靶向递送至 EAU 中的病变部位。一种特定的肽，用于引导包裹药物（例如甲氨蝶呤）的脂质体[到眼睛的患病部位 EAU，并比较该药物与使用普通脂质体或游离药物的药效学和安全性。这些结果将促进对人类葡萄膜炎发病机制的理解和新疗法的设计。