Treatment of lupus nephritis with nanoparticles that selectively target kidney glomeruli

用选择性靶向肾小球的纳米颗粒治疗狼疮性肾炎

基本信息

批准号：
10679184
负责人：
RUISHENG LIU
金额：
$ 57.92万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679184
关键词：
American Autoimmune Diseases Binding Biodistribution Biological Blood Cells Chitosan Collagen Type IV Coupled Coupling Data Dendritic Cells Deposition Development Disease Dose Drug Delivery Systems Drug Kinetics Drug Targeting Encapsulated End stage renal failure Endothelium Evaluation Exhibits Extravasation Fenestrated Capillary Flow Cytometry Fluorescent Dyes Gene Delivery Glomerular Filtration Rate Goals Histology Histopathology Hour Immune Immune Tolerance Immune response Immunoglobulin G In Vitro Incidence Injections Kidney Kidney Glomerulus Label Laboratories Liposomes Liquid substance Liver Lupus Lupus Nephritis Morbidity - disease rate Morphology Mus Nephrons Particle Size Pathogenesis Patients Peptides Pharmaceutical Preparations Proteinuria Regulatory T-Lymphocyte Renal function Role Safety Signal Transduction Site Spleen Symptoms System Systemic Lupus Erythematosus Techniques Therapeutic Therapeutic immunosuppression Validation biomaterial compatibility controlled release crosslink design glomerular basement membrane improved in vivo innovation local drug delivery lupus prone mice mortality mouse model nanoparticle nanoparticle delivery new therapeutic target novel novel therapeutic intervention prednisolone side effect single-cell RNA sequencing surface coating targeted treatment therapeutic nanoparticles therapeutic target tool transcriptome sequencing tripolyphosphate zeta potential

项目摘要

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. Lupus nephritis is the renal involvement in SLE with predominate glomerulus damage and exhibits a wide variety of symptoms from asymptomatic proteinuria to end-stage renal disease. Lupus nephritis requires aggressive immunosuppressive therapy, however, unfortunately most of these medications are associated with severe side effects. Therefore, development of new treatment strategies is essential. The goal of this proposal is to develop a nanoparticle delivery system that enables targeted drug delivery with stable and sustained release of prednisolone at the glomeruli as a novel therapeutic approach for lupus nephritis. Collagen IV (Col4)-α3,4 and 5 are expressed in the glomerular basement membrane (GBM), which is the only site in the body that Col4 has direct contact with blood via fenestrated capillary endothelium. Liposomes are one of the most widely used carriers due to their excellent biocompatibility and non-immunogenicity, but are lack of stability in terms of leakage of the encapsulated contents. Tripolyphosphate (TPP) cross-linked chitosan nanoparticles are characterized with controlled release of the loaded contents. Consequently, we hypothesize that by coupling Col4 binding peptides on the shell of liposomes filled with TPP-chitosan nanoparticles, we would make a kidney glomerulus selective delivery system with stable and sustained release of the loaded contents. We further hypothesize that this system loaded with prednisolone exhibits highly therapeutic efficiency due to the locally sustained drug release at a high concentration, meanwhile, it significantly minimizes the systemic side effects due to the very low dose of total prednisolone administered.

全身性红斑狼疮（SLE）是一种典型的自身免疫性疾病。狼疮肾炎是肾脏参与SLE的主要肾小球损害，并表现出各种症状无症状的蛋白尿至末期肾脏疾病。狼疮性肾炎需要侵略性免疫抑制但是，不幸的是，这些药物大多数与严重的副作用有关。所以，制定新的治疗策略至关重要。该提案的目的是开发一个纳米颗粒输送系统，该系统可以通过肾小球在肾小球上的稳定和持续释放，是狼疮肾炎的一种新型治疗方法。胶原蛋白IV（COL4）-α3,4和5在肾小球基底膜（GBM）中表达，这是唯一的 Col4通过毛细管内皮直接与血液接触的位置。脂质体是一个由于其出色的生物相容性和非免疫原性，使用最广泛的载体，但缺乏就包封的内容的泄漏而言稳定性。三聚磷酸盐（TPP）交联的壳聚糖纳米颗粒的特征是加载内容的受控释放。因此，我们假设通过将col4结合肽耦合到充满TPP-Chitosan纳米颗粒的脂质体的壳上，我们将使肾脏肾小球选择性输送系统具有稳定且持续的载荷内容物的释放。我们进一步假设，该系统加载了泼尼松龙与此由于总泼尼松龙的剂量非常低而产生的影响。