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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.

系统性红斑狼疮(SLE)是一种典型的自身免疫病。狼疮性肾炎是指肾脏以肾小球损害为主的系统性红斑狼疮，并表现出多种症状无症状蛋白尿到终末期肾病。狼疮性肾炎需要积极的免疫抑制然而，不幸的是，大多数这些药物都与严重的副作用有关。因此，开发新的治疗策略是至关重要的。这项提议的目标是开发一种纳米颗粒递送系统，该系统能够通过强的松龙在肾小球的稳定和持续释放是狼疮性肾炎的一种新的治疗方法。 IV型胶原(COL4)-α3、4和5在肾小球基底膜表达，是唯一的体内COL4通过有孔的毛细血管内皮细胞与血液直接接触的部位。脂质体是一种由于其良好的生物相容性和非免疫原性，是使用最广泛的载体之一，但缺乏在密封内容物泄漏方面的稳定性。三聚磷酸盐(TPP)交联壳聚糖纳米颗粒的特征是对所加载的内容物进行控制释放。因此，我们假设通过将COL4结合肽偶联到填充了TPP-壳聚糖纳米颗粒的脂质体外壳上，我们将制备稳定、持续释放所载内容物的肾小球选择性给药系统。我们进一步假设，该系统负载强的松龙显示出很高的治疗效率，因为在高浓度的局部药物缓释的同时，它显著减少了全身副作用由于总剂量很小的强的松龙所致的效果。