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性疾病。参与以肾小球损伤为主的 SLE，并表现出多种症状无症状蛋白尿至终末期肾病需要积极的免疫抑制。然而，不幸的是，大多数这些药物都会产生严重的副作用。制定新的治疗策略至关重要。该提案的目标是开发一种纳米颗粒递送系统，能够实现靶向药物递送在肾小球稳定持续释放泼尼松龙作为狼疮性肾炎的新型治疗方法。 IV 型胶原蛋白 (Col4)-α3,4 和 5 在肾小球基底膜 (GBM) 中表达，这是唯一的 Col4 通过有孔毛细血管内皮与血液直接接触的部位之一。由于其优异的生物相容性和非免疫原性，成为最广泛使用的载体，但缺乏三聚磷酸盐（TPP）交联壳聚糖的泄漏稳定性。纳米颗粒的特点是负载内容物的受控释放。通过将 Col4 结合肽偶联到填充有 TPP-壳聚糖纳米颗粒的脂质体外壳上，我们可以制作肾小球选择性递送系统，稳定且持续释放负载内容物。我们进一步探索，该加载泼尼松龙的系统由于以下原因而表现出很高的治疗效率：局部高浓度药物持续释放，同时显着减少全身副作用由于施用的总泼尼松龙剂量非常低而产生的影响。