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Nanotechnology as a therapeutic approach in arteriovenous fistula maturation

纳米技术作为动静脉瘘成熟的治疗方法

基本信息

批准号：
10666430
负责人：
EDGAR A JAIMES
金额：
$ 43.45万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666430
关键词：
Affinity Animals Area Arteriovenous fistula Binding Biocompatible Materials Blood Vessels Blood flow Cardiovascular Diseases Cell Culture System Chronic Kidney Failure Circulation Clinical Data Development Dialysis procedure Disease Dose Limiting Drug Delivery Systems Drug Kinetics Drug Targeting Effectiveness Encapsulated Endothelial Cells Engineering Exhibits Exposure to Failure Gelatinase A Gelatinase B Gene set enrichment analysis Generations Goals Half-Life Hemodialysis Human Hyperplasia In Vitro Knock-out Knockout Mice Knowledge Ligands Liposomes Malignant Neoplasms Mediator Mission Modification Molecular Morbidity - disease rate Mus NADPH Oxidase Nanotechnology Operative Surgical Procedures P-Selectin Pathologic Pathway interactions Patients Peptides Pharmaceutical Preparations Phosphorylation Polysaccharides Prevention strategy Proto-Oncogenes Public Health Rattus Reactive Oxygen Species Renal function Research Rodent Role Serum Site Testing Therapeutic Tissues Toxic effect Ubiquitination United States United States National Institutes of Health Veins Work chemical property effective therapy fucoidan genetic approach improved inhibitor injured innovation intravenous administration intravenous injection mortality nanomedicine nanomolar nanoparticle nanoparticle delivery nanoparticle drug novel novel therapeutic intervention patient population posttranscriptional prevent promoter small molecule inhibitor targeted delivery transcription factor transcriptome sequencing treatment strategy

项目摘要

Arteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis patient population. Targeted nanomedicine is a rapidly growing area of research that is a promising approach to treat a wide spectrum of diseases, including cardiovascular disease and cancer. However, there is a paucity of research regarding the use of targeted nanomedicine to treat or prevent AVF maturation failure. Moreover, a better understanding of the pathways involved in AVF maturation failure is essential to develop novel therapeutic strategies, including targeted nanomedicine. The first objective of this proposal is to investigate the role of the transcription factor ETS proto-oncogene 1 (ETS-1), matrix metalloproteinase (MMP)-2, and MMP-9 in AVF development. Extensive work from our team has provided a strong rationale that the ETS-1 and MMP-2/9 axis is a major driver of pathological AVF remodeling. The second objective of this proposal is to investigate the effectiveness of drug-loaded P-selectin- targeted nanoparticles (NPs) to treat or prevent AVF maturation failure. AVF maturation failure is a regional problem, and therefore, targeted delivery of drugs to the AVF site may reduce dose-limiting toxicity, undesirable off-target effects, and unfavorable pharmacokinetics due to rapid drug degradation. We have recently engineered innovative NPs that display high affinity to P-selectin expressed in injured/activated endothelial cells. We found that AVF creation surgery was followed by increased P-selectin expression at the AVF site and that P-selectin- targeted NPs were preferentially aggregated at the AVF site. Furthermore, our team has developed various NPs for drugs with different sizes and chemical properties. The NPs for small drugs are based on fucoidan (a polysaccharide), which exhibits nanomolar affinity to P-selectin. The NPs for large drugs are based on liposomes conjugated with P-selectin ligands. Both carriers are made of natural and synthetic biocompatible materials that have been shown to be safe for use in humans. Our long-term goal is to develop novel therapeutic strategies to prevent AVF maturation failure that can ultimately be safely used in humans. Our central hypothesis is that maturation failure is caused by upregulated ETS-1 and MMP-2/9, and that the blockade of this pathway using nanoparticle-targeted delivery of drugs can improve AVF maturation. This hypothesis will be tested in two Specific Aims, using a combination of genetic approach (Aim 1) and nanotechnology (Aim 2). Aim 1: To determine the causal role of ETS-1 and MMP-2/9 in pathological AVF development in rodents with CKD. Aim 2: To investigate the therapeutic potency of ETS-1 and MMP-2/9 inhibition by targeted nanomedicine in enhancing AVF development in rodents with CKD. This translational project is innovative and significant, as it investigates a novel molecular pathway of AVF maturation failure and uses a novel nanotechnology for treating/preventing this clinical problem. Successful completion of these aims will identify important targets for developing innovative nanomedicine to enhance AVF maturation.

动静脉瘘（AVF）成熟失败是血液透析患者的一个重要临床问题