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

• 批准号: 10418812
• 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
• 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/10418812
• 关键词: Affinity; Animals; Area; Arteriovenous fistula; Binding; Biocompatible Materials; Blood Circulation; Blood Vessels; Blood flow; Cardiovascular Diseases; Cell Culture System; Chronic Kidney Failure; 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 of activation protein; Mission; Modification; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; Nanotechnology; Operative Surgical Procedures; P-Selectin; Pathologic; Pathway interactions; Patients; 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; base; 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; prevent; promoter; retinal S antigen peptide M; small molecule inhibitor; targeted delivery; transcription factor; transcriptome sequencing; treatment strategy

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重大临床问题 人口。靶向纳米医学是一个迅速增长的研究领域，是一种有希望的治疗方法 广泛的疾病，包括心血管疾病和癌症。但是，研究很少 关于使用靶向纳米医学来治疗或防止AVF成熟失败。而且，更好 了解AVF成熟失败涉及的途径对于发展新型治疗至关重要 策略，包括靶向纳米医学。 该提议的第一个目的是研究转录因子ETS原始癌基因的作用 AVF开发中的1（ETS-1），基质金属蛋白酶（MMP）-2和MMP-9。我们团队的大量工作 已经提供了一个很强的理由，即ETS-1和MMP-2/9轴是病理AVF的主要驱动力 重塑。该提案的第二个目标是研究载有药物的P-选择蛋白的有效性 靶向纳米颗粒（NP）治疗或防止AVF成熟失败。 AVF成熟失败是一个区域 问题，因此，有针对性的药物向AVF部位输送可能会降低限制剂量的毒性，不良 由于药物迅速降解而导致的脱靶效应和不利的药代动力学。我们最近设计了 在受伤/活化的内皮细胞中表达的对P-选择素的高亲和力的创新NP。我们发现 AVF创建手术之后是AVF位点的P-选择素表达增加，并且P-选择素 - 在AVF位点优先汇总了靶向的NP。此外，我们的团队已经开发了各种NP 对于具有不同尺寸和化学特性的药物。小药物的NP基于岩藻依氨基（a） 多糖），它表现出纳摩尔亲和力与p-选择蛋白。大型药物的NP基于脂质体 与p-选择蛋白配体共轭。两种载体都是由天然和合成生物相容性材料制成的 已被证明可以安全地用于人类。 我们的长期目标是制定新颖的治疗策略，以防止AVF成熟失败 最终安全地用于人类。我们的中心假设是成熟失败是由上调引起的 ETS-1和MMP-2/9，以及使用纳米颗粒靶向药物的封锁可以 改善AVF成熟。该假设将使用遗传的组合以两个特定的目的进行检验 方法（AIM 1）和纳米技术（AIM 2）。目标1：确定ETS-1和MMP-2/9的因果作用 CKD啮齿动物的病理AVF发育。目标2：调查ETS-1和 靶向纳米医学抑制MMP-2/9，以增强CKD啮齿动物的AVF发育。这 翻译项​​目是创新的，而且很重要，因为它研究了一种新型的AVF成熟分子途径 失败并使用新型的纳米技术来治疗/预防此临床问题。成功完成 这些目标将确定开发创新纳米医学以增强AVF成熟的重要目标。