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: 10275814
• 负责人: EDGAR A JAIMES
• 金额: $ 44.76万
• 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/10275814
• 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/antagonist; 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.

动静脉内瘘（AVF）成熟失败是血液透析患者的一个重要临床问题 人口靶向纳米医学是一个快速发展的研究领域，是治疗糖尿病的一种有前途的方法。 广泛的疾病，包括心血管疾病和癌症。然而，缺乏研究， 关于使用靶向纳米药物治疗或预防AVF成熟失败。此外，更好的 了解AVF成熟失败的相关途径对于开发新的治疗方法至关重要。 战略，包括有针对性的纳米医学。 该建议的第一个目标是研究转录因子ETS原癌基因的作用 1（ETS-1）、基质金属蛋白酶（MMP）-2和MMP-9在AVF发生中的作用。我们团队的大量工作 ETS-1和MMP-2/9轴是病理性AVF的主要驱动因素，这提供了强有力的理论依据 重塑该建议的第二个目的是研究载药P-选择素的有效性， 靶向纳米颗粒（NP）治疗或预防AVF成熟失败。AVF成熟失败是区域性的 因此，将药物靶向递送到AVF部位可以减少剂量限制性毒性、不期望的毒性和/或毒性。 脱靶效应和由于药物快速降解而导致的不利的药代动力学。我们最近设计了 对在受损/活化的内皮细胞中表达的P-选择素显示高亲和力的创新NP。我们发现 AVF形成手术后AVF部位P-选择素表达增加， 靶向的NP优先聚集在AVF位点。此外，我们的团队开发了各种NP 用于不同大小和化学性质的药物。用于小药物的NP基于岩藻依聚糖（a 多糖），其对P-选择素表现出纳摩尔亲和力。用于大型药物的纳米粒基于脂质体 与P-选择素配体缀合。两种载体均由天然和合成生物相容性材料制成， 已经被证明对人类是安全的。 我们的长期目标是开发新的治疗策略来预防AVF成熟失败， 最终可以安全地用于人类。我们的中心假设是，成熟失败是由上调的 ETS-1和MMP-2/9，并且使用纳米颗粒靶向递送药物阻断该途径可以 改善AVF成熟。这一假设将在两个特定目标中进行测试，使用遗传学的组合， 方法（目标1）和纳米技术（目标2）。目的1：确定ETS-1和MMP-2/9在 CKD啮齿类动物的病理性AVF发展。目的2：探讨ETS-1的治疗功效， 靶向纳米药物对MMP-2/9的抑制作用增强了CKD啮齿动物的AVF发展。这 该翻译项目具有创新性和重要意义，因为它研究了AVF成熟的新分子途径 失败，并使用新的纳米技术来治疗/预防这种临床问题。成功完成 这些目标将确定重要的目标，为发展创新的纳米药物，以提高AVF的成熟。