Nanotechnology as a therapeutic approach in arteriovenous fistula 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增长的研究领域，是一种有希望的治疗 各种疾病，包括心血管疾病和癌症。然而，这方面的研究很少。 关于使用靶向纳米药物治疗或预防动静脉瘘成熟失败。此外，一个更好的 了解AVF成熟失败的途径对于开发新的治疗方法是至关重要的 战略，包括靶向纳米医学。 这项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(MMPs)-2、MMP9在动静脉瘘发生发展中的作用。我们团队的广泛工作 为ETS-1和MMP-2/9轴是病理性AVF的主要驱动因素提供了有力的理论基础 改建。这项建议的第二个目标是研究载药P-选择素的有效性。 靶向纳米颗粒(NPs)用于治疗或预防AVF成熟失败。AVF成熟度断裂是区域性的 问题，因此，将药物定向输送到AVF部位可能会降低剂量限制毒性，这是不可取的 非靶点效应，以及由于药物快速降解而产生的不利的药代动力学。我们最近设计了 与损伤/激活的内皮细胞表达的P-选择素具有高亲和力的创新NPs。我们发现 动静脉动静脉瘘手术后，动静脉动静脉瘘部位的P-选择素表达增加，而P-选择素- 靶向NPs优先聚集在AVF部位。此外，我们的团队还开发了各种NP 适用于不同大小和化学性质的药物。用于小型药物的NPs是基于岩藻糖胶(a 多糖)，表现出对P-选择素的纳摩尔亲和力。用于大型药物的纳米粒是以脂质体为基础的 与P-选择素配体偶联。这两种载体都是由天然和合成的生物兼容材料制成的 已经证明在人类身上使用是安全的。 我们的长期目标是开发新的治疗策略来防止aVF成熟失败，这种方法可以 最终在人类身上安全使用。我们的中心假设是成熟失败是由 Ets-1和MMP-2/9，并且使用纳米粒靶向递送药物来阻断这一途径可以 提高AVF成熟度。这一假设将在两个特定的目标上进行检验，使用基因组合 方法(目标1)和纳米技术(目标2)。目的1：探讨Ets-1和MMP2/9在骨质疏松症发病中的作用。 慢性肾脏病啮齿动物病理性动静脉动静脉瘘的发生。目的2：探讨Ets-1和Ets-1的治疗作用。 靶向纳米药物抑制CKD啮齿动物动静脉瘘的发生。这 翻译计划具有创新性和重大意义，因为它探索了AVF成熟的一种新的分子途径 并使用一种新的纳米技术来治疗/预防这种临床问题。成功完成 这些目标将确定开发创新纳米药物以促进AVF成熟的重要靶点。

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.