Glomerular Filtration of Sub-nm Gold Nanoparticles

摘要 超过10%的美国成年人患有各种肾脏疾病，这些疾病通常始于 对肾小球滤过屏障的轻微损害，但在常规治疗的早期阶段很难发现 生物标志物。然而，这种损害最终会在不知情的情况下导致严重的肾功能障碍。 直到超过60%的肾功能丧失。因此，开发纳米药物可以早期检测到 肾小球功能障碍是肾脏疾病进展的一个非常开始的步骤，这是非常必要的，这 要求我们全面了解工程纳米颗粒(NPs)的肾小球滤过。 虽然肾小球滤过屏障被认为是一个“大小截断”的狭缝，以保留更大的工程NPs或蛋白质 在体内大于6纳米，并迅速通过肾脏排泄较小的，我们最近发现肾脏 一类亚纳米谷胱甘肽包覆金纳米颗粒(亚纳米GS-AuNPs)的清除率显著提高 在早期消除阶段被肾小球减慢，尽管它们最终清除了 身体通过泌尿系统。这一令人惊讶的观察不仅提出了一个根本的问题，即 亚纳米工程纳米粒子在体内与肾小球屏障相互作用，但也可能打开一种新的 早期发现肾脏疾病的途径。 这项建议的目的是从根本上了解亚急性肾小球疾病的肾小球滤过。 并探索将新发现的纳米生物相互作用应用于早期检测的可行性 肾小球损伤。为实现这一目标提出了三个具体目标：目的一是调查 具有明确尺寸和表面化学成分的亚纳米AuNPs的肾小球过滤。目标二是调查 控制良好的肾小球内皮糖催化剂对亚纳米AuNPs的肾小球滤过作用 退化。目的III将近红外发射的亚纳米AuNPs应用于临床前期耿氏损伤的早期检测 设置。申请的成功不仅将极大地促进我们对 基因工程NPs的肾小球滤过也导致了一类新的用于早期检测的肾脏纳米探针 在临床前环境下，耿氏损伤的敏感性高，但成本低。此外，它还将制定一项 为未来肾脏纳米药物的早期诊断奠定基础。

Abstract More than 10% of adults in US are suffering from a variety of kidney diseases, which often start with trivial damages to the glomerular filtration barrier but are hard to detect in their early stages with conventional biomarkers. However, such damages can eventually lead to severe kidney dysfunctions without awareness until more than 60% of kidney function is lost. Thus, developing nanomedicines that allow early detection of glomerular dysfunction, a very beginning step in the kidney disease progression, is highly desired, which demands our comprehensive understanding of the glomerular filtration of engineered nanoparticles (NPs). While the glomerular filtration barrier is known a “size cut-off” slit to retain engineered NPs or proteins larger than 6nm in the body and to rapidly excrete the smaller ones through the kidneys, we recently found that renal clearance of a class of sub-nm glutathione coated gold nanoparticles (sub-nm GS-AuNPs) was significantly slowed down by the glomeruli in the early elimination stage even though they eventually cleared out of the body through the urinary system. This surprising observation not only raises a fundamental question of how sub-nm engineered NPs interact with the glomerular barrier in vivo but potentially also opens up a new pathway for early detection of kidney diseases. The objective of this proposal is to fundamentally understand the glomerular filtration of sub- nm AuNPs and explore the feasibility of applying the newly discovered nano-bio interactions in early detection of glomerular injury. Three specific aims are proposed to accomplish the objective: Aim I is to investigate glomerular filtration of sub-nm AuNPs with well-defined size and surface chemistries. Aim II is to investigate glomerular filtration of sub-nm AuNPs with well-controlled glomerular endothelial glycocalyx (GEnG) degradation. Aim III is to apply NIR-emitting sub-nm AuNPs for early detection of GEnG injury in the preclinical settings. The success of the application will not only significantly advance our fundamental understanding of the glomerular filtration of engineered NPs but also lead to a new class of renal nanoprobes for early detection of GEnG injury at high sensitivity but low cost in the preclinical settings. Moreover, it will also lay down a foundation for future translation of renal nanomedicines for early diagnosis of kidney diseases.