Glomerular Filtration of Sub-nm Gold Nanoparticles

摘要 在美国，超过10%的成年人患有各种肾脏疾病，这些疾病通常始于 肾小球滤过屏障的轻微损伤，但在其早期阶段难以用常规方法检测到。 生物标志物。然而，这种损害最终可能导致严重的肾功能障碍，而没有意识到 直到超过60%的肾功能丧失因此，开发纳米药物，允许早期检测 肾小球功能障碍是肾脏疾病进展的一个非常开始的步骤， 需要我们对工程纳米颗粒（NPs）的肾小球过滤的全面理解。 虽然肾小球滤过屏障是已知的“大小截止”狭缝，以保留较大的工程化NP或蛋白质， 我们最近发现，肾脏中的小分子可以通过肾脏快速排出， 一类亚纳米谷胱甘肽包被的金纳米颗粒（亚纳米GS-AuNPs）的清除率显著高于 在早期的消除阶段，肾小球减慢了它们的速度，尽管它们最终清除了肾小球。 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问题， 亚纳米工程纳米粒子与肾小球屏障在体内相互作用，但也可能开辟一个新的 早期发现肾脏疾病的途径。 本提案的目的是从根本上了解亚慢性肾小球滤过， 纳米金纳米粒子，并探讨应用新发现的纳米生物相互作用在早期检测的可行性 肾小球损伤为实现这一目标，提出了三个具体目标： 肾小球过滤的亚纳米金纳米粒子具有明确的大小和表面化学。目的二是调查 具有良好控制的肾小球内皮糖萼（GEnG）的亚nm AuNP的肾小球过滤 降解目的III是应用近红外发射的亚纳米金纳米颗粒在临床前早期检测GEnG损伤。 设置.申请的成功不仅将大大推进我们对 工程化纳米颗粒的肾小球过滤，而且还导致一类新的肾脏纳米探针用于早期检测 在临床前环境中以高灵敏度但低成本检测GEnG损伤。此外，它还将制定一项 为肾脏纳米药物在肾脏疾病早期诊断中的应用奠定了基础。

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.