Unravel Nanoparticle Transport and Interactions in Renal Proximal Tubules

摘要 肾脏，作为一个主要的废物清除器官，正在被利用来加速身体 清除“脱靶”工程纳米颗粒，以满足FDA对临床转化的规定 纳米医学，这需要彻底了解纳米颗粒的运输和相互作用， 基本水平。然而，肾近曲小管与 尽管近端小管是一个非常小的结构，但对工程纳米颗粒的肾小球过滤的广泛研究 最活跃的网站参与浓缩，保留和重吸收的过滤蛋白质 穿过肾小球虽然大小和电荷被认为是重要的蛋白质重吸收， 独特的微绒毛覆盖的近曲小管细胞表面，它在很大程度上仍然是未知的，如何工程 纳米颗粒将被保留，并在过滤通过近端小管后与近端小管相互作用。 肾小球 本申请的目的是推进我们对尺寸的基本理解， 电荷和表面化学对工程纳米粒子在水中的传输和相互作用的影响 不仅正常，而且受损的近端小管;因此，我们可以获得一个通用的策略， 最大限度地减少其在未来临床应用中的潜在健康危害。五个具体目标是 建议实现的目标：在目标1-3，我们将解开大小，表面化学， 表面电荷对肾可清除纳米金在肾组织中转运和相互作用的影响 近端小管目的4是重新审视这些尺寸，电荷和表面化学依赖性， 近端肾小管损伤的病变肾脏。目的5评价生物相容性和肾毒性 在正常小鼠和小鼠中，肾可清除的AuNPs与近端小管具有不同的相互作用 近端肾小管损伤建议的研究如能成功，将大大推动我们的 对工程化纳米颗粒与肾近端细胞的体内相互作用的基本理解 小管，为进一步开发新的设计策略奠定了坚实的基础， 最大限度地减少纳米药物在未来临床应用中的肾毒性。

Abstract Kidneys, as a major organ for waste removal, are being exploited to accelerate the body clearance of “off-target” engineered nanoparticles to meet FDA regulation for the clinical translation of nanomedicines, which demands thorough understanding of nanoparticle transport and interactions at the fundamental level. However, renal proximal tubule is often overlooked in comparison with extensive studies on glomerular filtration of engineered nanoparticles even though proximal tubule is the most active site involved in concentration, retention and reabsorption of the filtered proteins through glomeruli. While the sizes and charges are recognized important in protein reabsorption due to unique microvilli-covered surface of proximal tubule cells, it is still largely unknown how engineered nanoparticles will be retained and interact with the proximal tubules after being filtered through the glomeruli. The objective of this application is to advance our fundamental understanding of the size, charge and surface chemistry effects on the transport and interactions of engineered nanoparticles in not only the normal but also injured proximal tubules; so that we can obtain a general strategy in minimizing their potential health hazards in their future clinical applications. Five specific aims are proposed to accomplish the objective: In Aims 1-3, we will unravel size, surface chemistry, and surface charge effects on the transport and interaction of renal clearable gold nanoparticle in renal proximal tubules. Aim 4 is to revisit these size, charge and surface chemistry dependencies in the diseased kidneys with proximal tubular injury. Aim 5 is to evaluate biocompatibility and nephrotoxicity of renal clearable AuNPs with distinct interactions with proximal tubules in both normal mice and mice with proximal tubular injury. Success of the proposed studies will significantly advance our fundamental understanding of in vivo interactions of engineered nanoparticles with renal proximal tubules, laying down a solid foundation for further development of new design strategies that can minimize nephrotoxicity of nanomedicines in their future clinical translation.