Unravel Nanoparticle Transport and Interactions in Renal Proximal Tubules

摘要 肾脏作为排泄废物的主要器官，正被用来加速身体。 清除“非靶标”的工程纳米粒以满足FDA对临床翻译的规定 纳米医学，这需要彻底了解纳米颗粒的传输和相互作用 最基本的层面。然而，与肾近端小管相比，肾近端小管常常被忽视。 工程纳米颗粒对肾小球滤过的广泛研究，即使近端小管 最活跃的部位与过滤后蛋白质的浓缩、保留和重吸收有关 通过肾小球。而大小和电荷在蛋白质重吸收中被认为是重要的 对于近端小管细胞独特的微绒毛覆盖表面，如何进行工程处理在很大程度上仍不清楚。 经过过滤后，纳米颗粒将被保留并与近端小管相互作用 肾小球。 这个应用程序的目的是促进我们对大小的基本理解， 电荷和表面化学对工程纳米颗粒在体内的传输和相互作用的影响 不仅是正常的近端小管，也包括受损的近端小管，这样我们就可以得到一个普遍的策略 在未来的临床应用中将其潜在的健康危害降至最低。五个具体目标是 建议实现目标：在目标1-3中，我们将揭开尺寸、表面化学和 表面电荷对肾可清除金纳米颗粒在肾脏中传输和相互作用的影响 近端小管。目标4是重新讨论这些尺寸、电荷和表面化学的依赖关系 伴有近端肾小管损伤的病变肾脏。目的5是评估生物相容性和肾毒性。 正常小鼠和小鼠肾脏可清除AuNPs与近曲小管的明显相互作用 近端肾小管损伤。拟议研究的成功将大大促进我们的 基因工程纳米颗粒与肾脏近端在体相互作用的基本认识 微管，为进一步开发新的设计策略奠定了坚实的基础 在未来的临床翻译中将纳米药物的肾毒性降至最低。

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.