Renal tubule-specific nanotherapeutics for acute kidney injury

总结 我们建议开发一种方法来解决药物动力学差和由此导致的低浓度的问题。 急性肾损伤（阿基）的实验性治疗的有效性。阿基约占医院的2% 在美国，它与发病率和死亡率的增加有关。之时尚 阿基在重症监护患者中高达67%，其中56%进展为更晚期形式 疾病。尽管对阿基的流行病学和发病机制的理解有所进展， 预防措施仍然不足，治疗方法基本上证明是徒劳的。多药 试验一直不成功，主要是由于药物特异性低或药代动力学特征差。最近我们 合成了选择性靶向肾单位的新型纳米级药物递送平台（威廉姆斯，纳米 Letters，2015）。我们发现中尺度纳米颗粒靶向肾小管和肾小管周围内皮 同时绕过体内其他组织纳米颗粒定位到25倍更有效地在 肾比在任何其他器官中释放药物，同时对肾没有毒性作用， 其他器官。这一发现是前所未有的，需要进一步调查以评估其影响 用于治疗肾脏疾病。我们建议调查这项技术，以确定其路线， 肾小管，以及其治疗阿基的潜力。为了实现这些目标，我们最近制定了两个 初步发现：我们详细描述了外源性纳米材料进入肾脏的途径， 肾小管和肾小管（Stamatiades，Cell，2016）通过肾小管周毛细血管和 由常驻巨噬细胞监测。我们假设我们的中尺度纳米颗粒通过这种方式内化， 管周运输途径我们建议在此解决这一假设。我们成功治疗了一只 通过将ROS抑制剂特异性靶向肾小管来治疗阿基模型。我们给了中尺度的 纳米颗粒装载自由基清除剂，导致对顺铂介导的模型的显著疗效 使用比先前在啮齿动物模型中显示的治疗AKI的剂量低154倍的剂量来治疗AKI。我们建议 研究中尺度纳米颗粒包封的ROS抑制剂的作用机制，并评估 它们的药理学参数和相对于单独的抑制剂的功效。在建议的目标1中，我们 将表征纳米颗粒在肾小管和肾小管中的摄取途径。在目标2中，我们将评估 肾靶向ROS抑制剂的药理学参数。在目标3中，我们将评估疗效， 肾小管特异性ROS抑制剂治疗的治疗机制。结果：这些研究将解决 通过研究改善药物在肾脏中PK以治疗阿基的新方法的未满足需求 中尺度纳米粒子技术。我们将确定这种新型药物输送载体的国产化路线 其调节药物PK的能力，以及其改善药物治疗指数的潜力， 阿基患者的治疗。

SUMMARY We propose to develop a method to address the problem of the poor pharmacokinetics and resulting low efficacy of experimental therapies for acute kidney injury (AKI). AKI accounts for approximately 2% of hospital admissions in the United States and is associated with increased morbidity and mortality. The prevalence of AKI is up to 67% in patients admitted to intensive care, with 56% of those progressing to more advanced forms of the disease. Despite advances in the understanding of the epidemiology and pathogenesis of AKI, preventive measures remain inadequate and therapeutic approaches have largely proven futile. Multiple drug trials have been unsuccessful, mainly due to low drug specificity or poor pharmacokinetic profiles. Recently, we synthesized a novel nanoscale drug delivery platform that selectively targets the nephron (Williams, Nano Letters, 2015). We found that ‘mesoscale’ nanoparticles target the renal tubules and peritubular endothelium while bypassing other tissues in the body. The nanoparticles localize up to 25-fold more efficiently in the kidneys than in any other organ and release their drug cargo while exhibiting no toxic effects on the kidneys or other organs. This finding is unprecedented, and additional investigations are needed to assess its implications for the treatment of kidney diseases. We propose to investigate this technology to determine its route to the tubules, as well as its potential for treating AKI. In service of these these goals, we recently made two preliminary findings: We characterized in detail a route of entry for exogenous nanomaterials into the renal tubules and interstitium (Stamatiades, Cell, 2016) mediated by transport through the peritubular capillaries and monitored by resident macrophages. We hypothesize that our mesoscale nanoparticles internalize by this peritubular transport route. We propose to address this hypothesis herein. We successfully treated a murine model of AKI by targeting an ROS inhibitor specifically to the renal tubules. We administered mesoscale nanoparticles loaded with a radical scavenger, resulting in striking efficacy against a cisplatin-mediated model of AKI using a dose 154 times lower than that previously shown to treat AKI in a rodent model. We propose to investigate the mechanism of action of mesoscale nanoparticle-encapsulated ROS inhibitors and to assess their pharmacologic parameters and efficacy with respect to the inhibitors alone. In Aim 1 of the proposal, we will characterize the route of nanoparticle uptake in the renal interstitium and tubules. In Aim 2, we will assess the pharmacologic parameters of kidney-targeted ROS inhibitors. In Aim 3, we will assess the efficacy and therapeutic mechanism of tubule-specific ROS inhibitor therapy. Outcomes: These studies will address the unmet need for new methods to improve drug PK in the kidneys for the treatment of AKI by investigating mesoscale nanoparticle technology. We will determine the route of localization of this new drug delivery vehicle to the kidneys, its ability to modulate drug PK, and its potential to improve therapeutic index of drugs for the treatment of AKI in patients.