Renal tubule-specific nanotherapeutics for acute kidney injury

摘要 我们建议开发一种方法来解决药代动力学差和由此导致的低 急性肾损伤(AKI)的实验治疗效果Aki约占医院总数的2% 在美国的入院人数，与发病率和死亡率的增加有关。疾病的流行 在重症监护室的患者中，AKI的发病率高达67%，其中56%的患者进展为更晚期的形式 这种疾病的危害。尽管对AKI的流行病学和发病机制的了解取得了进展， 预防措施仍然不足，治疗方法在很大程度上证明是徒劳的。多种药物 试验没有成功，主要是因为药物特异性低或药代动力学特征不佳。最近，我们 合成了一种新型的纳米级药物输送平台，选择性地靶向肾单位(Williams，Nano 信件，2015)。我们发现“中尺度”纳米颗粒以肾小管和肾小管周内皮细胞为靶标 同时绕过体内的其他组织。纳米粒子的局部化效率最高可达25倍 肾脏比在任何其他器官中都要好，并在释放药物的同时对肾脏或 其他器官。这一发现是史无前例的，需要进行更多的调查来评估其影响 用于治疗肾脏疾病。我们建议对这项技术进行研究，以确定其到达 小管及其治疗AKI的潜力。为了实现这些目标，我们最近制定了两个目标 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。 肾小管和间质(Stamatiade，Cell，2016)通过肾小管周毛细血管和肾小管间质转运 由常驻巨噬细胞监测。我们假设我们的中尺度纳米粒子通过这种方式内化 肾小管周围转运途径。我们建议在这里讨论这一假设。我们成功地治疗了一只小鼠 通过靶向肾小管的ROS抑制剂建立AKI模型。我们实施了中尺度 载有自由基清除剂的纳米颗粒对顺铂介导的模型具有显著的疗效 在啮齿动物模型中，使用比先前显示的剂量低154倍的剂量来治疗AKI。我们建议 研究中尺度纳米颗粒包裹的ROS抑制剂的作用机理并评估 它们单独与抑制剂相关的药理参数和疗效。在建议的目标1中，我们 将表征纳米颗粒在肾间质和肾小管中摄取的途径。在目标2中，我们将评估 肾靶向ROS抑制剂的药理参数。在目标3中，我们将评估疗效和 肾小管特异性ROS抑制剂的治疗机制。结果：这些研究将解决 通过调查发现未满足的改善肾脏药物PK治疗AKI的新方法的需求 中尺度纳米粒子技术。我们将确定这种新型药物输送工具的国产化路线 对肾脏，其调节药物PK的能力，以及其改善药物治疗指数的潜力 AKI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.