Nanoprobes for imaging RONS and drug-induced hepatotoxicity

描述（由申请人提供）：活性氧和氮物质（RONS）的产生增加是许多病理过程的标志，范围从缺血/再灌注或无菌损伤到急性和慢性细菌感染，再到慢性疾病，如癌症、心血管疾病和关节炎。确定RONS何时何地作为病理化学信使产生的能力对于理解这些疾病的病因和优化针对这些潜在危及生命的疾病的治疗干预至关重要。由于其半衰期短，RONS的产生发生在病理学局部，并且通常发生在疾病发病机制的亚临床时间点。体内RONS水平的早期和实时分子成像将影响广泛的疾病状态。 RONS的产生与药物代谢密切相关。在代谢时，高反应性代谢物通常与肝毒性相关。虽然每种药物的反应性代谢物特征对其化学结构都是独特的，但候选药物和获批药物分子几乎普遍存在的代谢物诱导的肝毒性的潜在机制是氧化和亚硝化应激：产生与各种亚细胞组分（例如蛋白质，脂质和DNA）快速反应的RONS，并产生有害结果。据估计，在进入I期临床试验的候选新药中，只有10%被批准用于人类。药物诱导的肝毒性是美国FDA批准药物停药的最常见原因，占美国急性肝衰竭病例的50%以上。 本研究旨在开发一种用于RONS体内成像的平台技术，并验证其在小鼠模型中用于成像药物诱导的RONS肝毒性的应用。该传感器平台是基于共轭聚合物纳米粒子，已被证明具有优异的光学性能和生物相容性。将设计、制备和验证一系列纳米探针，用于对体内产生的特异性RONS进行成像。具体而言，有三个目的：1）设计用于RONS体内成像的生物相容性基于FRET的荧光纳米探针; 2）开发用于RONS体内成像的基于CRET的荧光探针。3)小鼠肝脏中药物诱导的RONS的实时体内监测。这些RONS纳米探针将显著影响我们对疾病病理学和检测的理解，并提供以前无法获得的关于肝毒性倾向的信息，并有助于早期选择有前途的候选药物进入临床试验。

DESCRIPTION (provided by applicant): The elevated generation of reactive oxygen and nitrogen species (RONS) is a hallmark of many pathological processes ranging from ischemia/reperfusion or sterile injury, to acute and chronic bacterial infections, to chronic diseases such as cancer, cardiovascular disease, and arthritis. The ability to determine when and where RONS are being generated as pathological chemical messengers is critical to both understanding the etiology of these diseases and optimizing therapeutic interventions against these potentially life-threatening conditions. Due to their short half-lives, the generation of RONS occurs locally to pathology and often at subclinical time points in the pathogenesis of disease. Early and real-time molecular imaging of RONS levels in vivo will impact a wide array of diseased states. RONS generation also highly involves with drug metabolism. Upon metabolism, highly reactive metabolites are often associated with hepatotoxicity. While the reactive metabolite profile of each drug is unique to its chemical structure, an underlying mechanism of metabolite-induced hepatotoxicity nearly universal to both drug candidates and approved drug molecules is oxidative and nitrosative stress: the generation of RONS that react rapidly with a variety of subcellular components (e.g. protein, lipid, and DNA) with deleterious outcomes. It is estimated that of new drug candidates entering Phase I clinical trial, only 10% are ever approved for human use. Drug-induced hepatotoxicity is the most common reason for withdrawal of US FDA-approved drugs, which account for more than 50% of acute liver failure cases in the US. This research proposes to develop a platform technology for in vivo imaging RONS, and validate its application for imaging drug-induced RONS hepatotoxicity in a mouse model. The sensor platform is based on conjugated polymer nanoparticles that have been shown with excellent optical properties and biocompatibilities. A series of nanoprobes will be designed, prepared and validated for imaging specific RONS generated in vivo. Specifically, there are three Aims: 1) Design of biocompatible FRET-based fluorescent nanoparobes for in vivo imaging of RONS; 2) Development of CRET-based chemiluminescent probes for in vivo imaging of RONS. 3) Real-time in vivo monitoring of drug-induced RONS in mouse liver. These RONS nanoprobes will significantly impact on our understanding of disease pathology and detection, and provide previously unattainable information regarding the propensity for hepatotoxicity and aid the early selection of promising drug candidates to enter into clinical tria.