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.
The proposed research aims to develop novel nanotechnology to detect and image reactive oxygen and nitrogen species (RONS) in diseases. This new nanotechnology will then be applied to study drug-induced RONS toxicity in liver. The research will highly impact on understanding of RONS roles in diseases and facilitate drug discovery by allowing earlier selection of promising drug candidates to enter clinical trials.
|Pu, Kanyi; Shuhendler, Adam J; Jokerst, Jesse V et al. (2014) Semiconducting polymer nanoparticles as photoacoustic molecular imaging probes in living mice. Nat Nanotechnol 9:233-9|
|Shuhendler, Adam J; Pu, Kanyi; Cui, Lina et al. (2014) Real-time imaging of oxidative and nitrosative stress in the liver of live animals for drug-toxicity testing. Nat Biotechnol 32:373-80|