Abstract 369: Redox nanoparticle for tumor imaging and anticancer drug enhancer
Authors: Yukio Nagasaki, Yuki Ozaki, Toru Yoshitomi
Journal: Cancer Research (2011)

Abstract Recently, a non-invasive in vivo imaging of low pH circumstances has attracted attention as new means of detecting disease and response to clinical treatment. Low pH circumstances, which are an aberration of normal pH homeostasis, are caused by ischemia, infection or inflammation, extracellular acidosis in tumors, wound healing, and so forth. However, there is currently no clinical tool available to capture an image of low pH circumstances in vivo. We have been focusing on preparation of core-shell type nanoparticles by self-assembling of amphiphilic block copolymers. Especially, we have succeeded to prepare pH-sensitive nanoparticles, which disintegrate under acidic environment. Thus, using these nanoparticles, ON-OFF regulation of signals in responce to the acidic environment could be monitored. Since nitroxyl radical is susceptible to both electron spin and nuclear magnetic resonances (ESR and NMR), it is anticipated to utilize as imaging compound. Under in vivo conditions, however, low-molecular-weight nitroxyl radicals pose several problems, such as nonspecific accumulation in normal tissues, preferential renal clearance, and rapid reduction of the nitroxyl radical. To solve these difficulties, we have confined nitroxyl radicals in the core of pH-sensitive nanoparticle (RNP) using a self-assembling amphiphilic block copolymer composed of a hydrophilic poly(ethylene glycol) segment and a hydrophobic polystyrene segment carrying nitroxyl radical in each repeating unit as side chain. The cumulant average diameter of the RNP under neutral pH was about 40 nm, and the RNP collapses under the acidic conditions. At the same time, the RNP emitted an intense ESR and NMR signals. Due to the confinement of nitroxyl radical in the core of the RNP, the blood circulation was extended. The nitroxyl radicals in the nanoparticles showed reduction resistance even in the presence of ascorbic acid. In vitro and in vivo toxicity were also reduced significantly. Thus, we can utilize it as a bioimaging probe, which observe acid environment in vivo. An excessive reactive oxygen species (ROS) causes severe side effects in versatile diseases. For example, ischemia-reperfusion injury is one of the most famous damages by ROS, which are produced after a long ischemic period. Therefore, the protection of organs affected by ROS must be considered in order to minimize the area of damage associated with ischemia-reperfusion. Since nitroxyl radical can react catalytically with ROS, RNP was anticipated to scavenge ROS after reperfusion. The RNP was confirmed to show protective effect to several types of ischemia-reperfusion injuries such as brain, heart and kidney. It is also interested to note that RNP improved efficiency of anticancer drug doxorubicin (DOX) when RNP is administered before DOX administration. Thus, RNP is promising as new nanomedicine for clinical applications for versatile therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 369. doi:10.1158/1538-7445.AM2011-369