RT Journal Article SR Electronic T1 Clearance and Biodistribution of Liposomally-Encapsulated Nitroxides: a Model for Targeted Delivery of Electron Paramagnetic Resonance Imaging Probes to Tumors JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.111.039636 DO 10.1124/dmd.111.039636 A1 Scott R. Burks A1 Eric A. Legenzov A1 Gerald M. Rosen A1 Joseph P. Y. Kao YR 2011 UL http://dmd.aspetjournals.org/content/early/2011/07/07/dmd.111.039636.abstract AB Electron paramagnetic resonance (EPR) imaging using nitroxides as molecular probes is potentially a powerful tool for the detection and physiological characterization of micrometastatic lesions. Encapsulating nitroxides in anti-HER2 immunoliposomes at high concentrations, to take advantage of the "self-quenching" phenomenon of nitroxides, allows generation of robust EPR signals in HER2-overexpressing breast tumor cells with minimal background from indifferent tissues or circulating liposomes. We investigated the pharmacological properties in vivo, of nitroxides encapsulated in sterically-stabilized liposomes designed for long circulation times. We show that circulation times of nitroxides can be extended from hours to days; this increases the proportion of liposomes in circulation to enhance tumor targeting. Furthermore, nitroxides encapsulated in sterically-stabilized anti-HER2 immuno-liposomes can be delivered to HER2-overexpressing tumors at micromolar concentrations, which should be imageable by EPR. Lastly, after administration in vivo, liposomally-encapsulated nitroxide signal also appears in the liver, spleen, and kidneys. While these organs are spatially distinct and would not hinder tumor imaging in our model, understanding nitroxide signal retention in these organs is essential for further improvements in EPR imaging contrast between tumors and other tissues. These results lay the foundation to use liposomally-delivered nitroxides and EPR imaging to visualize tumor cells in vivo.