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We demonstrate a novel approach to ultrasonic detection of molecularly targeted nanoparticle contrast agent accumulation in a xenographic mouse tumor model in vivo. This is accomplished by imaging the entire mouse tumor volume at 15 minute intervals following injection of αvβ3-targeted perfluoro carbon core nanoparticles. Radiofrequency (RF) data were stored for off-line analysis using signal energy and a limiting form of the Renyi entropy suitable for real-time calculation, If,∞. The results indicate that If,∞ may be used to reliably detect accumulation of targeted nanoparticles within 15 minutes of injection without the need for image subtraction, whereas signal energy images showed less sensitivity to nanoparticle accumulation. The ability to detect nanoparticle accumulation without requiring image subtraction or fixing the transducer in place are necessary prerequisites for translation of this technology to the clinic.