Earlier tumor detection can improve 5-year survival of patients, particularly among those presenting with cancers less than 1 cm in diameter. a m b 3 - Targeted 111 In nanoparticles (NP) were developed and studied for detection of tumor angiogenesis. Studies were conducted in New Zealand white rabbits implanted 12 days earlier with Vx-2 tumor. a m b 3 - Targeted 111 In/NP bearing 10 111In/NP vs. 1 111In/NP nuclide payloads were compared to nontargeted radiolabeled control particles. In vivo competitive binding studies were used to assess ligand-targeting specificity. a m b 3 -Integrin-targeted NP with 10 111In/NP provided better (p < 0.05) tumor-to-muscle ratio contrast (6.3 6 0.2) than 1 111In/NP (5.1 6 0.1) or nontargeted particles with 10 111In/NP (3.7 6 0.1) over the initial 2-hr postinjection. At 18 hr, mean tumor activity in rabbits receiving a m b 3 -integrin-targeted NP was 4-fold higher than the nontargeted control. Specificity of the NP for the tumor neovasculature was supported by in vivo competition studies and by fluorescence microscopy of a m b 3 -targeted fluorescent-labeled NP. Biodistribution studies revealed that the primary clearance organ in rabbits as a %ID/g tissue was the spleen. Circulatory half-life (t 1/2b ) was estimated to be 5 hr using a 2-compartment model. a m b 3 - Targeted 111 In perfluorocarbon NP may provide a clinically useful tool for sensitively detecting angiogenesis in nascent tumors, particularly in combination with secondary highresolution imaging modalities, such as MRI. ' 2007 Wiley-Liss, Inc.Key words: indium; angiogenesis; integrin; nanoparticles; Vx2; cancer Data accumulated over the last 25 years in the surveillance, epidemiology and end results cancer registry support the principle that earlier tumor detection improves 5-year survival of patients with either localized or regional invasive breast carcinoma. 1 Improvements in survival were correlated with an overall downward shift in tumor size distribution, with particular advantage noted among patients presenting with cancers less than 1 cm. A widespread desire to detect and treat cancer earlier has spawned interest in molecular imaging and genomic-proteomic technologies, which in combination with new strategies to treat cancer may further improve cancer survival.One approach to identifying small solid tumors has involved early detection of angiogenesis by targeting unique biosignatures of neovascular endothelium, such as a v b 3 -integrin. We have previously demonstrated that paramagnetic perfluorocarbon emulsions targeted to the a v b 3 -integrin can be used to detect the neovasculature of tumors 30 mm 3 at clinical field strengths (1.5 T). Because perfluorocarbon nanoparticles (NP) have a nominal particle size of 250 nm and are constrained within the vasculature, access to a v b 3 -integrin expressed on extravascular macrophages, smooth muscle and other cells is sterically precluded. MRI provides outstanding high-resolution images of even minute tumors enhanced by the bound paramagnetic NP; however, the ...

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A lipid-encapsulated perfluorocarbon nanoparticle molecular imaging contrast agent that utilizes a paramagnetic chemical exchange saturation transfer (PARACEST) chelate is presented. PARACEST agents are ideally suited for molecular imaging applications because one can switch the contrast on and off at will simply by adjusting the pulse sequence parameters. This obviates the need for pre-and postinjection images to define contrast agent binding. Spectroscopy (4.7T) of PARACEST nanoparticles revealed a bound water peak at 52 ppm, in agreement with results from the water-soluble chelate. Imaging of control nanoparticles showed no appreciable contrast, while PARA-CEST nanoparticles produced >10% signal enhancement. PARACEST nanoparticles were targeted to clots via antifibrin antibodies and produced a contrast-to-noise ratio ( Myocardial disease and stroke continue to be the nation's leading killer and are responsible for nearly 1 million American deaths (42%) annually. Approximately 160,000 of these losses involve individuals between the ages of 35 and 64 years (1) for whom the current early-diagnosis techniques have little effectiveness. New early-detection strategies are needed to prevent a patient's first symptomatic presentation from being the last. Although a variety of invasive approaches can be used to characterize atherosclerotic plaques and follow their changes serially (2), these techniques are primarily confined to research studies due to the increased risk, cost, and time required.We previously proposed that early recognition and quantification of microthrombi in ruptured plaques could provide an important biomarker to justify and guide aggressive therapeutic strategies to impede disease progression (3). We also reported the use of a lipid-encapsulated, perfluorocarbon nanoparticle system for molecular MRI of fibrin, an abundant component of thrombus. This agent affords specific detection of fibrin deposits using paramagnetic gadolinium chelates on the surface (4,5). The highly amplified paramagnetic signal provides a robust way to image targeted nanoparticles; however, routine use requires the collection of pre-and postinjection images to determine signal changes.Chemical exchange saturation transfer (CEST) agents have exchangeable protons (-NH, -OH, etc.) that resonate at a chemical shift that is distinguishable from the bulk water signal. RF prepulses applied at the appropriate frequency and power level can saturate the exchangeable protons, which transfer into the bulk water pool and lead to reduced equilibrium magnetization (6). Therefore, with the use of CEST agents one can switch the image contrast "on" and "off" by simply changing the pulse sequence parameters-an ability that is unique in the realm of MRI. This can minimize the time delays and motion-induced artifacts inherent in normal pre-and postcontrast imaging protocols. Although several agents contain exchangeable protons and can produce CEST contrast (7), the chemical shifts are often very close to the bulk water signal, which makes it dif...