Molecular imaging of macrophage protease activity in cardiovascular inflammation in vivo

 

 Buy Article Permissions and Reprints

Summary

Macrophages contribute pivotally to cardiovascular diseases (CVD), notably to atherosclerosis. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Proteolytic enzymes serve as key effectors of many macrophage contributions to CVD. Therefore, intravital imaging of protease activity could aid evaluation of the progress and outcome of atherosclerosis, aortic aneurysm formation, or rejection of cardiac allografts. Among the large families of proteases, matrix metalloproteinases (MMPs) and cysteinyl cathepsins have garnered the most interest because of their participation in extra-cellular matrix remodelling. These considerations have spurred the development of dedicated imaging agents for protease activity detection. Activatable fluorescent probes, radiolabelled inhibitors, and nanoparticles are currently under exploration for this purpose. While some agents and technologies may soon see clinical use, others will require further refinement. Imaging of macrophages and protease activity should provide an important adjunct to understanding pathophysiology in vivo, evaluating the effects of interventions, and ultimately aiding clinical care.

• References

• 1 Ransohoff KJ, Wu JC. Advances in cardiovascular molecular imaging for tracking stem cell therapy. Thromb Haemost 2010; 104: 13-22.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
  CrossrefPubMedGoogle Scholar
• 3 Mitchell RN, Libby P. Vascular remodeling in transplant vasculopathy. Circ Res 2007; 100: 967-978.
  CrossrefPubMedGoogle Scholar
• 4 Shimizu K, Mitchell RN, Libby P. Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2006; 26: 987-994.
  CrossrefPubMedGoogle Scholar
• 5 Nahrendorf M, Jaffer FA, Kelly KA. et al. Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis. Circulation 2006; 114: 1504-1511.
  CrossrefPubMedGoogle Scholar
• 6 Chen W, Jarzyna PA, van Tilborg GA. et al. RGD peptide functionalized and reconstituted high-density lipo-protein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe. FASEB J 2010; 24: 1689-1699.
  CrossrefPubMedGoogle Scholar
• 7 Laitinen I, Saraste A, Weidl E. et al. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging 2009; 2: 331-338.
  CrossrefPubMedGoogle Scholar
• 8 Wadas TJ, Deng H, Sprague JE. et al. Targeting the alphavbeta3 integrin for small-animal PET/CT of osteolytic bone metastases. J Nucl Med 2009; 50: 1873-1880.
  CrossrefPubMedGoogle Scholar
• 9 Tawakol A, Castano AP, Gad F. et al. Intravascular detection of inflamed athero-sclerotic plaques using a fluorescent photosensitizer targeted to the scavenger receptor. Photochem Photobiol Sci 2008; 7: 33-39.
  CrossrefPubMedGoogle Scholar
• 10 Amirbekian V, Lipinski MJ, Briley-Saebo KC. et al. Detecting and assessing macrophages in vivo to evaluate atherosclerosis noninvasively using molecular MRI. Proc Natl Acad Sci USA 2007; 104: 961-966.
  CrossrefPubMedGoogle Scholar
• 11 Choi KS, Kim SH, Cai QY. et al. Inflammation-specific T1 imaging using anti-intercellular adhesion molecule 1 antibody-conjugated gadolinium diethylenetriaminepentaacetic acid. Mol Imaging 2007; 6: 75-84.
  PubMedGoogle Scholar
• 12 Hartung D, Petrov A, Haider N. et al. Radiolabeled Monocyte Chemotactic Protein 1 for the detection of inflammation in experimental atherosclerosis. J Nucl Med 2007; 48: 1816-1821.
  CrossrefPubMedGoogle Scholar
• 13 Christen T, Nahrendorf M, Wildgruber M. et al. Molecular imaging of innate immune cell function in transplant rejection. Circulation 2009; 119: 1925-1932.
  CrossrefPubMedGoogle Scholar
• 14 Nahrendorf M, Sosnovik DE, Waterman P. et al. Dual channel optical tomo-graphic imaging of leukocyte recruitment and protease activity in the healing myocardial infarct. Circ Res 2007; 100: 1218-1225.
  CrossrefPubMedGoogle Scholar
• 15 Puente XS, Sanchez LM, Gutierrez-Fernandez A. et al. A genomic view of the complexity of mammalian proteolytic systems. Biochem Soc Trans 2005; 33: 331-334.
  CrossrefPubMedGoogle Scholar
• 16 Quesada V, Ordonez GR, Sanchez LM. et al. The Degradome database: mammalian proteases and diseases of proteolysis. Nucleic Acids Res 2009; 37 Database issue D239-243.
  CrossrefPubMedGoogle Scholar
• 17 Conus S, Simon HU. Cathepsins: key modulators of cell death and inflammatory responses. Biochem Pharmacol 2008; 76: 1374-1382.
  CrossrefPubMedGoogle Scholar
• 18 Fanjul-Fernandez M, Folgueras AR, Cabrera S. et al. Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. Biochim Biophys Acta 2010; 1803: 3-19.
  CrossrefPubMedGoogle Scholar
• 19 Libby P. Perplexity of plaque proteinases. Arterioscler Thromb Vasc Biol 2006; 26: 2181-2182.
  CrossrefPubMedGoogle Scholar
• 20 Zheng QH, Fei X, DeGrado TR. et al. Synthesis, biodistribution and micro-PET imaging of a potential cancer biomarker carbon-11 labeled MMP inhibitor (2R)-2-[[4-(6-fluorohex-1-ynyl)phenyl]sulfonylamino]-3-methylbutyric acid [11C]methyl ester. Nucl Med Biol 2003; 30: 753-760.
  CrossrefPubMedGoogle Scholar
• 21 Zheng QH, Fei X, Liu X. et al. Synthesis and preliminary biological evaluation of MMP inhibitor radiotracers [11C]methyl-halo-CGS 27023A analogs, new potential PET breast cancer imaging agents. Nucl Med Biol 2002; 29: 761-770.
  CrossrefPubMedGoogle Scholar
• 22 Breyholz HJ, Wagner S, Levkau B. et al. A 18F-radiolabeled analogue of CGS 27023A as a potential agent for assessment of matrix-metalloproteinase activity in vivo. Q J Nucl Med Mol Imaging 2007; 51: 24-32.
  PubMedGoogle Scholar
• 23 Wagner S, Breyholz HJ, Holtke C. et al. A new 18F-labelled derivative of the MMP inhibitor CGS 27023A for PET: radiosynthesis and initial small-animal PET studies. Appl Radiat Isot 2009; 67: 606-610.
  CrossrefPubMedGoogle Scholar
• 24 Wagner S, Breyholz HJ, Law MP. et al. Novel fluorinated derivatives of the broad-spectrum MMP inhibitors N-hydroxy-2(R)-[[(4-methoxyphenyl)sulfonyl] (benzyl)- and (3-picolyl)-amino]-3-methyl-butanamide as potential tools for the molecular imaging of activated MMPs with PET. J Med Chem 2007; 50: 5752-5764.
  CrossrefPubMedGoogle Scholar
• 25 Fujimoto S, Hartung D, Ohshima S. et al. Molecular imaging of matrix metalloproteinase in atherosclerotic lesions: resolution with dietary modification and statin therapy. J Am Coll Cardiol 2008; 52: 1847-1857.
  CrossrefPubMedGoogle Scholar
• 26 Haider N, Hartung D, Fujimoto S. et al. Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis. J Nucl Cardiol 2009; 16: 753-762.
  CrossrefPubMedGoogle Scholar
• 27 Ohshima S, Petrov A, Fujimoto S. et al. Molecular imaging of matrix metalloproteinase expression in atherosclerotic plaques of mice deficient in apolipoprotein e or low-density-lipoprotein receptor. J Nucl Med 2009; 50: 612-617.
  CrossrefPubMedGoogle Scholar
• 28 Schafers M, Riemann B, Kopka K. et al. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 2004; 109: 2554-2559.
  CrossrefPubMedGoogle Scholar
• 29 Zhang J, Nie L, Razavian M. et al. Molecular imaging of activated matrix metalloproteinases in vascular remodeling. Circulation 2008; 118: 1953-1960.
  CrossrefPubMedGoogle Scholar
• 30 Su H, Spinale FG, Dobrucki LW. et al. Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling. Circulation 2005; 112: 3157-3167.
  CrossrefPubMedGoogle Scholar
• 31 Khurana A, Runge VM, Narayanan M. et al. Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan). Invest Radiol 2007; 42: 139-145.
  CrossrefPubMedGoogle Scholar
• 32 Wu YL, Ye Q, Sato K. et al. Noninvasive evaluation of cardiac allograft rejection by cellular and functional cardiac magnetic resonance. JACC Cardiovasc Imaging 2009; 2: 731-741.
  CrossrefPubMedGoogle Scholar
• 33 Ye Q, Wu YL, Foley LM. et al. Longitudinal tracking of recipient macrophages in a rat chronic cardiac allograft rejection model with noninvasive magnetic resonance imaging using micrometer-sized paramagnetic iron oxide particles. Circulation 2008; 118: 149-156.
  CrossrefPubMedGoogle Scholar
• 34 Schellenberger E, Rudloff F, Warmuth C. et al. Protease-specific nanosensors for magnetic resonance imaging. Bioconjug Chem 2008; 19: 2440-2445.
  CrossrefPubMedGoogle Scholar
• 35 Olson ES, Jiang T, Aguilera TA. et al. Activatable cell penetrating peptides linked to nanoparticles as dual probes for in vivo fluorescence and MR imaging of proteases. Proc Natl Acad Sci USA 2010; 107: 4311-4316.
  CrossrefPubMedGoogle Scholar
• 36 Ntziachristos V, Tung CH, Bremer C. et al. Fluorescence molecular tomography resolves protease activity in vivo. Nat Med 2002; 8: 757-760.
  CrossrefPubMedGoogle Scholar
• 37 Funovics MA, Weissleder R, Mahmood U. Catheter-based in vivo imaging of enzyme activity and gene expression: feasibility study in mice. Radiology 2004; 231: 659-666.
  CrossrefPubMedGoogle Scholar
• 38 Shalhoub J, Owen DR, Gauthier T. et al. The use of contrast enhanced ultrasound in carotid arterial disease. Eur J Vasc Endovasc Surg 2010; 39: 381-387.
  CrossrefPubMedGoogle Scholar
• 39 Lindner JR. Molecular imaging of cardiovascular disease with contrast-enhanced ultrasonography. Nat Rev Cardiol 2009; 6: 475-481.
  CrossrefPubMedGoogle Scholar
• 40 Libby P. The molecular mechanisms of the thrombotic complications of atherosclerosis. J Intern Med 2008; 263: 517-527.
  CrossrefPubMedGoogle Scholar
• 41 Etoh T, Joffs C, Deschamps AM. et al. Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs. Am J Physiol Heart Circ Physiol 2001; 281: H987-994.
  CrossrefPubMedGoogle Scholar
• 42 Kandalam V, Basu R, Abraham T. et al. TIMP2 deficiency accelerates adverse post-myocardial infarction remodeling because of enhanced MT1-MMP activity despite lack of MMP2 activation. Circ Res 2010; 106: 796-808.
  CrossrefPubMedGoogle Scholar
• 43 Hellenthal FA, Buurman WA, Wodzig WK. et al. Biomarkers of AAA progression. Part 1: extracellular matrix degeneration. Nat Rev Cardiol 2009; 6: 464-474.
  CrossrefPubMedGoogle Scholar
• 44 Chen J, Tung CH, Allport JR. et al. Near-infrared fluorescent imaging of matrix metalloproteinase activity after myocardial infarction. Circulation 2005; 111: 1800-1805.
  CrossrefPubMedGoogle Scholar
• 45 Deguchi JO, Aikawa M, Tung CH. et al. Inflammation in atherosclerosis: visualizing matrix metalloproteinase action in macrophages in vivo. Circulation 2006; 114: 55-62.
  CrossrefPubMedGoogle Scholar
• 46 Kaijzel E, van Heijningen P, Wielopolski P. et al. Multimodality imaging reveals a gradual increase in matrix metalloproteinase activity at aneurysmal lesions in live fibulin-4 mice. Circ Cardiovasc Imaging 2010; 3: 567-577.
  CrossrefPubMedGoogle Scholar
• 47 Sheth RA, Maricevich M, Mahmood U. In vivo optical molecular imaging of matrix metalloproteinase activity in abdominal aortic aneurysms correlates with treatment effects on growth rate. Atherosclerosis 2010; 212: 181-187.
  CrossrefPubMedGoogle Scholar
• 48 Breyholz HJ, Schafers M, Wagner S. et al. C-5-disubstituted barbiturates as potential molecular probes for noninvasive matrix metalloproteinase imaging. J Med Chem 2005; 48: 3400-3409.
  CrossrefPubMedGoogle Scholar
• 49 Breyholz HJ, Wagner S, Faust A. et al. Radiofluorinated pyrimidine-2,4,6-triones as molecular probes for noninvasive MMP-targeted imaging. Chem Med Chem 2010; 5: 777-789.
  CrossrefPubMedGoogle Scholar
• 50 Furumoto S, Takashima K, Kubota K. et al. Tumor detection using 18F-labeled matrix metalloproteinase-2 inhibitor. Nucl Med Biol 2003; 30: 119-125.
  CrossrefPubMedGoogle Scholar
• 51 Sprague JE, Li WP, Liang K. et al. In vitro and in vivo investigation of matrix metalloproteinase expression in metastatic tumor models. Nucl Med Biol 2006; 33: 227-237.
  CrossrefPubMedGoogle Scholar
• 52 Watkins GA, Jones EF, Scott Shell M. et al. Development of an optimized activatable MMP-14 targeted SPECT imaging probe. Bioorg Med Chem 2009; 17: 653-659.
  CrossrefPubMedGoogle Scholar
• 53 Ohshima S, Fujimoto S, Petrov A. et al. Effect of an antimicrobial agent on athero-sclerotic plaques: assessment of metalloproteinase activity by molecular imaging. J Am Coll Cardiol 2010; 55: 1240-1249.
  CrossrefPubMedGoogle Scholar
• 54 Razavian M, Zhang J, Nie L. et al. Molecular imaging of matrix metalloproteinase activation to predict murine aneurysm expansion in vivo. J Nucl Med 2010; 51: 1107-1115.
  CrossrefPubMedGoogle Scholar
• 55 Zhang Z, Mascheri N, Dharmakumar R. et al. Cellular magnetic resonance imaging: potential for use in assessing aspects of cardiovascular disease. Cytotherapy 2008; 10: 575-586.
  CrossrefPubMedGoogle Scholar
• 56 Garcia-Touchard A, Henry TD, Sangiorgi G. et al. Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol 2005; 25: 1119-1127.
  CrossrefPubMedGoogle Scholar
• 57 Lutgens SP, Cleutjens KB, Daemen MJ. et al. Cathepsin cysteine proteases in cardiovascular disease. FASEB J 2007; 21: 3029-3041.
  CrossrefPubMedGoogle Scholar
• 58 Chen J, Tung CH, Mahmood U. et al. In vivo imaging of proteolytic activity in atherosclerosis. Circulation 2002; 105: 2766-2771.
  CrossrefPubMedGoogle Scholar
• 59 Kim DE, Kim JY, Schellingerhout D. et al. Molecular imaging of cathepsin B proteolytic enzyme activity reflects the inflammatory component of atherosclerotic pathology and can quantitatively demonstrate the antiatherosclerotic therapeutic effects of atorvastatin and glucosamine. Mol Imaging 2009; 8: 291-301.
  PubMedGoogle Scholar
• 60 Jaffer FA, Kim DE, Quinti L. et al. Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. Circulation 2007; 115: 2292-2298.
  CrossrefPubMedGoogle Scholar
• 61 Aikawa E, Aikawa M, Libby P. et al. Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease. Circulation 2009; 119: 1785-1794.
  CrossrefPubMedGoogle Scholar
• 62 Jaffer FA, Vinegoni C, John MC. et al. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation 2008; 118: 1802-1809.
  CrossrefPubMedGoogle Scholar
• 63 Suchy M, Ta R, Li AX. et al. A paramagnetic chemical exchange-based MRI probe metabolized by cathepsin D: design, synthesis and cellular uptake studies. Org Biomol Chem 2010; 8: 2560-2566.
  CrossrefPubMedGoogle Scholar
• 64 Tung CH, Bredow S, Mahmood U. et al. Preparation of a cathepsin D sensitive near-infrared fluorescence probe for imaging. Bioconjug Chem 1999; 10: 892-896.
  CrossrefPubMedGoogle Scholar
• 65 Re G, Azzimondi G, Lanzarini C. et al. Plasma lipoperoxidative markers in ischaemic stroke suggest brain embolism. Eur J Emerg Med 1997; 4: 5-9.
  PubMedGoogle Scholar
• 66 Brennan ML, Penn MS, Van Lente F. et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349: 1595-1604.
  CrossrefPubMedGoogle Scholar
• 67 Meuwese MC, Stroes ES, Hazen SL. et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol 2007; 50: 159-165.
  CrossrefPubMedGoogle Scholar
• 68 Nahrendorf M, Sosnovik D, Chen JW. et al. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 2008; 117: 1153-1160.
  CrossrefPubMedGoogle Scholar
• 69 Mocatta TJ, Pilbrow AP, Cameron VA. et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction. J Am Coll Cardiol 2007; 49: 1993-2000.
  CrossrefPubMedGoogle Scholar
• 70 Querol M, Chen JW, Weissleder R. et al. DTPA-bisamide-based MR sensor agents for peroxidase imaging. Org Lett 2005; 7: 1719-1722.
  CrossrefPubMedGoogle Scholar
• 71 Ronald JA, Chen JW, Chen Y. et al. Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 2009; 120: 592-599.
  CrossrefPubMedGoogle Scholar
• 72 Ronald JA, Chen Y, Belisle AJ. et al. Comparison of gadofluorine-M and Gd-DTPA for noninvasive staging of atherosclerotic plaque stability using MRI. Circ Cardiovasc Imaging 2009; 2: 226-234.
  CrossrefPubMedGoogle Scholar
• 73 Hyafil F, Cornily JC, Feig JE. et al. Noninvasive detection of macrophages using a nanoparticulate contrast agent for computed tomography. Nat Med 2007; 13: 636-641.
  CrossrefPubMedGoogle Scholar
• 74 Nahrendorf M, Waterman P, Thurber G. et al. Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors. Arterioscler Thromb Vasc Biol 2009; 29: 1444-1451.
  CrossrefPubMedGoogle Scholar
• 75 Nahrendorf M, Zhang H, Hembrador S. et al. Nanoparticle PET-CT imaging of macrophages in inflammatory atherosclerosis. Circulation 2008; 117: 379-387.
  CrossrefPubMedGoogle Scholar
• 76 Graebe M, Pedersen SF, Borgwardt L. et al. Molecular pathology in vulnerable carotid plaques: correlation with [18]-fluorodeoxyglucose positron emission tomography (FDG-PET). Eur J Vasc Endovasc Surg 2009; 37: 714-721.
  CrossrefPubMedGoogle Scholar
• 77 Reeps C, Essler M, Pelisek J. et al. Increased 18F-fluorodeoxyglucose uptake in abdominal aortic aneurysms in positron emission/computed tomography is associated with inflammation, aortic wall instability, and acute symptoms. J Vasc Surg 2008; 48: 417-424.
  CrossrefPubMedGoogle Scholar
• 78 Wu YW, Kao HL, Chen MF. et al. Characterization of plaques using 18F-FDG PET/CT in patients with carotid atherosclerosis and correlation with matrix metalloproteinase-1. J Nucl Med 2007; 48: 227-233.
  PubMedGoogle Scholar
• 79 Fujimura Y, Hwang PM, Trout Iii H. et al. Increased peripheral benzodiazepine receptors in arterial plaque of patients with atherosclerosis: an autoradiographic study with [(3)H]PK 11195. Atherosclerosis 2008; 201: 108-111.
  CrossrefPubMedGoogle Scholar
• 80 Ishino S, Kuge Y, Takai N. et al. 99mTc-Annexin A5 for noninvasive characterization of atherosclerotic lesions: imaging and histological studies in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits. Eur J Nucl Med Mol Imaging 2007; 34: 889-899.
  CrossrefPubMedGoogle Scholar
• 81 Laitinen IE, Luoto P, Nagren K. et al. Uptake of 11C-choline in mouse athero-sclerotic plaques. J Nucl Med 2010; 51: 798-802.
  CrossrefPubMedGoogle Scholar
• 82 Tekabe Y, Li Q, Rosario R. et al. Development of receptor for advanced glycation end products-directed imaging of atherosclerotic plaque in a murine model of spontaneous atherosclerosis. Circ Cardiovasc Imaging 2008; 1: 212-219.
  CrossrefPubMedGoogle Scholar
• 83 Pugliese F, Gaemperli O, Kinderlerer AR. et al. Imaging of vascular inflammation with [11C]-PK11195 and positron emission tomography/computed tomography angiography. J Am Coll Cardiol 2010; 56: 653-661.
  CrossrefPubMedGoogle Scholar
• 84 Suzuki H, Sato M, Umezawa Y. Accurate targeting of activated macrophages based on synergistic activation of functional molecules uptake by scavenger receptor and matrix metalloproteinase. ACS Chem Biol 2008; 3: 471-479.
  CrossrefPubMedGoogle Scholar
• 85 Jaffer FA, Libby P, Weissleder R. Optical and multimodality molecular imaging: insights into atherosclerosis. Arterioscler Thromb Vasc Biol 2009; 29: 1017-1024.
  CrossrefPubMedGoogle Scholar
• 86 Silvera SS, Aidi HE, Rudd JH. et al. Multimodality imaging of atherosclerotic plaque activity and composition using FDG-PET/CT and MRI in carotid and femoral arteries. Atherosclerosis 2009; 207: 139-143.
  CrossrefPubMedGoogle Scholar
• 87 Sinusas AJ, Bengel F, Nahrendorf M. et al. Multimodality cardiovascular molecular imaging, part I. Circ Cardiovasc Imaging 2008; 1: 244-256.
  CrossrefPubMedGoogle Scholar
• 88 Nahrendorf M, Keliher E, Panizzi P. et al. 18F-4V for PET-CT imaging of VCAM-1 expression in atherosclerosis. JACC Cardiovasc Imaging 2009; 2: 1213-1222.
  CrossrefPubMedGoogle Scholar
• 89 Wunder A, Tung CH, Muller-Ladner U. et al. In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. Arthritis Rheum 2004; 50: 2459-2465.
  CrossrefPubMedGoogle Scholar
• 90 Cortez-Retamozo V, Swirski FK, Waterman P. et al. Real-time assessment of inflammation and treatment response in a mouse model of allergic airway inflammation. J Clin Invest 2008; 118: 4058-4066.
  CrossrefPubMedGoogle Scholar
• 91 Yang Y, Hong H, Zhang Y. et al. Molecular Imaging of Proteases in Cancer. Cancer Growth Metastasis 2009; 2: 13-27.
  PubMedGoogle Scholar
• 92 Weissleder R. Molecular imaging in cancer. Science 2006; 312: 1168-1171.
  CrossrefPubMedGoogle Scholar
• 93 Weissleder R, Pittet MJ. Imaging in the era of molecular oncology. Nature 2008; 452: 580-589.
  CrossrefPubMedGoogle Scholar