Article Figures & Data
Figures
- FIGURE 1.
Analysis of wild-type (eNOS+/+) and eNOS-deficient (eNOS−/−, or knockout) mice. (A) Representative micro-SPECT/CT images of eNOS+/+ and eNOS−/− mice injected with 99mTc-NC100692 at baseline and at 7 d and 4 wk after right femoral artery ligation. Yellow arrows indicate ischemic regions with increased 99mTc-NC100692 retention. Less retention was seen in eNOS−/− mice. (B) Serial micro-SPECT/CT images were analyzed, and ischemic-to-nonischemic 99mTc-NC100692 activity ratios were calculated. Significant (P < 0.05) increase in 99mTc-NC100692 retention was seen in ischemic leg at 7 d after surgery in both groups. However, significantly less retention was seen at 7 d in eNOS−/− mice than in wild-type mice. *P < 0.05 for eNOS−/− mice vs. wild-type mice; #P < 0.05 for value at 7 d vs. value at baseline. (Reprinted from (22).)
- FIGURE 2.
(A) In vivo micro-SPECT/CT images of 201Tl perfusion (top row, green) and 99mTc-NC100692 (middle row, red) in IGF-1 rat at 4 wk after myocardial infarction were reconstructed in short axis, horizontal long axis, and vertical long axis and fused (bottom row) with reference contrast CT image (gray scale). All rats had anterolateral 201Tl perfusion defect (yellow solid arrows) and focal uptake of 99mTc-NC100692 in defect area after myocardial infarction. Contrast agent permitted better definition of myocardium and allowed differentiation of focal myocardial uptake of targeted radiotracer from uptake within chest wall at thoracotomy site (yellow dashed arrow). (B) Representative circumferential count profile of middle myocardial section of IGF-1 rat at 4 wk after myocardial infarction. Count profiles for both 99mTc-NC100692 (•) and 201Tl perfusion (○) are shown. %ID/g = percentage injected dose per gram. (Reprinted with permission of (24).)
- FIGURE 3.
Noninvasive SPECT of angiogenesis in patient after percutaneous coronary intervention after myocardial infarction. After injection of αvβ3-integrin–targeted agent (99mTc-NC100692) 3 wk after myocardial infarction, focal signal enhancement (arrowheads) was noted in short-axis (A) and long-axis (B) views of infarct zone and confirmed by corresponding 99mTc-sestamibi (MIBI) perfusion images. (Reprinted with permission of (27). Images courtesy of Drs. Johan Verjans and Leonard Hofstra, University Hospital, Maastricht, The Netherlands.)
- FIGURE 4.
Cardiac MRI with delayed enhancement (arrows) extending from anterior wall to apical region in 4-chamber (A) and 2-chamber (D) views. Identically reproduced location and geometry with severely reduced myocardial blood flow obtained with 13N-ammonia, corresponding to regions of delayed enhancement on cardiac MRI (arrows) (B and E). Focal 18F-RGD signal colocalized to infarcted area. This signal may reflect angiogenesis within healing area (arrows) (C and F). LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle. (Reprinted with permission of (28).)
- FIGURE 5.
Noninvasive PET/CT images of angiogenesis induced by hind-limb ischemia in murine model. (A) Nontargeted dendritic nanoprobes (bottom center). (B) Uptake of αvβ3-targeted dendritic nanoprobes was higher in ischemic hind limb (left side of image) than in control hind limb (right side of image). (Reprinted with permission of (30).)
- FIGURE 6.
Examples of color-coded CEU images reflecting retention fraction of integrin-targeted microbubbles in control and ischemic proximal hind-limb adductor muscles from untreated (A) and FGF 2–treated (B) rat 4 d after iliac artery ligation. Color scales are shown at bottom. (Reprinted with permission of (38).)
- FIGURE 7.
Contrast ultrasound imaging of angiogenic endothelial cell phenotype in chronic limb ischemia. (A) High-frequency (30-MHz) 3D ultrasound rendering of mouse hind limb with single short-axis elevational plane (bottom) showing region of proximal (Prox) adductor muscle group (arrows). Dist = distal. (B) Perfusion imaging data from adductor muscle group before and after iliac ligation in which product of rate constant and plateau intensity of curves denotes blood flow and is reduced by 80% during acute ischemia but improves to 20% of normal by 21 d. (C) Molecular imaging with microbubbles targeted to kinase insert domain receptor (VEGFR-2) and to P-selectin at day 3 after production of ischemia.
- FIGURE 8.
Angiogenesis induced in cholesterol (Chol)-fed rabbits. Aortic cross sections were imaged at 1.5 T with αvβ3-integrin–targeted nanoparticles. Note heterogeneous distribution in aortic cross sections (false colored contrast enhancement) but little enhancement in nontargeted rabbits (αvβ3−) or rabbits on standard diet (Chol−). diaph = diaphragm; mid = mid-aorta. (Reprinted with permission of (56).)
Tables
- TABLE 1
Selected Operational Parameters, Advantages, and Disadvantages of Modalities Used in Molecular Imaging
Modality Probes Spatial resolution (mm) Sensitivity (mol/L) Advantages Disadvantages PET Positron emitters (18F, 15O, 13N, 11C, 64Cu, 76Br) 1–2 10−11−10−12 Superior sensitivity; tracer chemically identical to parent compound; established attenuation correction algorithms Short–half-life tracers; expensive equipment; requirement for on-site cyclotron; advanced radiochemistry SPECT Photon emitters (201Tl, 99mTc, 111In, 125I) 0.5–2 10−10−10−11 Superior sensitivity; multiple-isotope imaging; emission proportional to concentration of probe Exposure to ionizing radiation; accuracy limited by attenuation of low-energy photons Ultrasound Microbubbles 0.05–0.5 To be determined Widely available; relatively inexpensive; no ionizing radiation Limited penetration depth; lack of molecular probes CT Iodinated contrast agents 0.05–0.2 10−3−10−5 Absorption proportional to concentration of contrast agent; superior spatial resolution Exposure to ionizing radiation; contrast agent nephrotoxicity; low sensitivity MRI Gadolinium chelates, iron oxides 0.02–0.1 10−3−10−5 No ionizing radiation; superior spatial resolution; available instrumentation Low sensitivity; susceptibility to motion artifacts; lack of molecular probes Marker Probe Modality Biologic target or application Reference VEGF 124I-VG76e PET Tumor angiogenesis Collingridge et al. (5) 123I-VEGF165 SPECT Tumor angiogenesis Li et al. (6) 111In-VEGF121 SPECT Peripheral limb angiogenesis Lu et al. (63) 64Cu-DOTA-VEGF121 PET Tumor angiogenesis Cai et al. (7) 64Cu-DOTA-VEGF121 PET Myocardial angiogenesis Rodriquez-Porcel et al. (8) 99mTc-scVEGF SPECT Peripheral limb angiogenesis Levashova et al. (10) 64Cu-scVEGF PET Tumor angiogenesis Backer et al. (9) Anti-VEGFR2 antibody Ultrasound Tumor angiogenesis Willmann et al. (40) αvβ3 111In-RP748 SPECT Tumor angiogenesis Harris et al. (14) Myocardial angiogenesis Meoli et al. (16) 18F-AH111585 PET Tumor angiogenesis Kenny et al. (64), Morrison et al. (65) 123I-RGD SPECT Myocardial angiogenesis Johnson et al. (66) 125I-c(RGD(I)yV) SPECT Peripheral limb angiogenesis Lee et al. (67) 99mTc-NC100692 SPECT Peripheral limb angiogenesis Hua et al. (21) Myocardial angiogenesis Lindsey et al. (23) 18F-NC100717 PET Angiogenic tumor vasculature Indrevoll et al. (68) 11C-NC100717 PET Angiogenic tumor vasculature Indrevoll et al. (68) 76Br-nanoparticles PET Peripheral limb angiogenesis Almutairi et al. (30) Echistatin microbubbles Ultrasound Tumor angiogenesis Ellegala et al. (36) Peripheral angiogenesis Leong-Poi et al. (37,38) RRL microbubbles Ultrasound Tumor angiogenesis Weller et al. (39) LM609 antibody MRI Tumor angiogenesis Sipkins et al. (12) RGD-liposomal nanoparticles MRI Angiogenesis Kluza et al. (48) RGD-SPIO nanoparticles MRI Tumor angiogenesis Zhang et al. (50) RGD-cross-linked iron oxide-Cy5.5 MRI Tumor angiogenesis Montet et al. (51) CD13/aminopeptidase N quantum dots MRI Tumor angiogenesis Oostendorp et al. (57) scVEGF = single-chain VEGF.
Chemical nucleus Biologic process Model system Molecular target Ligand Particle Quantification methods Validation of binding of molecular target 19F (53) Atherosclerotic plaque thrombosis Blood clot in vitro, plaque ex vivo Fibrin Monoclonal antibody Perfluorocarbon in lipid capsule with Gd chelates Spectroscopy normalized to signal intensity standard; calculation of no. of bound particles from integrated 19F signal and calibration curves Localization of 19F spectrum to clot by overlay with 1H MRI and to plaque by overlay with optical image 19F (54) Inflammation of endothelial cells Kidneys from hypercholesterolemic mice imaged ex vivo VCAM-1 VHPKQHRGGSGC peptide Perfluorocarbon in lipid capsule with Gd chelates Spectroscopy normalized to signal intensity standard; conversion to no. of nanoparticles/g of tissue from standard curve of relevant spectra Competitive blockade of binding in vitro; VCAM-1 staining by IHC; comparison of fluorescence from nanoparticles with VCAM-1 by IHC IHC = immunohistochemistry.
Contrast agent Biologic process Model system Molecular target Ligand Particle Quantification method Validation method Gd (55) Atherosclerotic plaque angiogenesis Atherosclerotic NZW rabbits αvβ3-integrin RGD peptidomimetic agent Perfluorocarbon in lipid capsule with Gd chelates Relaxivity normalized to signal intensity standard, expressed as % enhancement compared with baseline Competitive blockade of binding in vivo; demonstration of αvβ3-integrin on plaque capillaries by IHC Gd (57) Tumor angiogenesis Tumor-bearing mice CD13/aminopeptidase N NGR peptide Quantum dot with Gd chelates Relaxivity normalized to Gd content measured by mass spectrometry, expressed as % enhancement compared with baseline Competitive blockade of binding in vivo; fluorescence intensity and colocalization with endothelial cells ex vivo SPIO (52) Lipoprotein metabolism Wild-type, ApoE−/−, and LDL receptor−/− mice Hepatocyte lipoprotein receptor ApoE and lipoprotein lipase SPIO embedded in lipoprotein Relaxivity normalized to radioactivity from radiolabeled SPIO nanoparticles Localization of SPIO nanoparticles and quantum dot nanoparticles in hepatocytes; studies with ApoE−/− and LDL receptor−/− mice NZW = New Zealand White; IHC = immunohistochemistry; LDL = low-density lipoprotein.
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