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Multimodality Molecular Imaging of Tumor Angiogenesis

¹ Molecular Imaging Program at Stanford, Department of Radiology, Biophysics, and Bio-X Program, School of Medicine, Stanford University, Stanford, California; and ² Department of Radiology and Medical Physics, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, Wisconsin

View larger version (66K): [in this window] [in a new window]   FIGURE 1.  SPECT of VEGFR expression. (A) Transverse CT image of pancreatic adenocarcinoma patient (left) and transverse SPECT image of same patient at 1.5 h after injection of 123I-VEGF165 (right). (B) Bioluminescence imaging (BLI; after injection of D-luciferin) and SPECT (after injection of 99mTc-VEGF121) images of tumor-bearing mouse. Tumor cells were transfected with firefly luciferase. (C) Posterior whole-body images of tumor-bearing mouse at 48 h after injection of 111In-hnTf-VEGF and after coinjection of 100-fold excess of unlabeled apotransferrin (Block). Arrows in all images indicate tumors. (Adapted from (33,36,39).)

View larger version (77K): [in this window] [in a new window]   FIGURE 2.  PET of VEGF/VEGFR expression. (A) Coronal small-animal PET images of tumor-bearing mouse at 24 and 168 h after injection of 89Zr-bevacizumab. (B) Coronal small-animal PET images of U87MG tumor-bearing mice at 2 and 16 h after injection of 64Cu-DOTA-VEGF121. Small tumor expresses high level of VEGFR-2, and large tumor expresses low level of VEGFR-2. (C) Coronal small-animal PET images of 4T1 tumor–bearing mice at 1 and 19 h after injection of either 64Cu-scVEGF (single-chain VEGF that binds to VEGFR) or equivalent amount of 64Cu-inVEGF (inactive VEGF that does not bind to VEGFR). (D) Coronal and sagittal slices containing kidneys (arrowheads) at 4 h after injection of 64Cu-DOTA-VEGF121 (binds to both VEGFR-1 and VEGFR-2) or 64Cu-DOTA-VEGFDEE (VEGFR-2 specific). Arrows or arrowheads in A–C indicate tumors. (Adapted from (37,44,48,53).)

View larger version (76K): [in this window] [in a new window]   FIGURE 3.  Non–radionuclide-based imaging of VEGFR expression. (A) CEU images obtained with VEGFR-2–targeted microbubbles in control and treated animals. Video intensity is significantly lower in mice receiving anti-VEGF treatment. Arrows indicate periphery of tumor; Ctr = center of tumor. (B) Bioluminescence imaging (BLI; after injection of D-luciferin), fluorescence imaging (after injection of Cy5.5–VEGF), and merged images for 4T1 tumor–bearing mouse. (Adapted from (37,70).)

View larger version (14K): [in this window] [in a new window]   FIGURE 4.  Integrin family, composed of 24 heterodimers.

View larger version (55K): [in this window] [in a new window]   FIGURE 5.  Examples of nanoparticles that have been used for imaging tumor angiogenesis.

View larger version (38K): [in this window] [in a new window]   FIGURE 6.  SWNTs for tumor integrin vβ3 targeting. (A) Schematic drawing of functionalized SWNTs. Phospholipid (blue segments) bind strongly to side walls of SWNTs. Polyethylene glycol (PEG) chains provide water solubility, and DOTA molecules are used to chelate 64Cu for PET. (B) Two-dimensional projection of small-animal PET images of U87MG tumor–bearing mice at 8 h after injection of RGD-conjugated SWNTs with (Block) or without coinjection of RGD peptides. Arrowheads indicate tumors. (C) Raman spectra of tissue homogenate, providing direct evidence of presence of SWNTs in tumor. (D) Good agreement of biodistribution data obtained by PET and ex vivo Raman measurements, confirming in vivo stability and tumor-targeting efficacy of RGD-conjugated SWNTs. (Adapted from (122).)

View larger version (75K): [in this window] [in a new window]   FIGURE 7.  Non–radionuclide-based imaging of integrin vβ3 during tumor angiogenesis. (A) T1-weighted images of rabbits before (Pre) and after (Post) injection of targeted liposomes (a and c) and control liposomes (b and d). Arrows indicate tumors. (B) CEU images of rat with brain tumor, depicting parametric perfusion data (top) and signal enhancement from integrin vβ3–targeted microbubbles (bottom). M = periventricular metastasis; T = tumor; V = ventricles. (C) In vivo NIRF imaging of U87MG tumor–bearing mice injected with 200 pmol of QD705–RGD or QD705. Mouse autofluorescence is color coded green, and unmixed QD signal is color coded red. Arrows indicate tumors. (Adapted from (132,139,143).)

View larger version (34K): [in this window] [in a new window]   FIGURE 8.  Dual-modality imaging of integrin vβ3 in tumor vasculature. (A) Schematic structure of PET/NIRF imaging probe DOTA–QD–RGD. (B) Coronal small-animal PET images of U87MG tumor–bearing mice at 1 and 5 h after injection of 64Cu-labeled DOTA–QD or DOTA–QD–RGD. Arrowheads indicate tumors. (C) Excellent overlay between CD31 staining and QD fluorescence (top), as well as between murine β3 staining and QD fluorescence (bottom), confirming that DOTA–QD–RGD mainly targeted integrin vβ3 in tumor vasculature. (Adapted from (154).)