Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging

Sipkins, Dorothy A.; Cheresh, David A.; Kazemi, Mahmood R.; Nevin, Linda M; Bednarski, Mark D.; Li, King C.

doi:10.1038/nm0598-623

Cited by 833 publications

(505 citation statements)

References 13 publications

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“…The criterion is that the signal be greater than or equal to three times the standard deviation (σ) of the noise level [26,27]. This criterion results in the following condition: [4] where N is the magnitude of the signal in the region of interest of the MR images. [5] where C Gd (M) is the concentration of GdDO3A-FLAG in TBS buffer or on the anti-FLAG® M2-agarose affinity gel layer as determined by ICP-MS, N Gd is the MR signal intensity after addition of GdDO3A-FLAG, N 0 is the MR signal intensity without addition of GdDO3A-FLAG, and the standard deviation (σ) was determined from the signal intensity without addition of GdDO3A-FLAG.…”

Section: Detection Limits (Dl) In Solutions and Gelsmentioning

confidence: 99%

“…There is a great deal of interest in enhancing the utility of these tools in medicine and research through the development of molecularly-targeted MRI contrast agents. One example might be a chimeric molecule comprised of a contrast agent tethered to a molecule capable of binding to a specific protein or other biomolecular target with high affinity and specificity [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. For example, we previously reported that a peptide selected from a phage display library to bind the yeast Gal80 protein can be linked to GdDOTA to create a reagent capable of imaging Gal80 protein in vitro [18,19].…”

Section: Introductionmentioning

confidence: 99%

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The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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Simple low MW chelates of Gd 3+ such as those currently used in clinical MR imaging are considered too insensitive for most molecular imaging applications. Here, we evaluated the detection limit of a molecularly targeted, low MW Gd 3+ -based, T 1 agent in a model where the receptor concentration was precisely known. The data demonstrate that receptors clustered together to form a microdomain of high local concentration can be imaged successfully even when the bulk concentration of the receptor is quite low. A GdDO3A-peptide identified by phage display to target the anti-FLAG antibody was synthesized, purified and characterized. T 1 weighted MR images were compared with the agent bound to antibody in bulk solution and with the agent bound to the antibody localized on agarose beads. Fluorescence competition binding assays show that the agent has a high binding affinity (K D = 150 nM) for the antibody while the fully bound relaxivity of the GdDO3A-peptide:anti-FLAG antibody in solution was a relatively modest 17 mM −1 s −1 . The agent:antibody complex was MR silent at concentrations below ~9 µM but was detectable down to 4 µM bulk concentrations when presented to antibody clustered together on the surface of agarose beads. These results provided an estimate of the detection limits for other T 1 -based agents with higher fully bound relaxivities or multimeric structures bound to clustered receptor molecules. The results demonstrate that the sensitivity of molecularly-targeted contrast agents depends on the local microdomain concentration of the target protein and the molecular relaxivity of the bound complex. A model is presented which predicts that for a molecularly targeted agent consisting of a single Gd 3+ complex with bound relaxivity of 100 mM −1 s −1 or, more reasonably, four tethered Gd 3+ complexes each having a bound relaxivity of 25 mM −1 s −1 , the detection limit of a protein microdomain is ~690 nM at 9.4T. These experimental and extrapolated detection limits are both well below current literature estimates and suggests that detection of low MW molecularly targeted T 1 agents is not an unrealistic goal.

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Section: Detection Limits (Dl) In Solutions and Gelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Hanaoka

Lubag

Castillo-Muzquiz³

et al. 2008

Magnetic Resonance Imaging

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“…Therefore, antibodies or peptides capable of blocking the activity of integrin ␣ v ␤ 3 are classified as anti-angiogenic (4 -8). In this vein, several reports suggest that integrin ␣ v ␤ 3 is a target for anti-angiogenic therapy (7)(8)(9)(10). Several growth factors including FGF2 and tumor necrosis factor-␣ increase ␣ v ␤ 3 expression in the developing blood vessels of chick embryo (11) and rabbit cornea (5).…”

mentioning

confidence: 99%

Pharmacoproteomic Analysis of a Novel Cell-permeable Peptide Inhibitor of Tumor-induced Angiogenesis

Bang

Kim

Kang

et al. 2011

Molecular & Cellular Proteomics

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P11, a novel peptide ligand containing a PDZ-binding motif (Ser-Asp-Val) with high affinity to integrin ␣ v ␤ 3 was identified from a hexapeptide library (PS-SPCL) using a protein microarray chip-based screening system. Here, we investigated the inhibitory mechanism of P11 (HSD-VHK) on tumor-induced angiogenesis via a pharmacoproteomic approach. P11 was rapidly internalized by , human umbilical vein endothelial cells (HUVECs) via an integrin ␣ v ␤ 3 -mediated event. Caveolin and clathrin appeared to be involved in the P11 uptake process. The cell-penetrating P11 resulted in suppression of bFGF-induced HUVEC proliferation in a dose-dependent manner. Phosphorylation of extracellular-signal regulated kinase (ERK1/2) and mitogen-activated protein kinase kinase (MEK) in bFGFstimulated HUVECs was inhibited by cell-permeable P11. Proteomic analysis via antibody microarray showed upregulation of p53 in P11-treated HUVECs, resulting in induction of apoptosis via activation of caspases-3, -8, and -9. Several lines of experimental evidence strongly suggest that the molecular mechanism of P11, a novel antiangiogenic agent, inhibits bFGF-induced HUVEC proliferation via mitogen-activated protein kinase kinase and extracellular-signal regulated kinase inhibition as well as p53-mediated apoptosis related with activation of

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“…Antibody-coated paramagnetic liposomes (35), Gd-perfluorocarbon nanoparticles conjugated to anti-integrin a v h 3 monoclonal antibody (36), and integrin a v h 3 -targeted paramagnetic nanoparticles (37) have been reported for magnetic resonance imaging of integrin a v h 3 expression (Fig. 4A).…”

Section: Non^radionuclide-based Imaging Of Integrinmentioning

confidence: 99%

How molecular imaging is speeding up antiangiogenic drug development

Cai¹,

Rao²,

Gambhir

et al. 2006

Molecular Cancer Therapeutics

172

149

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Drug development is a long process that generally spans about 10 to 15 years. The shift in recent drug discovery to novel agents against specific molecular targets highlights the need for more robust molecular imaging platforms. Using molecular probes, molecular imaging can aid in many steps of the drug development process, such as providing whole body readout in an intact system, decreasing the workload and speeding up drug development/validation, and facilitating individualized anticancer treatment monitoring and dose optimization. The main focus of this review is the recent advances in tumor angiogenesis imaging, and the targets include vascular endothelial growth factor and vascular endothelial growth factor receptor, integrin A v B 3 , matrix metalloproteinase, endoglin (CD105), and E-selectin. Through tumor angiogenesis imaging, it is expected that a robust platform for understanding the mechanisms of tumor angiogenesis and evaluating the efficacy of novel antiangiogenic therapies will be developed, which can help antiangiogenic drug development in both the preclinical stage and the clinical settings. Molecular imaging has enormous potential in improving the efficiency of the drug development process, including the specific area of antiangiogenic drugs.

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Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging

Cited by 833 publications

References 13 publications

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

The detection limit of a Gd3+-based T1 agent is substantially reduced when targeted to a protein microdomain

Pharmacoproteomic Analysis of a Novel Cell-permeable Peptide Inhibitor of Tumor-induced Angiogenesis

How molecular imaging is speeding up antiangiogenic drug development

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