Molecular and functional ultrasound imaging in differently aggressive breast cancer xenografts using two novel ultrasound contrast agents (BR55 and BR38)

Bzyl, Jessica; Lederle, Wiltrud; Rix, Anne; Grouls, Christoph; Tardy, Isabelle; Pochon, Sibylle; Siepmann, Monica; Penzkofer, Tobias; Schneider, Michel; Kießling, Fabian; Palmowski, Moritz

doi:10.1007/s00330-011-2138-y

Cited by 93 publications

(70 citation statements)

References 35 publications

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“…Whereas the transmembrane receptor tyrosine kinase VEGFR-2, which activates the PI3K/Akt/mTOR pathway and mediates endothelial cell proliferation, is mainly expressed on activated endothelium, the cell adhesion molecule α v ß 3 integrin, which binds to arginine-glycine-aspartic acid (RGD)-containing proteins and peptides, is up-regulated on tumor endothelium and on interstitial and tumor cells [7][8][9]. Importantly, as reported by previous studies [10][11][12], molecular ultrasound enables the non-invasive discrimination between breast neoplasms of different malignancy in mice and rats. In addition, phase II clinical trials have been recently launched evaluating the diagnostic potential of VEGFR-2-targeted microbubbles (BR55) using ultrasound in patients with breast or ovarian cancer (www.clinicaltrialsregister.eu, EudraCT: 2012-000699-40) and prostate cancer (www.clinicaltrials.gov, NCT02142608).…”

Section: Introductionsupporting

confidence: 48%

“…S4+5). [5,6,[10][11][12][23][24][25]. However, besides a pilot phase study on breast cancer patients using radiolabeled α V ß 3 -targeted RGD peptides and PET demonstrating a significant probe uptake in the primary lesion and in the metastases [19], clinical studies comparing the diagnostic power of functional vs. molecular imaging for differentiating (mammographically) suspect tumors or for monitoring recurrent lesions upon breast cancer surgery have not yet been reported.…”

Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionsmentioning

confidence: 99%

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In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

et al. 2016

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Vascular endothelial growth factor receptor 2 (VEGFR-2) and α v ß 3 integrin are the most frequently addressed targets in molecular imaging of tumor angiogenesis. In preclinical studies, molecular imaging of angiogenesis has shown potential to detect and differentiate benign and malignant lesions of the breast. Thus, in this retrospective clinical study employing patient tissues, the diagnostic value of VEGFR-2, α v ß 3 integrin and vascular area fraction for the diagnosis and differentiation of breast neoplasia was evaluated. To this end, tissue sections of breast cancer (n=40), pre-invasive ductal carcinoma in situ (DCIS; n=8), fibroadenoma (n=40), radial scar (n=6) and normal breast tissue (n=40) were used to quantify (i) endothelial VEGFR-2, (ii) endothelial α v ß 3 integrin and (iii) total α v ß 3 integrin expression, as well as (iv) the vascular area fraction.Sensitivity and specificity to differentiate benign from malignant lesions were calculated for each marker by receiver operating characteristics (ROC) analyses. Whereas vessel density, as commonly used, did not significantly differ between benign and malignant lesions (AUROC: 0.54), VEGFR-2 and α v ß 3 integrin levels were gradually up-regulated in carcinoma vs. fibroadenoma vs. healthy tissue. The highest diagnostic accuracy for differentiating carcinoma from fibroadenoma was found for total α v ß 3 integrin expression (AUROC: 0.76), followed by VEGFR-2 (AUROC: 0.71) and endothelial α v ß 3 integrin expression (AUROC: 0.68). In conclusion, total α v ß 3 integrin expression is the best discriminator between breast cancer, fibroadenoma and normal breast tissue. With respect to vascular targeting and molecular imaging

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Section: Introductionsupporting

confidence: 48%

Section: Endothelial Vegfr-2 Levels But Not Vascular Area Fractionsmentioning

confidence: 99%

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

et al. 2016

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“…Therefore, microbubbles are highly suitable for molecular imaging of angiogenic and inflamed endothelial surfaces. 38 CEUS was used successfully in preclinical trials for tumor imaging [39][40][41] and thrombus characterization. 42 Moreover, anti-vascular cell adhesion molecule-1 antibody-coated microbubbles could localize successfully to atherosclerotic plaques in the aortic arch.…”

Section: Discussionmentioning

confidence: 99%

Rhodamine-Loaded Intercellular Adhesion Molecule–1-targeted Microbubbles for Dual-Modality Imaging Under Controlled Shear Stresses

Wu¹,

Curaj

Fokong

et al. 2013

Circ: Cardiovascular Imaging

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A therosclerosis, a chronic inflammatory disorder developing in arterial vessels, 1,2 is caused mainly by alterations in arterial shear stress, 3 followed by subendothelial accumulation of lipids and inflammatory cells leading to wall thickening and segmental lumen narrowing. The detection of atherosclerosis using imaging modalities, such as computed tomography, MRI, and ultrasound, is challenging and in many cases only possible in the late stages of disease progression, when the plaque narrows the arterial lumen and determines clinical manifestations. 4 The main challenge is to diagnose and ultimately to intervene therapeutically in the atherosclerotic process during the early stages of disease progression. Clinical Perspective on p 981The endothelium does play a prominent role not only in the early stage of atherosclerosis, but also after conventional balloon angioplasty. Abnormal shear stress and the aggressive fat accumulation in the vessel wall are followed by strong endothelial activation. Activated endothelial cells upregulate surface adhesion molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) that can initiate leukocyte recruitment and transmigration, thereby contributing to the plaque growth.5-7 These distinct adhesion molecules can be used for molecular imaging purposes. In this context, because of the fact that these are intravascular markers, ultrasound molecular imaging with target-specific micrometer-sized gas bubbles (which stay strictly intravascular) present a suitable method for the imaging of endothelial dysfunction. However, molecular imaging Background-The ability to image incipient atherosclerosis is based on the early events taking place at the endothelial level. We hypothesized that the expression of intercellular adhesion molecule-1 even in vessels with high flow rates can be imaged at the molecular level using 2 complementary imaging techniques: 2-photon laser scanning microscopy and contrast-enhanced ultrasound. Methods and Results-Using 2-photon laser scanning microscopy and contrast-enhanced ultrasound, intercellular adhesion molecule-1-targeted and rhodamine-loaded microbubbles were shown to be specifically bound to tumor necrosis factor-α-stimulated human umbilical vein endothelial cells and murine carotid arteries (44 wild-type mice) at shear stresses ranging from 1.25 to 120 dyn/cm 2 . Intercellular adhesion molecule-1-targeted and rhodamine-loaded microbubbles bound 8× more efficient (P=0.016) to stimulated human umbilical vein endothelial cells than to unstimulated cells and 14× more than nontargeted microbubbles (P=0.016). In excised carotids, binding efficiency did not decrease significantly when increasing the flow rate from 0.25 to 0.6 mL/min. Higher flow rates (0.8 and 1 mL/min) showed significantly reduced microbubbles retention, by 38% (P=0.03) and 55% (P=0.03), respectively. Ex vivo results were translatable in vivo, confirming that intercellular adhesion molecule-1-targeted and rhodamine-loaded microbubbles are able to b...

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“…In addition, with the assistance of ARF, recent studies have also demonstrated ultrasound targeted molecular imaging in large vessel environments using some new techniques [23], [50], [52]. In summary, state-of-the-art ultrasound molecular imaging methods have demonstrated efficacy in pre-clinical studies for detection and monitoring of various types of cancers [79], [155], [156] as well as cardiovascular inflammation [39], [138]. However, these approaches possess some limitations such as requiring a "control injection" (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Pre-clinical success of ultrasound molecular imaging has been demonstrated in small blood vessel environments for various diseases including breast [31], [34], [79], prostate [155], [165] and pancreatic [71] cancers, atherosclerosis [39], [40], [137], and inflammatory diseases of the bowels [94]. In these studies, various imaging strategies have been used to address the challenge of differentiating the signal arising uniquely from bound adherent microbubbles from the signals attributable freely circulating microbubbles and tissue.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Ultrasound Molecular Imaging in Large Blood Vessel Environments

Wang

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Stroke is the fourth leading cause of death in the United States. The current standard of care for carotid atherosclerosis addresses the disease after the plaque has developed to the point at which it is detectable using anatomical-based imaging to measure luminal stenosis. Ultrasound molecular imaging, possessing the ability to image the molecular signature of early vascular inflammation, potentially decades prior to the formation of plaque, may enable more timely diagnosis and treatment of atherosclerosis and atherosclerotic risk. Additionally, it simultaneously meets the needs for rapid, lowcost, and radiation-free molecular marker detection that may facilitate clinical adoption. Unfortunately, existing ultrasound-based molecular imaging is limited to small blood vessel environments, and unable to measure molecular marker concentration in large blood vessels.In the first part of the dissertation, the design, implementation, and validation of a In the second part of the dissertation, the characterization of an expanding-nozzle flow-focusing microfluidic device for the generation of monodisperse microbubbles is ii presented. Significantly, the characterization could facilitate real-time adjustment of microbubble diameter and production rate using microfluidic devices.iii

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Molecular and functional ultrasound imaging in differently aggressive breast cancer xenografts using two novel ultrasound contrast agents (BR55 and BR38)

Cited by 93 publications

References 35 publications

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

In situ validation of VEGFR-2 and α v ß 3 integrin as targets for breast lesion characterization

Rhodamine-Loaded Intercellular Adhesion Molecule–1-targeted Microbubbles for Dual-Modality Imaging Under Controlled Shear Stresses

Quantitative Ultrasound Molecular Imaging in Large Blood Vessel Environments

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