The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55)

Bzyl, Jessica; Palmowski, Moritz; Rix, Anne; Arns, Susanne; Hyvelin, Jean-Marc; Pochon, Sibylle; Ehling, Josef; Schrading, Simone; Kießling, Fabian; Lederle, Wiltrud

doi:10.1007/s00330-012-2594-z

Cited by 56 publications

(54 citation statements)

References 41 publications

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“…Furthermore, molecularly targeted US with BR55 accurately depicted the angiogenic activity in early breast tumors (27) and the malignant, angiogenic conversion of liver dysplasia, which was not possible using functional US with nontargeted microbubbles (28). In agreement with these findings, Bachawal et al (29) demonstrated that molecularly targeted US with BR55 was able to help differentiate between benign and malignant breast tumors with high sensitivity and specificity.…”

Section: Discussionsupporting

confidence: 70%

Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects

Baetke¹,

Rix²,

Tranquart³

et al. 2016

Radiology

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Purpose-To assess the ability of vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted and nontargeted ultrasonography (US) to depict antiangiogenic therapy effects and to investigate whether first-pass kinetics obtained with VEGFR2-targeted microbubbles provide independent data about tumor vascularization. Materials and Methods-Governmental approval was obtained for animal experiments.Vascularization in response to anti-vascular endothelial growth factor receptor or vehicle-control treatment (n=10/group) in HaCaT-ras A-5RT3 xenografts was longitudinally assessed in mice by means of first-pass kinetics of nontargeted microbubbles (BR1, BR38; Bracco, Geneva, Switzerland) and VEGFR2-targeted microbubbles (BR55; Bracco) before and 4, 7, and 14 days after therapy. VEGFR2 expression was determined 8 minutes after BR55 injection with destruction-replenishment analysis. US data were validated by immunohistochemistry. Significant differences were evaluated with the Mann-Whitney test.Results-First-pass analysis with BR1, BR38, and BR55 showed similar tendencies toward decreasing vascularization, with a stronger decrease in tumors treated with anti-VEGF antibody. Immunohistochemistry confirmed the lower microvessel density and VEGFR2-positive area fraction in tumors treated with anti-VEGF antibody. Europe PMC Funders GroupConclusion-Antiangiogenic therapy effects were detected earlier and more distinctly with VEGFR2-targeted US than with functional US. First-pass analyses with BR55, BR38, and BR1 revealed similar results, with a decrease in vascularization during therapy. Functional data showed that BR55 is not strongly affected by early binding of the microbubbles to VEGFR2. Thus, functional and molecular imaging of angiogenesis can be performed with BR55 within one examination.

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Section: Discussionsupporting

confidence: 70%

Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects

Baetke¹,

Rix²,

Tranquart³

et al. 2016

Radiology

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“…In contrast, we found that the expression of the pro-angiogenic marker proteins VEGFR-2 and α v ß 3 integrin differed significantly between breast cancer, pre-invasive cancerous lesions and benign breast lesions. In line with preclinical studies, our histopathological in situ findings support the notion that VEGFR-2 and α v ß 3 integrin may be suitable molecular imaging targets for tumor diagnosis and characterization in the breast [5,6,[10][11][12][23][24][25].…”

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

confidence: 71%

“…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%

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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“…In another study it was shown that multiple injections of tMBs did not block sufficient binding sites to bias molecular imaging data in serial studies [177], which is an important finding. Using the clinically promising BR55 agent, 3D UMI was shown to be very well suited in depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions at very early stages [178]. Combining the effort to selectively image bound tMBs and 3D UMI, Hu et al [179] used a broadband single pulse imaging sequence (transmitting at low frequencies and receiving at high frequencies) that is faster than the multi-pulse methods.…”

Section: Three Dimensional Umimentioning

confidence: 99%

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

Rooij

Daeichin

Skachkov

et al. 2015

International Journal of Hyperthermia

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Ultrasound contrast agents (UCAs) are used routinely in the clinic to enhance contrast in ultrasonography. More recently, UCAs have been functionalised by conjugating ligands to their surface to target specific biomarkers of a disease or a disease process. These targeted UCAs (tUCAs) are used for a wide range of pre-clinical applications including diagnosis, monitoring of drug treatment, and therapy. In this review, recent achievements with tUCAs in the field of molecular imaging, evaluation of therapy, drug delivery, and therapeutic applications are discussed. We present the different coating materials and aspects that have to be considered when manufacturing tUCAs. Next to tUCA design and the choice of ligands for specific biomarkers, additional techniques are discussed that are applied to improve binding of the tUCAs to their target and to quantify the strength of this bond. As imaging techniques rely on the specific behaviour of tUCAs in an ultrasound field, it is crucial to understand the characteristics of both free and adhered tUCAs. To image and quantify the adhered tUCAs, the state-of-the-art techniques used for ultrasound molecular imaging and quantification are presented. This review concludes with the potential of tUCAs for drug delivery and therapeutic applications.

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The high angiogenic activity in very early breast cancer enables reliable imaging with VEGFR2-targeted microbubbles (BR55)

Abstract: 3D molecular ultrasound using BR55 is very well suited to depicting the angiogenic activity in very small breast lesions, suggesting its potential for detecting and characterising these lesions.

Cited by 56 publications

References 41 publications

Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects

Squamous Cell Carcinoma Xenografts: Use of VEGFR2-targeted Microbubbles for Combined Functional and Molecular US to Monitor Antiangiogenic Therapy Effects

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

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

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