作者: Colevret, Delphine ; Tardy, Isabelle ; Von Wronski, Mathew ; Hyvelin, Jean-Marc ; Padilla, Frederic ; Helbert, Alexandre ; Bettinger, Thierry ; Botteron, Catherine

Objectives:

The aim of this study was to evaluate the added value of ultrasound molecular imaging of the vascular growth factor receptor 2 (VEGFR2) expression, using the clinical grade contrast agent BR55, for the early evaluation of antiangiogenic treatment efficacy in a chemo-induced rat mammary tumor model.

Materials and Methods:

In this preclinical study, chemo-induced rat mammary tumors were obtained after a single injection of N-nitroso-N-methylurea intraperitoneally in 46 prepubescent (age 38 ± 2 days) female rats. All experiments were performed under the authorization of the Direction Générale de la Santé, Geneva, Switzerland. Once tumor reached 0.8 cm in the largest cross-section, animals were enrolled in a sunitinib- or vehicle-treated group. Ultrasound molecular imaging was performed using BR55, a clinical grade targeted contrast agent against VEGFR2, before therapy and up to 72 hours. Anatomical changes of tumor over time, that is, area of the tumor largest cross-section and tumor volume, were measured in B-mode. Signal from microbubbles was detected in a nonlinear contrast mode (power modulation) using the iU22 diagnostic ultrasound system (Phillips, United States) equipped with a L12–5 linear transducer (transmit frequency 5 MHz). Peak enhancement and wash-in area under the curve were extracted from the time intensity curves generated by a dedicated quantification software for contrast ultrasound, so-called VueBox (Bracco Suisse SA, Switzerland). The signal of bound BR55 microbubbles in the tumor was quantified 10 minutes after injection. Altogether, these parameters were used to monitor tumoral response to treatment at the anatomical, functional, and molecular levels. At each time point, a cohort of tumors was harvested for the assessment of CD31 and VEGFR2 expression by immunohistochemistry staining.

Results:

Under sunitinib therapy, assessment of the expression of VEGFR2 by ultrasound molecular imaging with BR55 reveals a significant difference as early as 12 hours after first dosing (−25%), whereas tumor size significant change occurs only after 24 hours. At the end of the therapeutic protocol, 72 hours after the onset of treatment, molecular changes are more marked with a 80% decrease compared with only ~40% for the anatomic parameters. Ultrasound molecular imaging observations suggesting a decrease in VEGFR2 expression in treated tumors were corroborated by semiquantitative grading of VEGFR2, showing a decrease expression over time. Functional parameters measured in the perfusion phase also show a decrease along treatment, significant for 24 hours and of 48% of peak enhancement at the end of protocol.

Conclusions:

Anatomical, functional, and molecular evaluations are feasible in a single examination using BR55 ultrasound targeted contrast agent. Ultrasound molecular imaging of VEGFR2 can depict an early response to antiangiogenic treatment in a rat mammary tumor model. This imaging modality has a potential for early assessment of each patient's response, which could be useful to take decisions on therapeutic protocol, providing as such an imaging tool for personalized medicine.

2014-04-01·Investigative radiology1区 · 医学

Ultrasound Molecular Imaging of Transient Acute Myocardial Ischemia With a Clinically Translatable P- and E-Selectin Targeted Contrast Agent

1区 · 医学

Article

作者: Botteron, Catherine ; Colevret, Delphine ; Emmel, Patricia ; Costa, Maria ; Tranquart, Francois ; Bettinger, Thierry ; von Wronski, Mathew ; Tardy, Isabelle ; Hyvelin, Jean-Marc ; Nunn, Adrian ; Frinking, Peter ; Bussat, Philippe ; Lassus, Anne

OBJECTIVE:

The diagnosis of acute coronary syndrome remains challenging especially in patients without clear symptoms or electrocardiographic and/or biomarker features. A hallmark of ischemia/reperfusion is activation of endothelial cells leading to altered expression of molecular markers, including selectins. In this context, we aimed to validate the value of ultrasound molecular imaging for detecting transient myocardial ischemia by using a clinically translatable dual P- and E-selectin-targeted ultrasound contrast agent (UCA) and microbubble (MB(selectin)).

MATERIAL AND METHODS:

Transient (20 minutes) myocardial ischemia of rat heart was produced by ligation of the left anterior descending coronary artery ligation followed by 2-, 5-, or 24-hour reperfusion. Imaging of the transient ischemic event was achieved by the use of MB(selectin). Performance of this clinically translatable targeted UCA was compared with that of antibody-targeted streptavidin MBs. Finally, immunohistochemistry staining of rat myocardial ischemic tissue was performed to assess expression of selectins accessible to targeted UCA.

RESULTS:

In rats subjected to myocardial ischemia (20 minutes) followed by reperfusion (2 hours), injection of MB(selectin) produced high late phase (ie, 10-minute postinjection) ultrasound molecular imaging enhancement in the myocardium, which colocalized with the ischemic area. Late phase enhancement persisted 5 and 24 hours after reperfusion. Similarly, the use of MBP and MBE, comprising antibodies specific for P- and E-selectin, respectively, showed high late-phase enhancement within the ischemic area compared with remote myocardial tissue. Two and 5 hours after ischemia has resolved, a persistent expression of these 2 selectins was detected. After 24 hours of reperfusion, only MBE produced late phase enhancement within the ischemic myocardium. Immunohistochemical findings revealed that both P- and E-selectin were expressed and accessible on the surface of the activated endothelium 2 and 5 hours after the acute ischemic event, whereas only E-selectin remained accessible after 24 hours.

CONCLUSIONS:

Ultrasound molecular imaging of transient myocardial ischemia using dual selectin-targeted UCA is able to monitor the time course of expression of selectins after resolution of the ischemic event, paving the way for a large clinical diagnostic window.

2013-08-01·Investigative radiology1区 · 医学

Use of Ultrasound Contrast Agent Microbubbles in Preclinical Research

1区 · 医学

Review

作者: Tardy, Isabelle ; Arbogast, Christophe ; Helbert, Alexandre ; Emmel, Patricia ; Hyvelin, Jean-Marc ; Tranquart, Francois ; Costa, Maria ; Nunn, Adrian D. ; Theraulaz, Martine

Ultrasound contrast imaging techniques represent a real opportunity to improve efficiency in the preclinical drug discovery and development process. Ultrasound contrast agents (UCAs) combined with specific ultrasound contrast detection modes provide real-time, high spatial resolution of both organ and lesion blood perfusion, the so-called dynamic contrast-enhanced ultrasound imaging. With the advent of targeted UCA, ultrasound molecular imaging is gaining momentum in molecular imaging, particularly because of the simultaneous real-time anatomical and functional/molecular imaging capabilities. In preclinical research, contrast-enhanced ultrasound imaging, with either nontargeted or targeted UCA, is a fast-growing imaging modality that has not yet been standardized compared with other imaging modalities. Contrast-enhanced ultrasound imaging is an operator-dependent imaging modality, requiring adherence to rigorous step-by-step protocols. In this article, which is intended for advanced, hands-on researchers, we report key factors that can lead to variability in preclinical results and recommend some preventive methods to limit or cancel their effect on the final results. Standardized procedures are a prerequisite for acceptance of new contrast-enhanced ultrasound imaging methods to eliminate factors that could distort results, improve the reproducibility between different centers and studies, and, therefore, allow translation to clinical application.

项与 Bracco Suisse SA 相关的新闻（医药）

2023-04-13

·BioSpace

BRACCO IMAGING S.p.A. ANNOUNCES A NEW AGREEMENT WITH SONOTHERA™ TO EXPLORE THE EMERGING FIELD OF ULTRASOUND-GUIDED NONVIRAL GENE THERAPY

GENEVA, April 13, 2023 /PRNewswire/ -- Bracco Imaging S.p.A., a global leader in diagnostic imaging, and SonoThera, Inc., a biotechnology company dedicated to treating the root cause of human diseases through genetic therapy, have entered into an agreement under which Bracco Imaging will provide its cutting-edge gas-filled microbubbles technology platform to SonoThera for use in the development of its novel, ultrasound-guided nonviral gene therapy platform. "We are delighted to have signed this new agreement with SonoThera," said Thierry Bettinger, Ph.D., Director of Bracco Research Center in Geneva. "The combination of Bracco's innovative gas microbubbles platform with SonoThera's ongoing development of a nonviral gene delivery platform will undoubtedly advance development in this novel approach to gene therapy." As part of this new agreement, Bracco Imaging will grant SonoThera a non-exclusive license to use Bracco's microbubble for Research purposes. "SonoThera is pleased to partner with a leader in microbubble development and commercialization such as Bracco," said Kenneth Greenberg, Ph.D., Co-Founder and Chief Executive Officer of SonoThera. "As we develop a new generation of genetic therapies, important collaborations such as this make it possible to find alternative pathways to viral vectors, potentially increasing safety and efficacy." The combination of ultrasound energy with microbubble allows transient permeability of vessel walls and cell membranes to enable the delivery of therapeutic nucleic acid payloads. The agreement will allow SonoThera to fully explore the potential of this innovative approach to facilitate the safe and effective delivery of various genetic materials to target cells/organs with minimal off-target delivery. Bracco Imaging is a ground-breaking player in the field of microbubbles. This is demonstrated by the worldwide marketing of contrast-enhanced ultrasound products and the ongoing research and development (R&D) programs to further exploit the potential of microbubbles for new applications in molecular imaging and therapy. To enable the translation of these new projects into products, significant investment has been brought to the site of Bracco Suisse SA in Geneva, particularly to increase the production capacity of these different agents. About Bracco Imaging Bracco Imaging S.p.A., part of the Bracco Group, is a world-leading diagnostic imaging provider. Headquartered in Milan, Italy, Bracco Imaging develops, manufactures, and markets diagnostic imaging agents and solutions. It offers a product and solution portfolio for all key diagnostic imaging modalities: X-ray imaging (including Computed Tomography-CT, Interventional Radiology, and Cardiac Catheterization), Magnetic Resonance Imaging (MRI), Contrast Enhanced Ultrasound (CEUS), and Nuclear Medicine through radioactive tracers and novel PET imaging agents to inform clinical management and guide care for cancer patients in areas of unmet medical need. Our continually evolving portfolio is completed by a range of medical devices, advanced administration systems, and dose-management software. In 2019 Bracco Imaging enriched its product portfolio by expanding the range of oncology nuclear imaging solutions in the urology segment and other specialties with the acquisition of Blue Earth Diagnostics. In 2021, Bracco Imaging established Blue Earth Therapeutics as a separate, cutting-edge biotechnology dedicated to advancing next-generation targeted radiotherapeutics to treat patients who have cancer. Visit to learn more. About SonoThera™ Founded by Drs. Kenneth Greenberg, Michael Davidson, and Steve Feinstein, SonoThera, Inc. is a biotechnology company dedicated to treating the root cause of human disease through genetic therapy. SonoThera is developing an ultrasound-guided, nonviral gene therapy platform and treatments designed to provide patients with the next generation of safe and effective genetic medicines. The platform utilizes sonoporation, a microbubble-mediated biophysical process to non-invasively deliver genetic payloads selectively targeting a wide range of organs within the body. SonoThera is headquartered in South San Francisco, California. Visit to learn more. Micaela Colamasi PR Manager Bracco Imaging S.p.A. Email: micaela.colamasi@bracco.com Cell: +39 348 2314362

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