Bracco Research SA

Plan-les-Ouates, Switzerland

Bracco Research SA

Plan-les-Ouates, Switzerland
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Tardy I.,Bracco Research SA | Pochon S.,Bracco Research SA | Theraulaz M.,Bracco Research SA | Emmel P.,Bracco Research SA | And 3 more authors.
Investigative Radiology | Year: 2010

Objectives: To evaluate BR55, a new VEGFR2-specific ultrasound contrast agent, for imaging prostate tumors in an orthotopic model in the rat. Materials and Methods: Rat prostate adenocarcinoma were established by injection of G Dunning R-3327 tumor cells in one lobe of the prostate of Copenhagen rats. Imaging experiments were performed with BR55, SonoVue, and streptavidin- functionalized microbubbles coupled with an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody using a clinical ultrasound scanner. Contrast enhancement in the tumor and healthy prostate was followed over time by intermittent imaging at low acoustic power. Signal quantification and statistical analysis were performed in the tumor and healthy tissue to compare the behavior of the 3 contrast agents. Immunohistochemistry was performed on the prostate and tumor specimen to determine the expression of VEGFR2. RESULTS: Comparable contrast enhancement was observed in tumors at peak intensity for BR55 and SonoVue. Then, once unbound microbubbles had cleared from the circulation, a strong enhancement of the tumor was obtained with BR55, whereas no significant microbubble accumulation was detected in the healthy prostate tissue. SonoVue microbubbles were rapidly eliminated, and no significant binding was observed in the tumor. The tumor to prostate ratio calculated after signal quantification was about 20 for the 3 doses of BR55 tested. The enhancement obtained with BR55 in the tumor was not significantly different from the one observed with antibody-coupled streptavidin microbubbles. Intense staining for VEGFR2 was detected in the tumor vessels by immunohistochemistry. Conclusions: This study showed that BR55 binding to prostate tumors resulted in a strong enhancement of the lesions as early as a few minutes after contrast injection, whereas minimal nonspecific accumulation occurred in the healthy part of the gland. BR55, like Sonovue, provide information on tissue perfusion during the early vascular phase, but BR55 binding to the tumoral endothelium allows to gain additional information by highlighting the sites of active angiogenesis. The late phase enhancement of the tumor should be particularly valuable for prostate cancer detection and for biopsy guidance. © 2010 by Lippincott Williams & Wilkins.


Cherkaoui S.,Bracco Research SA | Bettinger T.,Bracco Research SA | Hauwel M.,Bracco Research SA | Navetat S.,Bracco Research SA | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

Due to their high specificity and efficiency, antibodies are ideal ligands for target-specific ultrasound contrast agents. The present study focuses on the chemical stability of antibodies during functionalisation with sulfosuccinimidyl-pyridyldithiopropionamidohexanoate (SPDP), a heterobifunctional linker, which exposes free thiol groups upon treatment with a reducing agent. Thiolated antibodies can then react with thiol-reactive group, such as maleimide present on the microbubble surface to form stable covalent complexes. The immunoglobulin structure relies on several intra- and inter-chain disulfide bridges which might be affected by reducing agents. A capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) method with UV detection was applied to address the effect of the functionalisation process on the structural integrity of the antibodies and revealed that antibody disulfide bonds are prone to reduction as function of the reducing agents. Depending on the coupling conditions, various IgG fragments were identified reflecting different combinations between the light and heavy chains. Furthermore, two commonly used reducing agents, namely triscarboxyethylphosphine (TCEP) and 1,4-dithiothreitol (DTT) were compared under various preparation conditions. Results showed that reduction conditions based on DTT as a reducing agent under acidic pH were more appropriate to preserve intra- and inter-disulfide bridges of SPDP-modified antibodies. © 2010 Elsevier B.V.


Pochon S.,Bracco Research SA | Tardy I.,Bracco Research SA | Bussat P.,Bracco Research SA | Bettinger T.,Bracco Research SA | And 4 more authors.
Investigative Radiology | Year: 2010

OBJECTIVES: BR55, an ultrasound contrast agent functionalized with a heterodimer peptide targeting the vascular endothelial growth factor receptor 2 (VEGFR2), was evaluated in vitro and in vivo, demonstrating its potential for specific tumor detection. MATERIALS AND METHODS: The targeted contrast agent was prepared by incorporation of a biospecific lipopeptide into the microbubble membrane. Experiments were performed in vitro to demonstrate the binding capacities of BR55 microbubbles on immobilized receptor proteins and on various endothelial or transfected cells expressing VEGFR2. The performance of BR55 microbubbles was compared with that of streptavidin-conjugated microbubbles targeted to the same receptor by coupling them to a biotinylated antibody. The specificity of BR55 binding to human and mouse endothelial cells was determined in competition experiments with the free lipopeptide, vascular endothelial growth factor (VEGF), or a VEGFR2-specific antibody. Molecular ultrasound imaging of VEGFR2 was performed in an orthotopic breast tumor model in rats using a nondestructive, contrast-specific imaging mode. RESULTS: BR55 was shown to bind specifically to the immobilized recombinant VEGFR2 under flow (dynamic conditions). BR55 accumulation on the target over time was similar to that of microbubbles bearing a specific antibody. BR55 avidly bound to cells expressing VEGFR2, and the pattern of microbubble distribution was correlated with the pattern of receptor expression determined by immunocytochemistry. The binding of targeted microbubbles on cells was competed off by an excess of free lipopeptide, the natural ligand (VEGF) and by a VEGFR2-specific antibody (P < 0.001). Although selected for the human receptor, the VEGFR2-binding lipopeptide was also shown to recognize the rodent receptor. Tumor perfusion was assessed during the vascular phase of BR55, and then the malignant lesion was highlighted by specific accumulation of the targeted microbubbles on tumoral endothelium. The presence of VEGFR2 was confirmed by immunofluorescence staining of tumor cryosections. CONCLUSIONS: VEGFR2-targeted ultrasound contrast agents such as BR55 will likely prove useful in human for the early detection of tumors as well as for the assessment of response to specific treatments. Copyright © 2010 by Lippincott Williams & Wilkins.


Bzyl J.,RWTH Aachen | Lederle W.,RWTH Aachen | Rix A.,RWTH Aachen | Grouls C.,RWTH Aachen | And 7 more authors.
European Radiology | Year: 2011

Objectives: To characterise clinically translatable long-circulating (BR38) and VEGFR2-targeted (BR55) microbubbles (MB) and to assess their ability to discriminate breast cancer models with different aggressiveness. Methods: The circulation characteristics of BR38 and BR55 were investigated in healthy mice. The relative blood volume (rBV) of MDA-MB-231 (n = 5) or MCF-7 (n = 6) tumours was determined using BR38. In the same tumours in-vivo binding specificity of BR55 was tested and VEGFR2 expression assessed. Data validation included quantitative immunohistological analysis. Results: BR38 had a longer blood half-life than BR55 (>600 s vs. 218 s). BR38-enhanced ultrasound showed greater vascularisation in MDA-MB-231 tumours (p = 0.022), which was in line with immunohistology (p = 0.033). In-vivo competitive binding experiments proved the specificity of BR55 to VEGFR2 (p = 0.027). Binding of BR55 was significantly higher in MDA-MB-231 than in MCF-7 tumours (p = 0.049), which corresponded with the VEGFR2 levels found histologically (p = 0.015). However, differences became smaller when normalising the levels of BR55 to the rBV. Conclusions: BR38 and BR55 are well suited to characterising and distinguishing breast cancers with different angiogenesis and aggressiveness. Long-circulating BR38 MB allow extensive 3-dimensional examinations of larger or several organs. BR55 accumulation faithfully reflects the VEGFR2 status in tumours and depicts even small differences in angiogenesis. © 2011 European Society of Radiology.


Frinking P.J.A.,Bracco Research S.A. | Gaud E.,Bracco Research S.A. | Brochot J.,Bracco Research S.A. | Arditi M.,Bracco Research S.A.
IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control | Year: 2010

Subharmonic scattering of phospholipid-shell microbubbles excited at relatively low acoustic pressure amplitudes (<30 kPa) has been associated with echo responses from compression-only bubbles having initial surface tension values close to zero. In this work, the relation between subharmonics and compression-only behavior of phospholipid-shell microbubbles was investigated, experimentally and by simulation, as a function of the initial surface tension by applying ambient overpressures of 0 and 180 mmHg. The microbubbles were excited using a 64-cycle transmit burst with a center frequency of 4 MHz and peak-negative pressure amplitudes ranging from 20 of 150 kPa. In these conditions, an increase in subharmonic response of 28.9 dB (P < 0.05) was measured at 50 kPa after applying an overpressure of 180 mmHg. Simulations using the Marmottant model, taking into account the effect of ambient overpressure on bubble size and initial surface tension, confirmed the relation between subharmonics observed in the pressure-time curves and compression-only behavior observed in the radius-time curves. The trend of an increase in subharmonic response as a function of ambient overpressure, i.e., as a function of the initial surface tension, was predicted by the model. Subharmonics present in the echo responses of phospholipid-shell microbubbles excited at low acoustic pressure amplitudes are indeed related to the echo responses from compression-only bubbles. The increase in subharmonics as a function of ambient overpressure may be exploited for improving methods for noninvasive pressure measurement in heart cavities or big vessels in the human body. © 2010 IEEE.


Patent
Bracco Research S.A. | Date: 2011-01-20

A power assisted method and injector device for controllably delivering to patients a dispersion medicament or diagnostically active agent, the homogeneity of which is preserved throughout delivery. Diagnostically active agents disclosed are gas microbubble suspensions useful in ultrasonic diagnostic imaging and liposomal formulations in which liposome vesicles are loaded with iodinated compounds.


Patent
Bracco Research S.A. | Date: 2012-05-09

A power assisted method and injector device for controllably delivering to patients a dispersion medicament or diagnostically active agent, the homogeneity of which is preserved throughout delivery. Diagnostically active agents disclosed are gas microbubble suspensions useful in ultrasonic diagnostic imaging and liposomal formulations in which liposome vesicles are loaded with iodinated compounds.


Assembly comprising a gas-filled microvesicle and a structural entity which is capable to associate through an electrostatic interaction to the outer surface of said microvesicle (microvesicle associated componentMAC), thereby modifying the physico-chemical properties thereof. Said MAC comprises a targeting ligand a diagnostic agent or any combination thereof. Optionally a bioactive agent can further be associated to the MAC. The assembly of the invention can be formed from gas-filled microbubbles or microballoons and a MAC having preferably nanometric dimensions, e.g. a micelle, and is used as an active component in diagnostically and/or therapeutically active formulations, in particular for enhancing the imaging in the field of ultrasound contrast imaging, including targeted ultrasound imaging, ultrasound-mediated drug delivery and other imaging techniques such as molecular resonance imaging (MRI) or nuclear imaging.


Composition comprising gas filled microcapsules and a bioactive agent, useful for an ultrasound-mediated delivery of said bioactive agent. The microcapsules comprise a relatively stiff shell of polymeric or lipid material and have in particular a resistance to a mechanical index of at least 0.15, while the bioactive agent is substantially unbound to the shell of the microcapsules. The composition of the invention is particularly suitable for effectively delivering a genetic material into a cell, upon exposure of the composition to a level of acoustic pressure capable of destroying a portion of the microcapsules and releasing the gas contained therein.


Patent
Bracco Research S.A. | Date: 2010-05-26

A diagnostic processing system (100), a data processing method and a corresponding computer-program are proposed. Particularly, the system includes means (903-906) for providing (A1-A3) a plurality of input signals representative of a body-part being perfused with a contrast agent over time, each input signal being indicative of a response to an interrogating stimulus of a corresponding location of the body-part possibly including the contrast agent, means (909-930) for generating (A4.1-A4.3) a plurality of filtered signals from selected input signals of selected locations, each filtered signal at each instant over time being generated from a corresponding selected input signal according to a portion of the selected input signal including said instant, and means (933-939) for monitoring (A4.4-A4.6) each filtered signal to detect a peak in the response to the interrogation stimulus of the corresponding selected location, the peak being detected in response to the fulfillment of a stability condition by a corresponding portion of the filtered signal.

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