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1. Applications of Magnetic Resonance in Model Systems: Tumor Biology and Physiology

Author

Robert J. Gillies, Zaver M. Bhujwalla, Jeffrey Evelhoch, Michael Garwood, Michal Neema, Simon P. Robinson, Christopher H. Sotak, and Boudewijn Van Der Sanden

Subjects
Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), Tumor Perfusion, Tumor Oxygenation, Tumor pH, Tumor Metabolism, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

A solid tumor presents a unique challenge as a system in which the dynamics of the relationship between vascularization, the physiological environment and metabolism are continually changing with growth and following treatment. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies have demonstrated quantifiable linkages between the physiological environment, angiogenesis, vascularization and metabolism of tumors. The dynamics between these parameters continually change with tumor aggressiveness, tumor growth and during therapy and each of these can be monitored longitudinally, quantitatively and non-invasively with MRI and MRS. An important aspect of MRI and MRS studies is that techniques and findings are easily translated between systems. Hence, pre-clinical studies using cultured cells or experimental animals have a high connectivity to potential clinical utility. In the following review, leaders in the field of MR studies of basic tumor physiology using pre-clinical models have contributed individual sections according to their expertise and outlook. The following review is a cogent and timely overview of the current capabilities and state-of-the-art of MRI and MRS as applied to experimental cancers. A companion review deals with the application of MR methods to anticancer therapy.

Published
2000
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2. Specific in vivo staining of astrocytes in the whole brain after intravenous injection of sulforhodamine dyes.

Author

Florence Appaix, Sabine Girod, Sylvie Boisseau, Johannes Römer, Jean-Claude Vial, Mireille Albrieux, Mathieu Maurin, Antoine Depaulis, Isabelle Guillemain, and Boudewijn van der Sanden

Subjects
Medicine, Science
Abstract

Fluorescent staining of astrocytes without damaging or interfering with normal brain functions is essential for intravital microscopy studies. Current methods involved either transgenic mice or local intracerebral injection of sulforhodamine 101. Transgenic rat models rarely exist, and in mice, a backcross with GFAP transgenic mice may be difficult. Local injections of fluorescent dyes are invasive. Here, we propose a non-invasive, specific and ubiquitous method to stain astrocytes in vivo. This method is based on iv injection of sulforhodamine dyes and is applicable on rats and mice from postnatal age to adulthood. The astrocytes staining obtained after iv injection was maintained for nearly half a day and showed no adverse reaction on astrocytic calcium signals or electroencephalographic recordings in vivo. The high contrast of the staining facilitates the image processing and allows to quantify 3D morphological parameters of the astrocytes and to characterize their network. Our method may become a reference for in vivo staining of the whole astrocytes population in animal models of neurological disorders.

Published
2012
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3. 3D two-photon polymerization of smart cell gelatin – collagen matrixes with incorporated ruthenium complexes for the monitoring of local oxygen tensions

Author

Olivier Stephan, Didier Wion, Laetitia Gredy, Boudewijn van der Sanden, Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205] (Brain Tech Lab ), CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy ), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)

Subjects
food.ingredient, 0206 medical engineering, Biomedical Engineering, chemistry.chemical_element, 02 engineering and technology, Biochemistry, Gelatin, Ruthenium, Polymerization, Biomaterials, Extracellular matrix, 3D cell culture, food, Molecular Biology, Mitosis, ComputingMilieux_MISCELLANEOUS, Chemistry, General Medicine, 021001 nanoscience & nanotechnology, 020601 biomedical engineering, Oxygen, Cell culture, Cancer cell, Biophysics, Collagen, 0210 nano-technology, [PHYS.COND.CM-SCM]Physics [physics]/Condensed Matter [cond-mat]/Soft Condensed Matter [cond-mat.soft], Biotechnology
Abstract

The extra cellular matrix plays a major role in the biomechanical properties of tissues that impact cell behavior and fate. It is therefore crucial to mimic these complex cell-matrix interactions in 3D cell cultures. Here, two-photon polymerization is applied to produce gelatin methacryloyl (GelMA) - collagen matrixes that further enable local pO2matrix measurement, when ruthenium complexes are used as photo-activators. The fluorescence intensity of these complexes has a direct and inverse relationship with the local pO2matrix. The 3D structures reached their maximum size in cell culture conditions after 3H with a swelling factor of ~1.5. Their shape and the ruthenium fluorescence intensity of the alveoli walls stayed constant for at least 2 weeks in the absence of cells. They were used in time series to monitor the local pO2matrix adjacent to cancer cells during their division, migration and the formation of a tumor tissue mass. At the presence of these cell activities that consume O2, a significant ~3-fold increase of the ruthenium fluorescence intensity in the alveoli walls was observed. This study demonstrates that online monitoring of the local pO2matrix is possible. The ruthenium complexes provide the bio-optical sensors that are useful for further analysis of cancer and healthy cell energy metabolism in a 3D matrix that better mimics in vivo conditions and migration paths. Unraveling the cancer cell metabolic adaptations in a changing micro-environment will help the development of new therapeutic opportunities. STATEMENT OF SIGNIFICANCE: In 3D cell cultures, monitoring pericellular pO2 is as critical as controlling pH. This facility is currently missing. Here, we take advantage of the direct and inverse relationship between pO2 and the fluorescence intensity of ruthenium complexes to generate stable gelatin-collagen matrixes able to continuously monitoring the pO2 at the pericellular level. The ruthenium complexes, which are photo-activators in the two-photon polymerization of these matrixes, became covalently bind to the collagen fibers. Indeed, local O2 consumption by cancer cells during migration, mitosis and tumor mass formation caused a 3-fold increase of the ruthenium fluorescence. In the future, incorporating ruthenium complexes with other bio-optical sensors will create new drug screening platforms that monitor cell culture parameters at the pericellular level.

Published
2021

4. Vascular bifurcation mapping with photoacoustic microscopy

Author

Boudewijn van der Sanden, Olivier Hugon, Mehdi Inglebert, Eric Lacot, Olivier Jacquin, Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), LIPhy-OPTIMA, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), and Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
0303 health sciences, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Materials science, Early detection, 01 natural sciences, Atomic and Molecular Physics, and Optics, Article, 010309 optics, 03 medical and health sciences, Photoacoustic microscopy, 0103 physical sciences, Medical imaging, sense organs, Bifurcation, 030304 developmental biology, Biotechnology, Biomedical engineering
Abstract

The early detection of microvascular changes in cancer diagnosis is needed in the clinic. A change in the vascular bifurcation density is a biomarker for the sprouting activity. Here, Optical-Resolution PhotoAcoustic Microscopy is used for quantitative vascular bifurcation mapping in 2D after the creation of Virtual Tubes out of Bifurcations. In stacks of OR-PAM images of the hemoglobin distribution, bifurcations become tubes and are selected by the 3D tubeness filter. These fast analyses will be compared to a classical approach and are easier to implement for functional analysis of the vascular bifurcation density in healthy and diseased tissues.

Published
2020

5. Multi-wavelength photo-acoustic microscopy in the frequency domain for simultaneous excitation and detection of dyes

Author

Olivier Hugon, Boudewijn van der Sanden, Mehdi Inglebert, Chaouqi Misbah, Eric Lacot, Olivier Jacquin, OPTIMA, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), LIPhy-OPTIMA, LIPHY-DYFCOM, and Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Materials science, Microscope, Optical power, 01 natural sciences, Article, law.invention, 010309 optics, 03 medical and health sciences, chemistry.chemical_compound, law, 0103 physical sciences, Microscopy, Medical imaging, Irradiation, 030304 developmental biology, Diode, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], 0303 health sciences, business.industry, Atomic and Molecular Physics, and Optics, eye diseases, chemistry, Frequency domain, Optoelectronics, business, Methylene blue, Biotechnology
Abstract

International audience; An optical-resolution photoacoustic microscope with modulated CW laser diodes allowing multi-channel imaging is presented that can be used for both imaging biological tissues and for targeted photo-dynamic therapy (PDT) varying the optical power and exposure time. The effects of this therapy are immediately monitored in order to optimize the time of irradiation. After the description of the experimental setup, in vitro and in vivo applications are presented on a synthetic sample and on the mouse ear using hemoglobin as endogenous and methylene blue as exogenous dye for imaging and PDT, respectively.

Published
2019

6. Photo-Acoustic Tomography (PAT) based on Laser Optical Feedback Imaging (LOFI) of surface displacements

Author

Olivier Hugon, Boudewijn van der Sanden, Eric Lacot, Olivier Jacquin, Bathilde Riviere, Vadim Girardeau, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), LIPhy-OPTIMA, Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), LIPhy-OLA, Lacot, Eric, OPTique et IMAgeries [Grenoble] (OPTIMA-LIPhy), and Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
[PHYS.PHYS.PHYS-OPTICS] Physics [physics]/Physics [physics]/Optics [physics.optics], [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Materials science, business.industry, Laser, 01 natural sciences, Atomic and Molecular Physics, and Optics, Imaging phantom, Surface energy, law.invention, 010309 optics, Amplitude, Optics, law, 0103 physical sciences, Medical imaging, Tomography, Irradiation, Electrical and Electronic Engineering, business, Engineering (miscellaneous), Laser Doppler vibrometer
Abstract

We present how a laser optical feedback imaging (LOFI) setup can be used for the optical detection of ultrasound in photo-acoustic tomography (PAT). A PAT image is reconstructed by an inversion algorithm using surface displacement measurements made at several locations with our LOFI setup and following the optical irradiation with a pulsed Nd:YAG laser of a sample with absorbing inclusions. The width of the reconstructed inclusions and the signal-to-noise ratio (SNR) of the reconstructed images are first studied on the numerical model of a sample with three absorbing inclusions (i.e., with three acoustic punctual sources). Finally, an experimental PAT image of a phantom composed of two polyamide tubes with an internal diameter of 800 μm filled with red ink and submerged at -3.5 mm depth in a tank filled with water is reconstructed. Experimentally, the water surface displacement measurements have been made with our LOFI vibrometer, which provides an amplitude sensitivity of 1 nm (for a single-shot measurement) in a detection bandwidth of roughly 1 MHz adapted to the detection of the polyamide tubes. Under our experimental conditions, the surface energy densities of the LOFI focalized beam for the detection and of the pulsed Nd:YAG laser used for the irradiation, are compatible with the maximum permissive exposure for future biomedical measurements. The SNR and the resolution of the reconstructed PAT images are in good agreement with the theoretical predictions.

Published
2019

7. General and Scalable Approach to Bright, Stable, and Functional AIE Fluorogen Colloidal Nanocrystals for in Vivo Imaging

Author

Chantal Andraud, Zheng Zheng, Stéphane Chambert, Christophe O. Soulage, Elsa Hoibian, Maxime Rémond, Yann Bretonnière, Xibo Yan, Julien Bernard, Boudewijn van der Sanden, François Ganachaud, Ingénierie des Matériaux Polymères (IMP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie - UMR5182 (LC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Chimie Organique et Bioorganique (COB), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR project PREPROPOSAL ANR-15-CE09-0021, French program 'Investissement d'Avenir', grant 'Infrastructure d'avenir en Biologie Sante' ANR11-INBS-0006, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Materials science, aggregation-induced emission, Polymers, Nanotechnology, 02 engineering and technology, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 010402 general chemistry, 01 natural sciences, Organic molecules, organic nanocrystals, nanoprecipitation, Colloid, In vivo, General Materials Science, Aggregation-induced emission, ComputingMilieux_MISCELLANEOUS, Fluorescent Dyes, Fluorescent nanoparticles, [CHIM.ORGA]Chemical Sciences/Organic chemistry, [CHIM.CATA]Chemical Sciences/Catalysis, [CHIM.MATE]Chemical Sciences/Material chemistry, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Science research, Nanocrystal, Ouzo domain, Nanoparticles, in vivo imaging, 0210 nano-technology, Preclinical imaging
Abstract

International audience; Fluorescent nanoparticles built from aggregation-induced emission-active organic molecules (AIE-FONs) have emerged as powerful tools in life science research for in vivo bioimaging of organs, biosensing, and therapy. However, the practical use of such biotracers has been hindered owing to the difficulty of designing bright nanoparticles with controlled dimensions (typically below 200 nm), narrow size dispersity and long shelf stability. In this article, we present a very simple yet effective approach to produce monodisperse sub-200 nm AIE fluorescent organic solid dispersions with excellent redispersibility and colloidal stability in aqueous medium by combination of nanoprecipitation and freeze-drying procedures. By selecting polymer additives that simultaneously act as stabilizers, promoters of amorphous-crystalline transition, and functionalization/cross-linking platforms, we demonstrate a straightforward access to stable nanocrystalline FONs that exhibit significantly higher brightness than their amorphous precursors and constitute efficient probes for in vivo imaging of the normal and tumor vasculature. FONs design principles reported here are universal, applicable to a range of fluorophores with different chemical structures and crystallization abilities, and are suitable for high-throughput production and manufacturing of functional imaging probes.

Published
2018

8. Keto-polymethines: a versatile class of dyes with outstanding spectroscopic properties for in cellulo and in vivo two-photon microscopy imaging

Author

San-Hui Chi, Boudewijn van der Sanden, Olivier Maury, Denis Jacquemin, Chantal Andraud, Joseph W. Perry, Alexei Grichine, Cyrille Monnereau, Alain Duperray, Boris Le Guennic, Jérôme Cuny, Simon Pascal, Florence Appaix, Sandrine Denis-Quanquin, Laboratoire de Chimie - UMR5182 (LC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), LIPHY-DYFCOM, Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), INSERM U823, équipe 8 (Immunologie Analytique des Pathologies Chroniques), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Modélisation, Agrégats, Dynamique (LCPQ) (MAD), Laboratoire de Chimie et Physique Quantiques (LCPQ), Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), School of Chemistry and Biochemistry, and Center for Organic Electronics and Photonics, Georgia Institute of Technology [Atlanta], D. J. acknowledges the ERC for financial support in the framework of a Starting Grant (Marches – 278845). J. W. P. and S.-H. C. acknowledge the support from the DARPA ZOE Program (W31P4Q-09-1-0012), and the AFOSR MURI (FA9550-10-1-0558)., Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), DYnamique des Fluides COmplexes et Morphogénèse [Grenoble] (DYFCOM-LIPhy), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Elefantis, Nicolas, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Chemistry, Stereochemistry, Hydrogen bond, Quantum yield, 02 engineering and technology, General Chemistry, 010402 general chemistry, 021001 nanoscience & nanotechnology, Photochemistry, 01 natural sciences, Fluorescence, 0104 chemical sciences, Molecular engineering, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, Molecular dynamics, Membrane, Two-photon excitation microscopy, Molecule, 0210 nano-technology
Abstract

International audience; The synthesis of keto-heptamethine derivatives has been expanded to various new symmetrical and asymmetrical structures, including an unprecedented di-anionic keto-polymethine. The spectroscopic behavior of these new dyes has been systematically and thoroughly investigated, revealing that the formation of hydrogen bond interactions with protic solvents is responsible for a dramatic enhancement of the fluorescence quantum yield in the far-red spectral region. The existence of these strong hydrogen-bond interactions was further confirmed by molecular dynamics simulations. These bis-dipolar polymethines exhibit large two-photon absorption (TPA) cross-sections (σ2 in GM) in the near-infrared, making them ideal candidates for NIR-to-NIR two-photon microscopy imaging applications. We demonstrate that the molecular engineering of the hydrophilic/hydrophobic balance enables targeting of different cellular components, such as cytoplasm or cell membranes. Addition of appropriate substituents provides the molecule with high-water-solubility, affording efficient two-photon probes for angiography.

Published
2017

9. Synergistic effect of cisplatin and synchrotron irradiation on F98 gliomas growing in nude mice

Author

Clément Ricard, Jean Claude Vial, Christoph Segebarth, Boudewijn van der Sanden, Manuel Fernandez, Herwig Requardt, Didier Wion, Issartel, Jean-Paul, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Synchrotron Radiation Facility (ESRF), Inserm U836, équipe 7, Nanomédecine et cerveau, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Interdisciplinaire de Physique [Saint Martin d’Hères] (LIPhy), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), INSERM, ESRF, Université Joseph Fourier, and Ministère Français de la Recherche et de l'Education

Subjects
Nuclear and High Energy Physics, synchrotron photoactivation therapy, Mice, Nude, cisplatin, Antineoplastic Agents, Hindlimb, macromolecular substances, 03 medical and health sciences, Mice, 0302 clinical medicine, Glioma, glioma, medicine, Tumor Cells, Cultured, Combined Modality Therapy, Animals, Irradiation, two-photon microscopy, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Instrumentation, Hemibody Irradiation, 030304 developmental biology, Cisplatin, 0303 health sciences, Radiation, Dose-Response Relationship, Drug, Chemistry, Brain Neoplasms, Cancer, Dose-Response Relationship, Radiation, medicine.disease, equipment and supplies, Research Papers, 3. Good health, Rats, Disease Models, Animal, 030220 oncology & carcinogenesis, biological sciences, Cancer research, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], synergistic effects, Perfusion, Synchrotrons, Glioblastoma, medicine.drug
Abstract

Synchrotron photoactivation therapy of cisplatin relies on a synergistic effect of synchrotron X-rays and platinum and leads to tumor-cell-killing effects and reduction of the tumor blood perfusion., Among brain tumors, glioblastoma multiforme appears as one of the most aggressive forms of cancer with poor prognosis and no curative treatment available. Recently, a new kind of radio-chemotherapy has been developed using synchrotron irradiation for the photoactivation of molecules with high-Z elements such as cisplatin (PAT-Plat). This protocol showed a cure of 33% of rats bearing the F98 glioma but the efficiency of the treatment was only measured in terms of overall survival. Here, characterization of the effects of the PAT-Plat on tumor volume and tumor blood perfusion are proposed. Changes in these parameters may predict the overall survival. Firstly, changes in tumor growth of the F98 glioma implanted in the hindlimb of nude mice after the PAT-Plat treatment and its different modalities have been characterized. Secondly, the effects of the treatment on tumor blood perfusion have been observed by intravital two-photon microscopy. Cisplatin alone had no detectable effect on the tumor volume. A reduction of tumor growth was measured after a 15 Gy synchrotron irradiation, but the whole therapy (15 Gy irradiation + cisplatin) showed the largest decrease in tumor growth, indicating a synergistic effect of both synchrotron irradiation and cisplatin treatment. A high number of unperfused vessels (52%) were observed in the peritumoral area in comparison with untreated controls. In the PAT-Plat protocol the transient tumor growth reduction may be due to synergistic interactions of tumor-cell-killing effects and reduction of the tumor blood perfusion.

Published
2013

10. The brain tissue response to surgical injury and its possible contribution to glioma recurrence

Author

David Ratel, Lauriane Hamard, Laurent Selek, Didier Wion, Boudewijn van der Sanden, François Berger, Institut National de la Santé et de la Recherche Médicale (INSERM), Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and wion, didier

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Microenvironment, Angiogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Wound healing, Inflammation, Neurosurgical Procedures, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, Glioma, medicine, Humans, Dormancy, Paradigm shift, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain Neoplasms, business.industry, Regeneration (biology), Brain, Immunotherapy, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Neurology, Oncology, 030220 oncology & carcinogenesis, Resection margin, Cancer research, Surgery, Neurology (clinical), Neoplasm Recurrence, Local, medicine.symptom, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Surgery is the first line therapy for glioma. However, glioma recurs in 90 % of the patients in the resection margin. The impact of surgical brain injury (SBI) on glioma recurrence is largely overlooked. Herein, we review some of the mechanisms involved in tissue repair that may impact glioma recurrence at the resection margin. Many processes or molecules involved in tissue repair after brain injury are also critical for glioma growth. They include a wide array of secreted growth factors, cytokines and transcription factors including NFКB and STAT3 which in turn activate proliferative and anti-apoptotic genes and processes such as angiogenesis and inflammation. Because some residual glioma cells always remain in the tumor resection margin, there are now compelling arguments to suggest that some aspects of the brain tissue response to SBI can also participate to glioma recurrence at the resection margin. Brain tissue response to SBI recruits angiogenesis and inflammation that precede and then follow tumor recurrence at the resection margin. The healingresponse to SBI is double edged, as inflammation is involved in regeneration and healing, and has both pro- and anti-tumorigenic functions. A promising therapeutic approach is to normalize and re-educate the molecular and cellular responses at the resection margin to promote anti- tumorigenic processes involved in healing while inhibiting pro-tumorigenic activities. Manipulation of the inflamma- tory response to SBI to prevent local recurrence could also enhance the efficacy of other therapies such as immunotherapy. However, our current knowledge is far from sufficient to achieve this goal. Acknowledging, understanding and manipulating the double-edged role played by SBI in glioma recurrence is surely challenging, but it cannot be longer delayed.

Published
2016

11. Glioma Recurrence following Surgery: Peritumoral or Perilesional?

Author

Didier Wion, Boudewijn van der Sanden, François Berger, and David Ratel

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Opinion, surgery injury, recurrence, business.industry, medicine.disease, microenvironment, lcsh:RC346-429, Surgery, 03 medical and health sciences, 030104 developmental biology, Text mining, Neurology, paradigm shift, inflammation, Glioma, glioma, medicine, Neurology (clinical), business, lcsh:Neurology. Diseases of the nervous system, Neuroscience
Published
2016
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12. Fluorescent Tobacco mosaic virus-derived bio-nanoparticles for intravital two-photon imaging

Author

Boudewijn van der Sanden, Annette Niehl, Sonia Boscá, Florence Appaix, Jean-François Nicoud, Frédéric Bolze, Manfred Heinlein, Institut de biologie moléculaire des plantes (IBMP), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Conception et application de molécules bioactives (CAMB), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie des Systèmes Fonctionnels, Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte

Subjects
0301 basic medicine, Plant virus, 02 engineering and technology, Plant Science, Biology, lcsh:Plant culture, Blood–brain barrier, 03 medical and health sciences, Two-photon excitation microscopy, Tobacco mosaic virus, medicine, Fluorescence microscope, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, lcsh:SB1-1110, two-photon microscopy, Original Research, viral nanoparticles, 021001 nanoscience & nanotechnology, Virology, Fluorescence, 030104 developmental biology, medicine.anatomical_structure, Biophysics, intravital imaging, Nanocarriers, 0210 nano-technology, Preclinical imaging
Abstract

Multi-photon intravital imaging has become a powerful tool to investigate the healthy and diseased brain vasculature in living animals. Although agents for multi-photon fluorescence microscopy of the microvasculature are available, issues related to stability, bioavailability, toxicity, cost or chemical adaptability remain to be solved. In particular, there is a need for highly fluorescent dyes linked to particles that do not cross the blood brain barrier (BBB) in brain diseases like tumor or stroke to estimate the functional blood supply. Plant virus particles possess a number of distinct advantages over other particles, the most important being the multi-valency of chemically addressable sites on the particle surface. This multi-valency, together with biological compatibility and inert nature, makes plant viruses ideal carriers for in vivo imaging agents. Here, we show that the well-known Tobacco mosaic virus is a suitable nanocarrier for two-photon dyes and for intravital imaging of the mouse brain vasculature.

Published
2016

13. Multiscale investigation of USPIO nanoparticles in atherosclerotic plaques and their catabolism and storage in vivo

Author

Valentin S. Teodorescu, Dominique Le Guellec, Florence Appaix, M.G. Blanchin, Boudewijn van der Sanden, Alexis Broisat, Valentin-Adrian Maraloiu, Catherine Ghezzi, Institut Lumière Matière [Villeurbanne] (ILM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
0301 basic medicine, Biodistribution, Pathology, medicine.medical_specialty, Materials science, Metabolic Clearance Rate, MRI contrast agent, Biomedical Engineering, Iron oxide, Contrast Media, Pharmaceutical Science, Medicine (miscellaneous), Bioengineering, 02 engineering and technology, Mice, 03 medical and health sciences, chemistry.chemical_compound, [SPI]Engineering Sciences [physics], Microscopy, Electron, Transmission, Two-photon excitation microscopy, In vivo, Materials Testing, medicine, Animals, [CHIM]Chemical Sciences, Tissue Distribution, General Materials Science, Magnetite Nanoparticles, High-resolution transmission electron microscopy, ComputingMilieux_MISCELLANEOUS, [PHYS]Physics [physics], biology, Dextrans, 021001 nanoscience & nanotechnology, Plaque, Atherosclerotic, Mice, Inbred C57BL, Ferritin, Metabolism, Microscopy, Fluorescence, Multiphoton, 030104 developmental biology, chemistry, biology.protein, Molecular Medicine, 0210 nano-technology, Ex vivo, Subcellular Fractions, Biomedical engineering
Abstract

The storage and catabolism of Ultrasmall SuperParamagnetic Iron Oxide (USPIO) nanoparticles were analyzed through a multiscale approach combining Two Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM) at different times after intravenous injection in an atherosclerotic ApoE(-/-) mouse model. The atherosclerotic plaque features and the USPIO heterogeneous biodistribution were revealed down from organ's scale to subcellular level. The biotransformation of the nanoparticle iron oxide (maghemite) core into ferritin, the non-toxic form of iron storage, was demonstrated for the first time ex vivo in atherosclerotic plaques as well as in spleen, the iron storage organ. These results rely on an innovative spatial and structural investigation of USPIO's catabolism in cellular phagolysosomes. This study showed that these nanoparticles were stored as non-toxic iron compounds: maghemite oxide or ferritin, which is promising for MRI detection of atherosclerotic plaques in clinics using these USPIOs. From the Clinical Editor: Advance in nanotechnology has brought new contrast agents for clinical imaging. In this article, the authors investigated the use and biotransformation of Ultrasmall Super-paramagnetic Iron Oxide (USPIO) nanoparticles for analysis of atherosclerotic plagues in Two Photon Laser Scanning Microscopy (TPLSM) and High-Resolution Transmission Electron Microscopy (HRTEM). The biophysical data generated from this study could enable the possible use of these nanoparticles for the benefits of clinical patients.

Published
2016

14. Towards the Design of a Patient-Specific Virtual Tumour

Author

Flavien Caraguel, Anne-Cécile Lesart, François Estève, Boudewijn van der Sanden, Angélique Stéphanou, Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), European Synchrotron Radiation Facility (ESRF), Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cell state, computer.software_genre, Mice, Neoplasms, Image Processing, Computer-Assisted, Precision Medicine, ComputingMilieux_MISCELLANEOUS, Neovascularization, Pathologic, Applied Mathematics, Cell Cycle, Ear, General Medicine, Patient specific, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Extracellular Matrix, 3. Good health, Proof of concept, Neoplasm Invasiveness, Modeling and Simulation, lcsh:R858-859.7, Intercellular Signaling Peptides and Proteins, Female, Cell Division, Research Article, Article Subject, Growth kinetics, Green Fluorescent Proteins, Mice, Nude, Image processing, Biology, lcsh:Computer applications to medicine. Medical informatics, Machine learning, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, Computer Simulation, Simulation, Cell Proliferation, General Immunology and Microbiology, business.industry, Oxygen, Disease Models, Animal, Kinetics, 030104 developmental biology, Tumour development, Personalized medicine, Artificial intelligence, business, computer
Abstract

The design of a patient-specific virtual tumour is an important step towards Personalized Medicine. However this requires to capture the description of many key events of tumour development, including angiogenesis, matrix remodelling, hypoxia, and cell state heterogeneity that will all influence the tumour growth kinetics and degree of tumour invasiveness. To that end, an integrated hybrid and multiscale approach has been developed based on data acquired on a preclinical mouse model as a proof of concept. Fluorescence imaging is exploited to build case-specific virtual tumours. Numerical simulations show that the virtual tumour matches the characteristics and spatiotemporal evolution of its real counterpart. We achieved this by combining image analysis and physiological modelling to accurately described the evolution of different tumour cases over a month. The development of such models is essential since a dedicated virtual tumour would be the perfect tool to identify the optimum therapeutic strategies that would make Personalized Medicine truly reachable and achievable.

Published
2016

15. Rapid-Steady-State-T1 signal modeling during contrast agent extravasation: toward tumor blood volume quantification without requiring the arterial input function

Author

Michel, Sarraf, Adriana Teodora, Perles-Barbacaru, Marie France, Nissou, Boudewijn, van der Sanden, François, Berger, Hana, Lahrech, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Blood Volume, Blood Volume Determination, Neovascularization, Pathologic, Brain Neoplasms, Contrast Media, Magnetic Resonance Imaging, Models, Biological, Rats, Inbred F344, Rats, Heterocyclic Compounds, Cell Line, Tumor, Image Interpretation, Computer-Assisted, Organometallic Compounds, Animals, Computer Simulation, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Extravasation of Diagnostic and Therapeutic Materials
Abstract

International audience; PURPOSE: This study demonstrates how to quantify the tumor blood volume fraction (BVf) using the dynamic Rapid-Steady-State-T1 (RSST1 )-MRI method despite contrast agent (CA) leakage and without arterial input function (AIF) determination. METHODS: For vasculature impermeable to CAs, the BVf is directly quantified from the RSST1 signal amplitude. In case of CA extravasation, we propose a two-compartment model to describe the dynamic RSST1 signal increase. We applied the mathematical model in a pilot-study on a RG2-glioma model to compare extravasation of two Gd-based CAs. The BVf quantification using the mathematical model in a C6-glioma model (n = 8) with the clinical CA Gd-DOTA was validated using a ΔR2 *-steady-state MRI method with an USPIO and by immunohistochemical staining of perfused vessels labeled with Hoechst-33342 dye in the same rats. RESULTS: BVf in tumor and in healthy brain tissues (0.034 ± 0.005 and 0.026 ± 0.004, respectively) derived from the dynamic RSST1 signal were confirmed by ΔR2 *-steady-state MRI (0.036 ± 0.003 and 0.027 ± 0.002, respectively, correlation coefficient rS = 0.74) and by histology (0.036 ± 0.003 and 0.025 ± 0.004 respectively, rS = 0.87). CONCLUSION: Straightforward tumor BVf quantification without AIF determination is demonstrated in presence of CA leakage. The method will facilitate angiogenesis assessment in longitudinal neuro-oncologic studies in particular when monitoring the response to antiangiogenic therapies.

Published
2015

16. Cancer research in need of a scientific revolution: Using 'paradigm shift' as a method of investigation

Author

François Berger, Meriwether Burruss, Boudewijn van der Sanden, Didier Wion, Florence Appaix, wion, didier, Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Math, École normale supérieure - Lyon (ENS Lyon), [GIN] Grenoble Institut des Neurosciences (GIN), and École normale supérieure de Lyon (ENS de Lyon)

Subjects
cancer stem cell, General method, Biomedical Research, extracellular matrix, [SDV]Life Sciences [q-bio], Disease, Biology, overdiagnosis, Reification (Marxism), General Biochemistry, Genetics and Molecular Biology, Neoplasms, Humans, cancer, Overdiagnosis, Infectious Disease Medicine, therapy, Cancer prevention, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, overtreatment, General Medicine, Kuhn, microenvironment, Scientific revolution, 3. Good health, [SDV] Life Sciences [q-bio], Paradigm shift, Cancer research, General Agricultural and Biological Sciences, Koch's postulate, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Despite important human and financial resources and considerable accumulation of scientific publications, patents, and clinical trials, cancer research has been slow in achieving a therapeutic revolution similar to the one that occurred in the last century for infectious diseases. It has been proposed that science proceeds not only by accumulating data but also through paradigm shifts. Here, we propose to use the concept of 'paradigm shift' as a method of investigation when dominant paradigms fail to achieve their promises. The first step in using the 'paradigm shift' method in cancer research requires identifying its founding paradigms. In this review, two of these founding paradigms will be discussed: (i) the reification of cancer as a tumour mass and (ii) the translation of the concepts issued from infectious disease in cancer research. We show how these founding paradigms can generate biases that lead to over-diagnosis and over-treatment and also hamper the development of curative cancer therapies. We apply the 'paradigm shift' method to produce perspective reversals consistent with current experimental evidence. The 'paradigm shift' method enlightens the existence of a tumour physiologic-prophylactic-pathologic continuum. It integrates the target/antitarget concept and that cancer is also an extracellular disease. The 'paradigm shift' method has immediate implications for cancer prevention and therapy. It could be a general method of investigation for other diseases awaiting therapy

Published
2015

17. Long-Term in Vivo Clearance of Gadolinium-Based AGuIX Nanoparticles and Their Biocompatibility after Systemic Injection

Author

Blandine Laurent, Olivier Tillement, Lucie Sancey, Eloise Thomas, Arthur Marais, Pascal Perriat, Jean-Philippe Klein, Gérard Panczer, Rodolphe Antoine, François Lux, Charles Truillet, Shady Kotb, Michèle Cottier, Vincent Motto-Ros, Philippe Dugourd, Florence Appaix, Boudewijn van der Sanden, Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Interdisciplinaire d'Etude des Nanoparticules Aérosolisées (LINA-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-CIS, Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), and Rayet, Béatrice

Subjects
Models, Molecular, Materials science, Kidney Cortex, Biocompatibility, MRI contrast agent, Electrospray ionization, Gadolinium, Molecular Conformation, General Physics and Astronomy, Nanoparticle, chemistry.chemical_element, Contrast Media, Metal Nanoparticles, Biocompatible Materials, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, Injections, Mice, Nuclear magnetic resonance, Two-photon excitation microscopy, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Animals, Humans, General Materials Science, Laser-induced breakdown spectroscopy, X-Rays, General Engineering, technology, industry, and agriculture, Biological Transport, 021001 nanoscience & nanotechnology, 0104 chemical sciences, 3. Good health, Kinetics, chemistry, Biophysics, Safety, 0210 nano-technology
Abstract

International audience; We previously reported the synthesis of gadolinium-based nanoparticles (NPs) denoted AGuIX (activation and guiding of irradiation by X-ray) NPs and demonstrated their potential as an MRI contrast agent and their efficacy as radiosensitizing particles during X-ray cancer treatment. Here we focus on the elimination kinetics of AGuIX NPs from the subcellular to whole-organ scale using original and complementary methods such as laser-induced breakdown spectroscopy (LIBS), intravital two-photon microscopy, inductively coupled plasma optical emission spectrometry (ICP-OES), transmission electron microscopy (TEM), and electrospray ionization mass spectrometry (ESI-MS). This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated, including their retention in proximal tubules and their excretion as degraded or native NPs. Finally, we demonstrated that systemic AGuIX NP administration induced moderate and transient effects on renal function. These results provide useful and promising preclinical information concerning the safety of theranostic AGuIX NPs.

Published
2015

18. Brain mesenchymal stem cells: The other stem cells of the brain?

Author

François Berger, Marie-France Nissou, Boudewijn van der Sanden, Matthieu Dreyfus, Didier Wion, Florence Appaix, and Jean-Paul Issartel

Subjects
Pathology, medicine.medical_specialty, Histology, business.industry, Mesenchymal stem cell, Cell Biology, Regenerative medicine, Neural stem cell, Cell biology, medicine.anatomical_structure, Cancer stem cell, Cell Plasticity, Genetics, medicine, Pericyte, Bone marrow, Topic Highlight, Stem cell, business, Molecular Biology, Genetics (clinical)
Abstract

Multipotent mesenchymal stromal cells (MSC), have the potential to differentiate into cells of the mesenchymal lineage and have non-progenitor functions including immunomodulation. The demonstration that MSCs are perivascular cells found in almost all adult tissues raises fascinating perspectives on their role in tissue maintenance and repair. However, some controversies about the physiological role of the perivascular MSCs residing outside the bone marrow and on their therapeutic potential in regenerative medicine exist. In brain, perivascular MSCs like pericytes and adventitial cells, could constitute another stem cell population distinct to the neural stem cell pool. The demonstration of the neuronal potential of MSCs requires stringent criteria including morphological changes, the demonstration of neural biomarkers expression, electrophysiological recordings, and the absence of cell fusion. The recent finding that brain cancer stem cells can transdifferentiate into pericytes is another facet of the plasticity of these cells. It suggests that the perversion of the stem cell potential of pericytes might play an even unsuspected role in cancer formation and tumor progression.

Published
2014

19. Two-voxel localization sequence for in vivo two-dimensional homonuclear correlation spectroscopy

Author

Boudewijn van der Sanden, Jean-Claude Beloeil, Klaas Nicolay, Florence Delmas, Brigitte Gillet, and University of Groningen

Subjects
multivoxel localization, Nuclear and High Energy Physics, Magnetic Resonance Spectroscopy, Biophysics, Hadamard encoding, RAT-BRAIN, PROTON, computer.software_genre, METABOLITES, LACTATE, Biochemistry, Aminobutyric acid, Homonuclear molecule, Brain Ischemia, Nuclear magnetic resonance, Reference Values, In vivo, Voxel, rat brain, Image Processing, Computer-Assisted, Animals, Lactic Acid, Threonine, Dominance, Cerebral, IN-VIVO, Alanine, Phantoms, Imaging, Chemistry, Brain, RADIOFREQUENCY PULSES, two-dimensional correlation H-1 MRS, Image Enhancement, Condensed Matter Physics, Magnetic Resonance Imaging, Rats, RF PULSES, Glutamine, PHOSPHORUS, NMR-SPECTROSCOPY, cerebral metabolites, Brain Damage, Chronic, Energy Metabolism, 1D-HADAMARD, computer, Two-dimensional nuclear magnetic resonance spectroscopy
Abstract

The combination of localized 2D 1H MR correlation spectroscopy and Hadamard encoding allows the simultaneous acquisition of multiple volumes of interest without an increase in the experimental duration, compared to single-voxel acquisition. In the present study, 2D correlation spectra were acquired simultaneously within 20 to 40 min in two voxels located in each hemisphere of the rat brain. An intervoxel distance of 20% of the voxel size was sufficient to limit spatial contamination. The following cerebral metabolites gave detectable crosspeaks: N-acetylaspartate, the glutamate/glutamine pool, aspartate, phosphoethanolamine, glucose, glutathione, taurine, myo-inositols, lactate, threonine, ¿-aminobutyric acid, and alanine. Most of the metabolites were measured without contamination of other resonances. two-dimensional correlation 1H MRS

Published
2001

20. Hypoxia-induced expression of VE-cadherin and Filamin B in gliomacell cultures and pseudopalisade structures

Author

Audrey Guttin, Catherine Godfraind, Emmanuel Garcion, Didier Wion, Marie-France Nissou, Jean-Paul Issartel, Boudewijn van der Sanden, Michèle El Atifi, Caroline Salon, François Berger, Nanomédecine et Cerveau, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Service de Pathologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Inserm U836, équipe 7, Nanomédecine et cerveau, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, and Ligue Nationale contre le Cancer (National, Rhône-Alpes, Isère et Puy de Dôme)

Subjects
Cancer Research, Pathology, Filamin, Immunoenzyme Techniques, 0302 clinical medicine, VE-cadherin, Cell Movement, Tumor Cells, Cultured, Hypoxia, Oligonucleotide Array Sequence Analysis, 0303 health sciences, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, Glioma, Cadherins, Filamin B, Endothelial stem cell, Neurology, Oncology, pseudopalisade, 030220 oncology & carcinogenesis, medicine.medical_specialty, Filamins, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Article, 03 medical and health sciences, Necrosis, Antigens, CD, Neurosphere, medicine, Biomarkers, Tumor, Humans, RNA, Messenger, 030304 developmental biology, Cell Proliferation, Cadherin, Cell growth, Gene Expression Profiling, medicine.disease, Cell culture, Cancer cell, Cancer research, Neurology (clinical), Endothelium, Vascular, endothelial to mesenchymal transition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Most of our knowledge regarding glioma cell biology comes from cell culture experiments. For many years the standards for glioma cell culture were the use of cell lines cultured in the presence of serum and 20 % O2. However, in vivo, normoxia in many brain areas is in close to 3 % O2. Hence, in cell culture, the experimental value referred as the norm is hyperoxic compared to any brain physiological value. Likewise, cells in vivo are not usually exposed to serum, and low-passaged glioma neurosphere cultures maintained in serum-free medium is emerging as a new standard. A consequence of changing the experimental normoxic standard from 20 % O2 to the more brain physiological value of 3 % O2, is that a 3 % O2 normoxic reference point enabled a more rigorous characterization of the level of regulation of genes by hypoxia. Among the glioma hypoxia-regulated genes characterized using this approach we found VE-cadherin that is required for blood vessel formation, and filamin B a gene involved in endothelial cell motility. Both VE-cadherin and filamin B were found expressed in pseudopalisades, a glioblastoma pathognomonic structure made of hypoxic migrating cancer cells. These results provide additional clues on the role played by hypoxia in the acquisition of endothelial traits by glioma cells and on the functional links existing between pseudopalisades, hypoxia, and tumor progression.

Published
2013

21. How stereological analysis of vascular morphology can quantify the blood volume fraction as a marker for tumor vasculature: comparison with magnetic resonance imaging.: Blood volume quantification by stereology and MRI

Author

Adriana T. Perles-Barbacaru, Régine Farion, Hana Lahrech, Boudewijn van der Sanden, Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and The study was funded by PhD and post doc stipends from the French Cancer Research Association (ARC, Association pour la Recherche sur le Cancer) and the French National Cancer Institute(INCa, Institut National du Cancer).

Subjects
Models, Anatomic, Pathology, MESH: Blood Volume, Angiogenesis, Gadolinium, Contrast Media, Stereology, MESH: Microscopy, Fluorescence, MESH: Models, Anatomic, 030218 nuclear medicine & medical imaging, MESH: Magnetic Resonance Imaging, MESH: Glioma, 0302 clinical medicine, Heterocyclic Compounds, Image Processing, Computer-Assisted, Medicine, MESH: Animals, MESH: Brain Mapping, Brain Mapping, Blood Volume, Blood Volume Determination, Neovascularization, Pathologic, medicine.diagnostic_test, Brain Neoplasms, Glioma, Magnetic Resonance Imaging, MESH: Image Processing, Computer-Assisted, vascular volume fraction, MESH: Microvessels, Neurology, Blood Volume Fraction, MESH: Brain Neoplasms, Original Article, RSST1-MRI, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, MESH: Cell Line, Tumor, MESH: Rats, MESH: Heterocyclic Compounds, MESH: Blood Volume Determination, chemistry.chemical_element, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Tumor vasculature, 03 medical and health sciences, vessel diameter, Cell Line, Tumor, MESH: Contrast Media, Organometallic Compounds, Animals, Rats, Wistar, business.industry, Magnetic resonance imaging, MESH: Organometallic Compounds, MESH: Rats, Wistar, Rats, Microscopy, Fluorescence, Vascular morphology, chemistry, blood volume fraction, Microvessels, stereology, Neurology (clinical), business, MESH: Neovascularization, Pathologic, Neoplasm Transplantation, 030217 neurology & neurosurgery, MESH: Neoplasm Transplantation, GADOTERATE MEGLUMINE
Abstract

To assess angiogenesis noninvasively in a C6 rat brain tumor model, the rapid-steady-state- T1 (RSST1) magnetic resonance imaging (MRI) method was used for microvascular blood volume fraction (BVf) quantification with a novel contrast agent gadolinium per (3,6 anhydro) α-cyclodextrin (Gd-ACX). In brain tissue contralateral to the tumor, equal BVfs were obtained with Gd-ACX and the clinically approved gadoterate meglumine (Gd-DOTA). Contrary to Gd-DOTA, which leaks out of the tumor vasculature, Gd-ACX was shown to remain vascular in the tumor tissue allowing quantification of the tumor BVf. We sought to confirm the obtained tumor BVf using an independent method: instead of using a ‘standard’ two-dimensional histologic method, we study here how vascular morphometry combined with a stereological technique can be used for three-dimensional assessment of the vascular volume fraction ( VV). The VV is calculated from the vascular diameter and length density. First, the technique is evaluated on simulated data and the healthy rat brain vasculature and is then applied to the same C6 tumor vasculature previously quantified by RSST1-MRI with Gd-ACX. The mean perfused VV and the BVf obtained by MRI in tumor regions are practically equal and the technique confirms the spatial heterogeneity revealed by MRI.

Published
2012

22. On the importance of the submicrovascular network in a computational model of tumour growth

Author

Lauriane Hamard, Boudewijn van der Sanden, Anne-Cécile Lesart, Angélique Stéphanou, François Estève, Issartel, Jean-Paul, Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 6, Rayonnement synchrotron et recherche médicale, Dynamiques Cellulaire, Tissulaire & Microscopie fonctionnelle (TIMC-IMAG-DyCTiM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CNRS (PEPS-INS2I 2010-2011) Rhˆone-Alpes Institute for Complex Systems (RNCS and IXXI respectively)French National Network, VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), and VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)

Subjects
Vascular Endothelial Growth Factor A, MESH: Tumor Burden, MESH: Models, Cardiovascular, Time Factors, Computer science, MESH: Cell Hypoxia, Tumor burden, hybrid model, Apoptosis, Biochemistry, MESH: Glioma, Mice, angiogenesis, 0302 clinical medicine, MESH: Animals, Skin, 0303 health sciences, Neovascularization, Pathologic, Models, Cardiovascular, Glioma, Cell Hypoxia, Tumor Burden, MESH: Reproducibility of Results, computational model, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cardiology and Cardiovascular Medicine, Hybrid model, Algorithm, MESH: Oxygen, Dorsum, Scale (ratio), Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Regular grid, 03 medical and health sciences, Necrosis, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Skin, MESH: Computer Simulation, MESH: Cell Proliferation, MESH: Mice, Nude, Animals, Computer Simulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], dorsal skinfold chamber, MESH: Mice, 030304 developmental biology, Mice nude, Cell Proliferation, Solid tumour, MESH: Necrosis, MESH: Capillaries, MESH: Apoptosis, MESH: Vascular Endothelial Growth Factor A, tumour growth, MESH: Time Factors, Reproducibility of Results, Cell Biology, Capillaries, Oxygen, Microvascular Network, microvascular network, multiscale model, MESH: Neovascularization, Pathologic
Abstract

International audience; A computational model is potentially a powerful tool to apprehend complex phenomena like solid tumour growth and to predict the outcome of therapies. To that end, the confrontation of the model with experiments is essential to validate this tool. In this study, we develop a computational model specifically dedicated to the interpretation of tumour growth as observed in a mouse model with a dorsal skinfold chamber. Observation of the skin vasculature at the dorsal window scale shows a sparse network of a few main vessels of several hundreds micrometers in diameter. However observation at a smaller scale reveals the presence of a dense and regular interconnected network of capillaries about ten times smaller. We conveniently designate this structure as the submicrovascular network (SMVN).(1) The question that we wish to answer concerns the necessity of explicitly taking into account the SMVN in the computational model to describe the tumour evolution observed in the dorsal chamber. For that, simulations of tumour growth realised with and without the SMVN are compared and lead to two distinct scenarios. Parameters that are known to strongly influence the tumour evolution are then tested in the two cases to determine to which extent those parameters can be used to compensate the observed differences between these scenarios. Explicit modelling of the smallest vessels appears mandatory although not necessarily under the form of a regular grid. A compromise between the two investigated cases can thus be reached.

Published
2012

23. Deep in vivo two-photon imaging of blood vessels with a new dye encapsulated in pluronic nanomicelles

Author

Boudewijn van der Sanden, Seth R. Marder, Mathieu Maurin, Jean-Claude Vial, Olivier Stephan, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), School of Chemistry and Biochemistry, and Center for Organic Electronics and Photonics, Georgia Institute of Technology [Atlanta], Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by a grant from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche., and Issartel, Jean-Paul

Subjects
MESH: Photons, Optical Phenomena, 02 engineering and technology, Pluronic nanomicelles, 01 natural sciences, Micelle, chemistry.chemical_compound, Mice, Two-photon excitation microscopy, Blood plasma, MESH: Microscopy, Confocal, MESH: Animals, MESH: Dextrans, Micelles, Microscopy, Confocal, Blood Volume Determination, Chemistry, MESH: Micelles, Brain, Dextrans, 021001 nanoscience & nanotechnology, MESH: Fluorescent Dyes, Atomic and Molecular Physics, and Optics, Extravasation, Electronic, Optical and Magnetic Materials, Dextran, MESH: Neoplasms, Experimental, MESH: Styrenes, Intravital two-photon microscopy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 0210 nano-technology, MESH: Optical Phenomena, Preclinical imaging, Diagnostic Imaging, MESH: Cell Line, Tumor, MESH: Blood Volume Determination, Biomedical Engineering, Mice, Nude, Nanotechnology, Poloxamer, MESH: Rhodamines, Article, Styrenes, Biomaterials, MESH: Brain, MESH: Nanostructures, In vivo, Cell Line, Tumor, MESH: Mice, Nude, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, Fluorescent Dyes, Photons, MESH: Humans, 010405 organic chemistry, Rhodamines, MESH: Diagnostic Imaging, Neoplasms, Experimental, cerebral and tumor microvasculature, MESH: Blood Vessels, MESH: Poloxamer, 0104 chemical sciences, Nanostructures, Biophysics, Blood Vessels
Abstract

International audience; Our purpose is to test if Pluronic® fluorescent nanomicelles can be used for in vivo two-photon imaging of both the normal and the tumor vasculature. The nanomicelles were obtained after encapsulating a hydrophobic two-photon dye: di-stryl benzene derivative, in Pluronic block copolymers. Their performance with respect to imaging depth, blood plasma staining, and diffusion across the tumor vascular endothelium is compared to a classic blood pool dye Rhodamin B dextran (70 kDa) using two-photon microscopy. Pluronic nanomicelles show, like Rhodamin B dextran, a homogeneous blood plasma staining for at least 1 h after intravenous injection. Their two-photon imaging depth is similar in normal mouse brain, using 10 times less injected mass. In contrast with Rhodamin B dextran, no extravasation is observed in leaky tumor vessels due to their large size: 20-100 nm. In conclusion, Pluronic nanomicelles can be used as a blood pool dye, even in leaky tumor vessels. The use of Pluronic block copolymers is a valuable approach for encapsulating two-photon fluorescent dyes that are hydrophobic and not suitable for intravenous injection.

Published
2011

24. Optimizing stem cell culture

Author

Boudewijn van der Sanden, Mehdi Dhobb, François Berger, Didier Wion, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Contre le Cancer, and Issartel, Jean-Paul

Subjects
MESH: Stem Cell Niche, CELL CULTURE, Cell Culture Techniques, MESH: Stem Cells, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Stem cell culture, Biochemistry, Article, OXYGEN, law.invention, 03 medical and health sciences, MESH: Bioreactors, Bioreactors, 0302 clinical medicine, law, Animals, Humans, Nanotechnology, Nanotopography, MESH: Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stem Cell Niche, Molecular Biology, MESH: Nanotechnology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, MESH: Cell Culture Techniques, MESH: Humans, Recombinant Cytokines, Stem Cells, Petri dish, Cell Biology, STEM CELL, NANOTOPOGRAPHY, Cell biology, Cell metabolism, Cell culture, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Stem cell, Stem cell biology, 030217 neurology & neurosurgery
Abstract

International audience; Stem cells always balance between self-renewal and differentiation. Hence, stem cell culture parameters are critical and need to be continuously refined according to progress in our stem cell biology understanding and the latest technological developments. In the past few years, major efforts have been made to define more precisely the medium composition in which stem cells grow or differentiate. This led to the progressive replacement of ill-defined additives such as serum or feeder cell layers by recombinant cytokines or growth factors. Another example is the control of the oxygen pressure. For many years cell cultures have been done under atmospheric oxygen pressure which is much higher than the one experienced by stem cells in vivo. A consequence of cell metabolism is that cell culture conditions are constantly changing. Therefore, the development of high sensitive monitoring processes and control algorithms is required for ensuring cell culture medium homeostasis. Stem cells also sense the physical constraints of their microenvironment. Rigidity, stiffness, and geometry of the culture substrate influence stem cell fate. Hence, nanotopography is probably as important as medium formulation in the optimization of stem cell culture conditions. Recent advances include the development of synthetic bioinformative substrates designed at the micro- and nanoscale level. On going research in many different fields including stem cell biology, nanotechnology, and bioengineering suggest that our current way to culture cells in Petri dish or flasks will soon be outdated as flying across the Atlantic Ocean in the Lindbergh's plane.

Published
2010

25. Tolerance of arteries to microplanar X-ray beams.: Microplanar X-ray beam irradiation of arteries

Author

Boudewijn van der Sanden, E.A. Siegbahn, Elke Bräuer-Krisch, Clément Ricard, Jean-Claude Vial, Jean A. Laissue, INSERM U836, équipe 6, Rayonnement synchrotron et recherche médicale, ANTE-INSERM U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Synchrotron Radiation Facility (ESRF), Department of Oncology and Pathology, Karolinska Institutet [Stockholm], Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Oncology - Pathology - Anatomy, Institute of Pathology-University of Bern, and Clement Ricard received a grant of the French Ministry of Education and Research

Subjects
Cancer Research, MESH: Radiotherapy, medicine.medical_treatment, Radiation Tolerance, Muscle, Smooth, Vascular, 030218 nuclear medicine & medical imaging, Mice, 0302 clinical medicine, Occlusion, Medicine, MESH: Animals, Mice, Inbred BALB C, Microscopy, Radiation, Microbeam radiation, MESH: Radiation Tolerance, MESH: Hindlimb, Arteries, MESH: Muscle, Smooth, Vascular, Hindlimb, Muscular Atrophy, Radiation Injuries, Experimental, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Circulatory system, MESH: Fibrosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tunica Media, Blood vessel, Artery, MESH: Radiation Dosage, MESH: Microscopy, MESH: Mice, Inbred BALB C, Radiation Dosage, Radiosurgery, 03 medical and health sciences, Animals, Radiology, Nuclear Medicine and imaging, Irradiation, Two-photon microscopy, MESH: Arteries, MESH: Mice, Radiotherapy, business.industry, MESH: Muscular Atrophy, Radiation effect, Fibrosis, Radiation therapy, Artery smooth muscle cells, MESH: Tunica Media, MESH: Radiation Injuries, Experimental, business, Nuclear medicine
Abstract

International audience; PURPOSE: The purpose is to evaluate effects of a new radiotherapy protocol, microbeam radiation therapy, on the artery wall. In previous studies on animal models, it was shown that capillaries recover well from hectogray doses of X-rays delivered in arrays of narrow (< or = 50 microm) beams with a minimum spacing of 200 microm. Here, short- and long-term effects of comparable microplanar beam configurations on the saphenous artery of the mouse hind leg were analyzed in situ by use of nonlinear optics and compared with histopathologic findings. METHODS AND MATERIALS: The left hind leg of normal mice including the saphenous artery was irradiated by an array of 26 microbeams of synchrotron X-rays (50 microm wide, spaced 400 microm on center) with peak entrance doses of 312 Gy and 2,000 Gy. RESULTS: The artery remained patent, but narrow arterial smooth muscle cell layer segments that were in the microplanar beam paths became atrophic and fibrotic in a dose-dependent pattern. The wide tunica media segments between those paths hypertrophied, as observed in situ by two-photon microscopy and histopathologically. CONCLUSIONS: Clinical risks of long-delayed disruption or occlusion of nontargeted arteries from microbeam radiation therapy will prove less than corresponding risks from broad-beam radiosurgery, especially if peak doses are kept below 3 hectograys.

Published
2010

26. Existence of tumor-derived endothelial cells suggests an additional role for endothelial-to-mesenchymal transition in tumor progression

Author

Laurent Selek, Didier Wion, François Berger, Boudewijn van der Sanden, Mehdi Dhobb, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de neurochirurgie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, and Issartel, Jean-Paul

Subjects
0303 health sciences, Cancer Research, Pathology, medicine.medical_specialty, Transition (genetics), Mesenchymal stem cell, Tumor cells, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor-Derived, Biology, Endothelial stem cell, 03 medical and health sciences, 0302 clinical medicine, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Tumor progression, 030220 oncology & carcinogenesis, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2010

27. Short-term effects of synchrotron irradiation on vasculature and tissue in healthy mouse brain

Author

Jean-Claude Vial, Boudewijn van der Sanden, Laurette Somveille, Lucie Dupin, Régine Farion, Christoph Segebarth, Clément Ricard, Hélène Elleaume, Manuel Fernandez, Herwig Requardt, Jérôme Gastaldo, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimagerie Fonctionnelle et Metabolique, European Synchrotron Radiation Facility (ESRF), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Serduc, Raphael, and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
Collagen Type IV, Nuclear and High Energy Physics, Pathology, medicine.medical_specialty, Mice, Nude, synchrotron radiotherapy, Blood–brain barrier, Basement Membrane, law.invention, 03 medical and health sciences, Mice, 0302 clinical medicine, law, Glial Fibrillary Acidic Protein, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, blood-brain-barrier permeability, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Irradiation, Instrumentation, Cisplatin, Radiation, Chemistry, Brain, Radiotherapy Dosage, equipment and supplies, Fluorescence, Immunohistochemistry, Extravasation, Synchrotron, 3. Good health, medicine.anatomical_structure, gliosis, Gliosis, Permeability (electromagnetism), Blood-Brain Barrier, healthy brain tissue and irradiation, 030220 oncology & carcinogenesis, multiphoton microscopy, Female, medicine.symptom, 030217 neurology & neurosurgery, Synchrotrons, medicine.drug
Abstract

International audience; The purpose of this study is to measure the effects of a tomographic synchrotron irradiation on healthy mouse brain. The cerebral cortexes of healthy nude mice were irradiated with a monochromatic synchrotron beam of 79 keV at a dose of 15 Gy in accordance with a protocol of photoactivation of cisplatin previously tested in our laboratory. Forty-eight hours, one week and one month after irradiation, the blood brain barrier (BBB) permeability was measured in the irradiated area with intravital multiphoton microscopy using fluorescent dyes with molecular weights of 4 and 70 kDa. Vascular parameters and gliosis were also assessed using quantitative immunohistochemistry. No extravasation of the fluorescent dyes was observed in the irradiated area at any measurement time (48 h, 1 week, 1 month). It appears that the BBB remains impermeable to molecules with a molecular weight of 4 kDa and above. The vascular density and vascular surface were unaffected by irradiation and no gliosis was induced. These findings suggest that a 15 Gy/79 keV synchrotron irradiation does not induce important damage on brain vasculature and tissue on the short term following irradiation.

Published
2009

28. Fluorescent Pluronic nanodots for in vivo two-photon imaging

Author

Laeticia Vurth, Boudewijn van der Sanden, Patrice L. Baldeck, Mathieu Maurin, Olivier Stéphan, Seth R. Marder, Jean-Claude Vial, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Chemistry and Biochemistry, and Center for Organic Electronics and Photonics, Georgia Institute of Technology [Atlanta], and Serduc, Raphael

Subjects
Diagnostic Imaging, Hydrodynamic radius, Materials science, Analytical chemistry, Nanoparticle, Bioengineering, 02 engineering and technology, Poloxamer, 010402 general chemistry, Kidney, 01 natural sciences, Mice, Two-photon excitation microscopy, Animals, Surface Tension, General Materials Science, Electrical and Electronic Engineering, Particle Size, Fluorescent Dyes, Mice, Inbred BALB C, Rhodamines, Mechanical Engineering, Absorption cross section, Brain, Reproducibility of Results, Dextrans, General Chemistry, 021001 nanoscience & nanotechnology, Fluorescence, 0104 chemical sciences, 3. Good health, Liver, Mechanics of Materials, Nanoparticles, Nanodot, 0210 nano-technology, Luminescence, Visible spectrum
Abstract

International audience; We report the synthesis of new nanosized fluorescent probes based on bio-compatible polyethylene-polypropylene glycol (Pluronic) materials. In aqueous solution, mini-emulsification of Pluronic with a high fluorescent di-stryl benzene-modified derivative, exhibiting a two-photon absorption cross section as high as 2500 Goeppert-Mayer units at 800 nm, leads to nanoparticles exhibiting a hydrodynamic radius below 100 nm. We have demonstrated that these new probes with luminescence located in the spectral region of interest for bio-imaging (the yellow part of the visible spectrum) allow deep (500 microm) bio-imaging of the mice brain vasculature. The dose injected during our experiments is ten times lower when compared to the classical commercial rhodamine-B isothicyanate-Dextran system but gives similar results to homogeneous blood plasma staining. The mean fluorescent signal intensity stayed constant during more than 1 h.

Published
2009

29. An ethylene-glycol decorated ruthenium(ii) complex for two-photon photodynamic therapy

Author

Adeline Bonne, Gilles Lemercier, Boudewijn van der Sanden, Simion Astilean, Mickaël Four, Patrice L. Baldeck, Sanda Boca, Serduc, Raphael, Nanobiophotonics Laboratory, Babes-Bolyai University [Cluj-Napoca] (UBB), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie Fonctionnelle et Metabolique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Grenoble Institut des Neurosciences (GIN), Faculty of Physics, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC)

Subjects
Ethylene Glycol, medicine.medical_treatment, chemistry.chemical_element, Photodynamic therapy, 010402 general chemistry, Photochemistry, 01 natural sciences, Catalysis, Ruthenium, chemistry.chemical_compound, Two-photon excitation microscopy, Materials Chemistry, medicine, Organometallic Compounds, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Photons, Photosensitizing Agents, Molecular Structure, 010405 organic chemistry, Metals and Alloys, Water, General Chemistry, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, chemistry, Photochemotherapy, Solubility, Ceramics and Composites, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Ethylene glycol
Abstract

International audience; A novel water-soluble Ru(ii) complex has been prepared, which represents a promising new class of selective two-photon sensitizers for use in photodynamic therapy within a confined space.

Published
2009

30. Brain tumor vessel response to synchrotron microbeam radiation therapy: a short-term in vivo study

Author

Alberto Bravin, Boudewijn van der Sanden, Emmanuel L. Barbier, Régine Farion, Jean A. Laissue, Christoph Segebarth, Thomas Christen, Raphaël Serduc, Chantal Rémy, Audrey Bouchet, Elke Bräuer-Krisch, Géraldine Le Duc, INSERM U836, équipe 5, Neuro-imagerie fonctionnelle et métabolique, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncology - Pathology - Anatomy, Institute of Pathology-University of Bern, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), European Synchrotron Radiation Facility (ESRF), La Ligue Contre le Cancer, Association pour la Recherche sur le Cancer, Institut National du Cancer, Programme Interdisciplinaire Imagerie du Petit Animal, Région Rhône-Alpes, Cancéropôle Lyon Auvergne Rhône-Alpes (CLARA), Collaboration, Serduc, R, Christen, T, Laissue, J, Farion, R, Bouchet, A, van der Sanden, B, Segebarth, C, Braeuer-Krisch, E, Le Duc, G, Bravin, A, Remy, C, Barbier, E, and Dojat, Michel

Subjects
Male, Pathology, Time Factors, MESH: Radiotherapy, Angiogenesis, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Blood volume, 030218 nuclear medicine & medical imaging, Ionizing radiation, MESH: Magnetic Resonance Imaging, Mice, angiogenesis, 0302 clinical medicine, Medicine, MESH: Animals, MESH: Radiotherapy Dosage, MESH: Treatment Outcome, Neovascularization, Pathologic, Radiological and Ultrasound Technology, medicine.diagnostic_test, Brain Neoplasms, Radiotherapy Dosage, Magnetic Resonance Imaging, 3. Good health, Survival Rate, Treatment Outcome, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, MESH: Synchrotrons, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.medical_specialty, MESH: Survival Rate, Brain tumor, Mice, Nude, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), Gliosarcoma, Brain tumor vessel, response, synchrotron microbeam radiation therapy, 03 medical and health sciences, In vivo, MESH: Mice, Nude, Animals, Effective diffusion coefficient, Radiology, Nuclear Medicine and imaging, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Irradiation, MESH: Mice, Radiotherapy, business.industry, MESH: Time Factors, Magnetic resonance imaging, medicine.disease, MESH: Male, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Rat, MESH: Gliosarcoma, business, Nuclear medicine, MESH: Neovascularization, Pathologic, Neoplasm Transplantation, Synchrotrons, MESH: Neoplasm Transplantation
Abstract

International audience; The aim of this work focuses on the description of the short-term response of a 9L brain tumor model and its vasculature to microbeam radiation therapy (MRT) using magnetic resonance imaging (MRI). Rat 9L gliosarcomas implanted in nude mice brains were irradiated by MRT 13 days after tumor inoculation using two orthogonal arrays of equally spaced 28 planar microbeams (25 microm width, 211 microm spacing and dose 500 Gy). At 1, 7 and 14 days after MRT, apparent diffusion coefficient, blood volume and vessel size index were mapped by MRI. Mean survival time after tumor inoculation increased significantly between MRT-treated and untreated groups (23 and 28 days respectively, log-rank test, p < 0.0001). A significant increase of apparent diffusion coefficient was observed 24 h after MRT in irradiated tumors versus non-irradiated ones. In the untreated group, both tumor size and vessel size index increased significantly (from 7.6 +/- 2.2 to 19.2 +/- 4.0 mm(2) and +23%, respectively) between the 14th and the 21st day after tumor cell inoculation. During the same period, in the MRT-treated group, no difference in tumor size was observed. The vessel size index measured in the MRT-treated group increased significantly (+26%) between 14 and 28 days of tumor growth. We did not observe the significant difference in blood volume between the MRT-treated and untreated groups. MRT slows 9L tumor growth in a mouse brain but MRI results suggest that the increase in survival time after our MRT approach may be rather due to a cytoreduction than to early direct effects of ionizing radiation on tumor vessels. These results suggest that MRT parameters need to be optimized to further damage tumor vessels.

Published
2008

31. Subtraction method for intravital two-photon microscopy: intraparenchymal imaging and quantification of extravasation in mouse brain cortex

Author

Pascale Vérant, Boudewijn van der Sanden, Jonathan A. Coles, Raphaël Serduc, Rémy Chantal, Jean-Claude Vial, Clément Ricard, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dojat, Michel, and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, MESH: Subtraction Technique, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Sulforhodamine B, MESH: Blood-Brain Barrier, Mice, chemistry.chemical_compound, 0302 clinical medicine, Two-photon excitation microscopy, MESH: Extravasation of Diagnostic and Therapeutic Materials, Cortex (anatomy), Microscopy, MESH: Animals, Cerebral Cortex, 0303 health sciences, Chemistry, Subtraction, Atomic and Molecular Physics, and Optics, Extravasation, Electronic, Optical and Magnetic Materials, MESH: Reproducibility of Results, medicine.anatomical_structure, Blood-Brain Barrier, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Image Enhancement, Algorithms, medicine.medical_specialty, Biomedical Engineering, Mice, Nude, MESH: Algorithms, Blood–brain barrier, Sensitivity and Specificity, Biomaterials, 03 medical and health sciences, Image Interpretation, Computer-Assisted, Parenchyma, medicine, MESH: Mice, Nude, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Reproducibility of Results, Image Enhancement, MESH: Sensitivity and Specificity, MESH: Cerebral Cortex, Microscopy, Fluorescence, Multiphoton, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Subtraction Technique, MESH: Microscopy, Fluorescence, Multiphoton, MESH: Image Interpretation, Computer-Assisted, 030217 neurology & neurosurgery, Extravasation of Diagnostic and Therapeutic Materials, Biomedical engineering
Abstract

International audience; Brain pathologies, including stroke and tumors, are associated with a variable degree of breakdown of the blood-brain barrier (BBB), which can usefully be studied in animal models. We describe a new optical technique for quantifying extravasation in the cortex of the living mouse and for imaging intraparenchymal tissue. Leakiness of the BBB was induced by microbeam x-irradiation. Two fluorescent dyes were simultaneously infused intravenously, one of high molecular weight (fluorescein-labeled dextran, 70 kDa, green fluorescence) and one of low molecular weight (sulforhodamine B, 559 Da, red fluorescence). A two-photon microscope, directed through a cranial window, obtained separate images of the two dyes in the cortex. The gains of the two channels were adjusted so that the signals coming from within the vessels were equal. Subtraction of the image of the fluorescein-dextran from that of the sulforhodamine B gave images in which the vasculature was invisible and the sulforhodamine B in the parenchyma could be imaged with high resolution. Algorithms are presented for rapidly quantifying the extravasation without the need for shape recognition and for calculating the permeability of the BBB. Sulforhodamine B labeled certain intraparenchymal cells; these cells, and other details, were best observed using the subtraction method.

Published
2008

32. In vivo staining of neocortical astrocytes via the cerebral microcirculation using sulforhodamine B

Author

Clément Ricard, Pascale Vérant, Jean-Claude Vial, Raphaël Serduc, Boudewijn van der Sanden, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimagerie Fonctionnelle et Metabolique, and Serduc, Raphael

Subjects
Pathology, Sulforhodamine B, Contrast Media, Neocortex, Mice, chemistry.chemical_compound, MESH: Neocortex, 0302 clinical medicine, Blood plasma, MESH: Microcirculation, MESH: Animals, 0303 health sciences, Chemistry, Fluorescence, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, Cell biology, MESH: Staining and Labeling, medicine.anatomical_structure, MESH: Microvessels, Injections, Intravenous, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Image Enhancement, Preclinical imaging, medicine.medical_specialty, Biomedical Engineering, MESH: Rhodamines, Blood–brain barrier, Stain, Biomaterials, 03 medical and health sciences, In vivo, MESH: Contrast Media, medicine, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, 030304 developmental biology, Staining and Labeling, Rhodamines, Microcirculation, Image Enhancement, MESH: Injections, Intravenous, Staining, MESH: Astrocytes, Microscopy, Fluorescence, Multiphoton, Astrocytes, Microvessels, MESH: Microscopy, Fluorescence, Multiphoton, 030217 neurology & neurosurgery
Abstract

International audience; Staining and imaging glial cells in vivo while observing the microvasculature could help understand brain physiology, namely neuronal-glial-vascular communication. Two-photon excitation microscopy provides a means to monitor these interactions at the cellular level in living animals, but the cells of interest must be fluorescent. Injecting dyes intravenously is a rapid and quasi noninvasive method to stain cells in the brain. It necessitates that the dye is soluble in the blood plasma and crosses the blood brain barrier (BBB). We demonstrate here, using two-photon imaging, that sulforhodamine B (SRB) crosses the BBB and stains in vivo, specifically mouse astrocytes. This is confirmed by experiments on primary neurons and astrocytes cultures showing the preferential SRB staining of the latter. SRB is rapidly eliminated from the blood, which allows repeated injections in longitudinal studies.

Published
2008

33. Cell-permeant cytoplasmic blue fluorophores optimized for in vivo two-photon microscopy with low-power excitation

Author

Boudewijn van der Sanden, Jean-Claude Vial, Alexei Grichine, Frédéric Bolze, Yves Mély, Alain Duperray, Ali Hayek, Clément Ricard, Thomas Huault, Jean-François Nicoud, Patrice L. Baldeck, Institut de Physique et Chimie des Matériaux de Strasbourg (IPCMS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Institut Albert Bonniot - Ontogénèse et oncogénèse moléculaires, CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie Fonctionnelle et Metabolique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rayonnement Synchrotron et Recherche Medicale (RSRM), Université Joseph Fourier - Grenoble 1 (UJF)-European Synchrotron Radiation Facility (ESRF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Groupe de Recherche Sur Le Cancer du Poumon : Bases Moléculaires de la Progression Tumorale, Dépistage et Thérapie Génique, Institut Albert Bonniot-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur le Cancer du Poumon, Université Joseph Fourier - Grenoble 1 (UJF), Duperray, Alain, European Synchrotron Radiation Facility (ESRF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Masson, Beatrice

Subjects
[PHYS.PHYS.PHYS-OPTICS] Physics [physics]/Physics [physics]/Optics [physics.optics], Cytoplasm, Fluorescence-lifetime imaging microscopy, FLIM, Histology, Analytical chemistry, Mice, Nude, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, photostability, 01 natural sciences, Cell Line, Diffusion, Mice, 03 medical and health sciences, Two-photon excitation microscopy, Mouse Brain Imaging, Animals, Humans, Instrumentation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Two-Photon Dyes, Fluorescent Dyes, 030304 developmental biology, Fluorescence loss in photobleaching, Photons, 0303 health sciences, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Chemistry, Cell Microscopy, Brain, Fluorescence recovery after photobleaching, Fluorescence, Photobleaching, 0104 chemical sciences, Medical Laboratory Technology, Microscopy, Fluorescence, Multiphoton, Membrane, Biophysics, FRAP, Anatomy, BBB, Fluorescence Recovery After Photobleaching
Abstract

International audience; Because of the spreading of nonlinear microscopies in biology, there is a strong demand for specifically engineered probes in these applications. Herein, we report on the imaging properties in living cells and nude mice brains of recently developed water soluble blue fluorophores that show efficient diffusion through cell membranes and blood-brain barriers. They are characterized by two-photon absorption cross-sections of 100-150 Goeppert-Mayer range in the near IR and fluorescence efficiencies of up to 72% in water. They were found to stain homogeneously the cytoplasm of cultured living cells within minutes. Moreover, their diffusion times and fluorescence characteristics in the cytoplasm suggest a hydrophobic association with intracellular membranes. Their intracellular fluorescent decays were found to be almost mono-exponential, a very favorable feature for fluorescence lifetime imaging. Two photon images of living cells were obtained with a good signal to noise ratio using laser powers in the sub-milliwatt range. This allows continuous imaging without significant photobleaching for tens of minutes. In addition, these fluorophores allowed in vivo three-dimensional two-photon imaging of mice cortex vasculatures and extra vasculature structures, with no sign of toxicity. Microsc. Res. Tech., 2007. (c) 2007 Wiley-Liss, Inc.

Published
2007

34. A direct method for measuring mouse capillary cortical blood volume using multiphoton laser scanning microscopy

Author

Boudewijn van der Sanden, Chantal Rémy, Jean-Claude Vial, Raphaël Serduc, Pascale Vérant, Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimagerie Fonctionnelle et Metabolique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Dojat, Michel

Subjects
Pathology, MESH: Blood Volume, Capillary action, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Blood volume, 01 natural sciences, law.invention, 0302 clinical medicine, law, Cortex (anatomy), Microscopy, MESH: Microcirculation, Image Processing, Computer-Assisted, MESH: Microscopy, Confocal, MESH: Animals, Cerebral Cortex, Blood Volume, Microscopy, Confocal, cerebral blood volume, MESH: Cerebrovascular Circulation, Fluorescence, MESH: Image Processing, Computer-Assisted, MESH: Reproducibility of Results, medicine.anatomical_structure, Neurology, microvascularisation, two-photon laser scanning microscopy, Cerebrovascular Circulation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cardiology and Cardiovascular Medicine, Algorithms, medicine.medical_specialty, Materials science, mice, Confocal, Mice, Nude, MESH: Algorithms, 010309 optics, 03 medical and health sciences, MESH: Computer Simulation, In vivo, 0103 physical sciences, medicine, MESH: Mice, Nude, Animals, Computer Simulation, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, MESH: Capillaries, Microcirculation, Reproducibility of Results, Laser, MESH: Cerebral Cortex, Capillaries, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Neurology (clinical), 030217 neurology & neurosurgery, Biomedical engineering
Abstract

International audience; Knowledge of the blood volume per unit volume of brain tissue is important for understanding brain function in health and disease. We describe a direct method using two-photon laser scanning microscopy to obtain in vivo the local capillary blood volume in the cortex of anesthetized mouse. We infused fluorescent dyes in the circulating blood and imaged the blood vessels, including the capillaries, to a depth of 600 microm below the dura at the brain surface. Capillary cortical blood volume (CCBV) was calculated without any form recognition and segmentation, by normalizing the total fluorescence measured at each depth and integrating the collected intensities all over the stack. Theoretical justifications are presented and numerical simulations were performed to validate this method which was weakly sensitive to background noise. Then, CCBV had been estimated on seven healthy mice between 2%+/-0.3% and 2.4%+/-0.4%. We showed that this measure of CCBV is reproductible and that this method is highly sensitive to the explored zones in the cortex (vessel density and size). This method, which dispenses with form recognition, is rapid and would allow to study in vivo temporal and highly resolute spatial variations of CCBV under different conditions or stimulations.

Published
2007

35. In vivo two-photon microscopy study of short-term effects of microbeam irradiation on normal mouse brain microvasculature

Author

Elke Brauer, Alberto Bravin, Chantal Rémy, Linda Rocas, Régine Farion, Pascale Vérant, Taoufik Fadlallah, Jean-Claude Vial, Boudewijn van der Sanden, Raphaël Serduc, Hans Blattmann, Jean A. Laissue, Neuro-imagerie fonctionnelle et métabolique (ANTE-INSERM U836, équipe 5), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Spectrométrie Physique (LSP), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie Fonctionnelle et Metabolique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Synchrotron Radiation Facility (ESRF), Oncology - Pathology - Anatomy, Institute of Pathology-University of Bern, Paul Scherrer Institute (PSI), Ligue contre le Cancer, Association pour la recherche sur le Cancer, Programme Interdisciplinaire CNRS-INSERM-CEA IPA, Région Rhône Alpes, Cancéropôle CLARA, Serduc, R, Verant, P, Vial, J, Farion, R, Rocas, L, Remy, C, Fadlallah, T, Brauer, E, Bravin, A, Laissue, J, Blattmann, H, Van der Sanden, B, and Issartel, Jean-Paul

Subjects
Cancer Research, Time Factors, MESH: Blood Volume, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Vascular permeability, 030218 nuclear medicine & medical imaging, MESH: Blood-Brain Barrier, chemistry.chemical_compound, Mice, 0302 clinical medicine, Two-photon excitation microscopy, Microscopy, MESH: Behavior, Animal, MESH: Microcirculation, Medicine, MESH: Microscopy, Confocal, MESH: Animals, Fluorescein, Fluorescein isothiocyanate, MESH: Radiotherapy Dosage, Blood-brain barrier, Radiation, Blood Volume, Microscopy, Confocal, Behavior, Animal, Brain, Radiotherapy Dosage, Microbeam, Vascular volume, Immunohistochemistry, Radiation Injuries, Experimental, Oncology, MESH: Models, Animal, 030220 oncology & carcinogenesis, Models, Animal, Microbeam radiation therapy, Mice, Nude, FIS/07 - FISICA APPLICATA (A BENI CULTURALI, AMBIENTALI, BIOLOGIA E MEDICINA), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Permeability, Capillary Permeability, 03 medical and health sciences, MESH: Brain, In vivo, MESH: Dose-Response Relationship, Radiation, MESH: Mice, Nude, Animals, Radiology, Nuclear Medicine and imaging, Irradiation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Intravital multiphoton microscopy, MESH: Mice, Synchrotron radiation X-ray, business.industry, Microcirculation, MESH: Time Factors, MESH: Capillary Permeability, Dose-Response Relationship, Radiation, MESH: Immunohistochemistry, equipment and supplies, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, chemistry, MESH: Radiation Injuries, Experimental, business, Nuclear medicine
Abstract

International audience; PURPOSE: The purpose of this study was to assess the early effects of microbeam irradiation on the vascular permeability and volume in the parietal cortex of normal nude mice using two-photon microscopy and immunohistochemistry. METHODS AND MATERIALS: The upper part of the left hemisphere of 55 mice was irradiated anteroposteriorly using 18 vertically oriented beams (width 25 microm, interdistance 211 microm; peak entrance doses: 312 or 1000 Gy). At different times after microbeam exposure, the microvasculature in the cortex was analyzed using intravital two-photon microscopy after intravascular injection of fluorescein isothiocyanate (FITC)-dextrans and sulforhodamine B (SRB). Changes of the vascular volume were observed at the FITC wavelength over a maximum depth of 650 mum from the dura. The vascular permeability was detected as extravasations of SRB. RESULTS: For all times (12 h to 1 month) after microbeam irradiation and for both doses, the FITC-dextran remained in the vessels. No significant change in vascular volume was observed between 12 h and 3 months after irradiation. Diffusion of SRB was observed in microbeam irradiated regions from 12 h until 12 days only after a 1000 Gy exposure. CONCLUSION: No radiation damage to the microvasculature was detected in normal brain tissue after a 312 Gy microbeam irradiation. This dose would be more appropriate than 1000 Gy for the treatment of brain tumors using crossfired microbeams.

Published
2006

36. Novel two-photon absorbing styrylpyridine-based multi-branched dyes: towards pH responsive dyes for biological imaging

Author

Boudewijn van der Sanden, Clément Ricard, Fabrice Mathevet, André-Jean Attias, Patrice L. Baldeck, David Kreher, Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie des polymères (LCP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de synthèse organique (DCSO), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroimagerie Fonctionnelle et Metabolique, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinatec - Centre de recherche biomédicale Edmond J.Safra (SCLIN), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
[PHYS]Physics [physics], Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Protonation, Molar absorptivity, Chromophore, Photochemistry, Fluorescence, 3. Good health, [SPI]Engineering Sciences [physics], Two-photon excitation microscopy, [SPI.OPTI]Engineering Sciences [physics]/Optics / Photonic, Molecule, [CHIM]Chemical Sciences, Biological imaging, Luminescence, ComputingMilieux_MISCELLANEOUS
Abstract

We report on the design, synthesis and optical properties of new two-photon absorbing multi-branched chromophores, based on a pyridine core. Measurements of TPA using the two-photon fluorescence method in the fs regime indicate that these chromophores exhibit two-photon absorptivity. The results indicate that a change of the substitution of the electron-acceptor core influences significantly the TPA cross sections. Moreover, upon protonation, the TPA properties are greatly enhanced in the 700-900 nm range. Thus, these molecules can serve as pH-sensitive TPA dyes. Preliminary results related to biological applications will be presented.

Published
2006

37. Comparison of FAIR perfusion kinetics with DSC-MRI and functional histology in a model of transient ischemia

Author

Boudewijn van der Sanden, Matthias J.P. van Osch, Robert-Jan Pauw, Klaas Nicolay, Wouter B. Veldhuis, Janneke Schepers, and Jan-Willem de Groot

Subjects
Male, Transient ischemia, business.industry, Kinetics, Ischemia, Hemodynamics, Histology, Perfusion scanning, medicine.disease, Magnetic Resonance Imaging, Rats, Inbred F344, Brain Ischemia, Rats, Nuclear magnetic resonance, Text mining, Regional Blood Flow, Cerebrovascular Circulation, medicine, Image Processing, Computer-Assisted, Animals, Radiology, Nuclear Medicine and imaging, business, Perfusion
Abstract

Flow-sensitive alternating inversion recovery (FAIR) is a noninvasive method for perfusion imaging. It has been shown that the FAIR signal may depend on hemodynamic parameters other than perfusion, the most important one being transit delays of labeled spins to the observed tissue. These parameters are expected to change with ischemia. The goal of this study was to assess the effect of these changes on the interpretation of FAIR results in the case of altered perfusion. This was investigated in a rat model of transient cerebral ischemia. It was shown that the ratio of FAIR signal in the infarct compared to the contralateral side was lower at short inflow times, which suggests that transit times affected the effective FAIR signal. The FAIR results were compared with those from functional histology and dynamic susceptibility contrast MRI, and the findings indicated that the altered kinetics of the FAIR signal were related to reduced and delayed inflow in the infarct region—not to a decrease in the number of functional vessels. Magn Reson Med 51:312–320, 2004. © 2004 Wiley-Liss, Inc.

Published
2004

38. In vivo staining of neocortical astrocytes via the cerebral microcirculation using sulforhodamine B.

Author

Pascale Ve´rant, Cle´ment Ricard, Raphae¨l Serduc, Jean-Claude Vial, and Boudewijn van der Sanden

Subjects
NEUROGLIA, NERVE tissue, NERVES, ASTROCYTES, MICROGLIA
Abstract

Staining and imaging glial cells in vivo while observing the microvasculature could help understand brain physiology, namely neuronal-glial-vascular communication. Two-photon excitation microscopy provides a means to monitor these interactions at the cellular level in living animals, but the cells of interest must be fluorescent. Injecting dyes intravenously is a rapid and quasi noninvasive method to stain cells in the brain. It necessitates that the dye is soluble in the blood plasma and crosses the blood brain barrier (BBB). We demonstrate here, using two-photon imaging, that sulforhodamine B (SRB) crosses the BBB and stains in vivo, specifically mouse astrocytes. This is confirmed by experiments on primary neurons and astrocytes cultures showing the preferential SRB staining of the latter. SRB is rapidly eliminated from the blood, which allows repeated injections in longitudinal studies. [ABSTRACT FROM AUTHOR]

Published
2008
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39. In vivo imaging of elastic fibers using sulforhodamine B.

Author

Cle´ment Ricard, Jean-Claude Vial, Julien Douady, and Boudewijn van der Sanden

Subjects
FIBERS, IMAGING systems, MICROSCOPY, FLUORESCENCE
Abstract

Until now, the imaging of elastic fibers was restricted to tissue sections using the endofluorescence properties of elastin or histological dyes. Methods to study their morphology in vivo and in situ have been lacking. We present and characterize a new application of a fluorescent dye for two-photon microscopy: sulforhodamine B (SRB), which is shown to specifically stain elastic fibers in vivo. SRB staining of elastic fibers is demonstrated to be better than using elastin endofluorescence for two-photon microscopy. Our imaging method of elastic fibers is shown to be suitable for simultaneous imaging with both other fluorescent intravital dyes and second-harmonic generation (SHG). We illustrate these findings with intravital imaging of elastic and collagen fibers in muscle epimysium and endomysium and in blood vessel walls. We expect SRB staining to become a key method to study elastic fibers in vivo. [ABSTRACT FROM AUTHOR]

Published
2007
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