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5. Empirical and Theoretical Characterization of the Diffusion Process of Different Gadolinium-Based Nanoparticles within the Brain Tissue after Ultrasound-Induced Permeabilization of the Blood-Brain Barrier

Author

Conti, Allegra, Magnin, Remi, Gerstenmayer, Matthieu, Tsapis, Nicolas, Dumont, Erik, Tillement, Olivier, Lux, François, Le Bihan, Denis, Mériaux, Sébastien, Della Penna, Stefania, Larrat, Benoit, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Image Guided Therapy (IGT), Formation, élaboration de nanomatériaux et cristaux (FENNEC), Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Clinic Sciences and Bioimaging, University G. d'Annunzio Chieti-Pescara, European Project: 600382,EC:FP7:PEOPLE,FP7-PEOPLE-2012-COFUND,ENHANCED EUROTALENTS(2014), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Male, lcsh:Medical technology, Article Subject, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Sulfur Hexafluoride, Contrast Media, Nanoconjugates, Capillary Permeability, Rats, Sprague-Dawley, Diffusion, [SPI]Engineering Sciences [physics], Meglumine, Heterocyclic Compounds, Organometallic Compounds, Animals, Particle Size, Phospholipids, Microbubbles, Phantoms, Imaging, Settore FIS/07, Corpus Striatum, Rats, lcsh:R855-855.5, Ultrasonic Waves, Blood-Brain Barrier, Extracellular Space, Algorithms, Research Article
Abstract

International audience; Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the di usion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabilization. ree compounds were tested (MultiHance, Gadovist, and Dotarem). We characterized their di usion through in vivo experimental tests supported by theoretical models. Speci cally, by estimation of the free di usion coe cients from in vitro studies and of apparent di usion coe cients from in vivo experiments, we have assessed tortuosity in the right striatum of 9 Sprague Dawley rats through a model correctly describing both vascular permeability as a function of time and di usion processes occurring in the brain tissue. is model takes into account acoustic pressure, particle size, blood pharmacokinetics, and di usion rates. Our model is able to fully predict the result of a FUS-induced BBB opening experiment at long space and time scales. Recovered values of tortuosity are in agreement with the literature and demonstrate that our improved model allows us to assess that the chosen permeabilization protocol preserves the integrity of the brain tissue.

Published
2019
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6. Ultrasound Induced Blood-brain Barrier Opening on Rodents : from Nanoparticles Delivery to a Therapy for Alzheimer’s Disease

Author

Gerstenmayer, Matthieu, Unité d'imagerie par résonance magnétique à très haut champ et de spectroscopie (UNIRS), Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris Saclay (COmUE), Cyril Poupon, Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and STAR, ABES

Subjects
Barrière hémato-encéphalique, [PHYS.PHYS.PHYS-MED-PH] Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Ultrasound, Maladie d' Alzheimer, Ultrasons, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Alzheimer's disease, Mri, Blood-brain barrier, Irm
Abstract

The blood-brain barrier (BBB) plays a crucial role in maintaining the hemostasis of the brain and protects it from pathogens. The BBB prevents molecules with a molecular weight higher than 400 Da to enter the brain. Crucial, the BBB becomes a limit to deliver drugs to the brain. Low intensity focused ultrasound and microbubbles are a unique tool to open the BBB, in a safe and reversible way, to deliver drugs to the brain. The first part of the PhD was dedicated to developing new strategies for BBB opening. To do so, I measured the attenuation of the ultrasound beam by the skull and studied the dependency of the intensity and of the duration of the BBB opening on the acoustic parameters. Thanks to these developments, I was able to deliver many kinds of nanoparticles to rodent brains and I could observe their delivery with techniques such as magnetic resonance imaging (MRI), positron emission tomography, phase-contrast X-ray imaging, mass spectroscopy or histology. The second part of my PhD was focused on applying this technology to Alzheimer’s disease (AD). I optimized a T2* MRI protocol at very high resolution for ex vivo imaging of amyloid plaques in the cortex of mice modeling AD. I developed a semi-automatic image treatment to detect and quantify the amyloid load. Finally, I tested a repeated BBB opening as a therapy for AD and showed that repeated BBB openings could have a beneficial impact on the memory on rodents modeling AD., La barrière hémato-encéphalique (BHE) régule finement l’apport en oxygène et en nutriments du cerveau et le protège d’éventuels pathogènes, notamment en bloquant le passage des molécules de poids moléculaire supérieur à 400 Da. Malheureusement, cette barrière est un obstacle à la délivrance de nombreux médicaments. Les ultrasons focalisés de basse intensité, combinés avec des microbulles, représentent un outil de choix pour perméabiliser la BHE, de façon sûre et réversible, et ainsi permettre de délivrer efficacement des médicaments ou des agents de contraste dans le cerveau. Dans la première partie de ma thèse, j’ai développé de nouvelles stratégies ultrasonores de perméabilisation de la BHE chez le rongeur. J’ai mesuré l’atténuation du faisceau ultrasonore par le crâne et étudié l’influence des paramètres acoustiques sur l’intensité et la durée de la perméabilisation. Ces développements m’ont ensuite permis de délivrer des nanoparticules dans le cerveau de rongeurs et d’observer cette délivrance par imagerie par résonance magnétique (IRM), tomographie par émission de positrons, imagerie de contraste de phase par rayons-X, spectrométrie de masse ou encore histologie. La seconde partie de mon travail a porté sur l’application de cette technologie ultrasonore à la maladie d’Alzheimer (MA). J’ai tout d’abord optimisé un protocole IRM T2* à très haute résolution permettant l’imagerie ex vivo des plaques amyloïdes de souris modèles de la MA. J’ai développé un traitement semi-automatique des images pour détecter et quantifier la charge amyloïde dans le cortex. Enfin, j’ai évalué la perméabilisation répétée de la BHE en tant que thérapie pour la MA et démontré que des perméabilisations répétées de la BHE pouvaient avoir un effet bénéfique sur la mémoire de rongeurs modèles de la maladie.

Published
2018

7. International Society for Therapeutic Ultrasound Conference 2016

Author

Fowlkes, Brian, Ghanouni, Pejman, Sanghvi, Narendra, Coussios, Constantin, Lyon, Paul C., Gray, Michael, Mannaris, Christophoros, Victor, Marie de Saint, Stride, Eleanor, Cleveland, Robin, Carlisle, Robert, Wu, Feng, Middleton, Mark, Gleeson, Fergus, Aubry, Jean-Franҫois, Pauly, Kim Butts, Moonen, Chrit, Vortman, Jacob, Sharabi, Shirley, Daniels, Dianne, Last, David, Guez, David, Levy, Yoav, Volovick, Alexander, Grinfeld, Javier, Rachmilevich, Itay, Amar, Talia, Zibly, Zion, Mardor, Yael, Harnof, Sagi, Plaksin, Michael, Weissler, Yoni, Shoham, Shy, Kimmel, Eitan, Naor, Omer, Farah, Nairouz, Paeng, Dong-Guk, Xu, Zhiyuan, Snell, John, Quigg, Anders H., Eames, Matthew, Jin, Changzhu, Everstine, Ashli C., Sheehan, Jason P., Lopes, Beatriz S., Kassell, Neal, Looi, Thomas, Khokhlova, Vera, Mougenot, Charles, Hynynen, Kullervo, Drake, James, Slayton, Michael, Amodei, Richard C., Compton, Keegan, McNelly, Ashley, Latt, Daniel, Kearney, John, Melodelima, David, Dupre, Aurelien, Chen, Yao, Perol, David, Vincenot, Jeremy, Chapelon, Jean-Yves, Rivoire, Michel, Guo, Wei, Ren, Guoxin, Shen, Guofeng, Neidrauer, Michael, Zubkov, Leonid, Weingarten, Michael S., Margolis, David J., Lewin, Peter A., McDannold, Nathan, Sutton, Jonathan, Vykhodtseva, Natalia, Livingstone, Margaret, Kobus, Thiele, Zhang, Yong-Zhi, Schwartz, Michael, Huang, Yuexi, Lipsman, Nir, Jain, Jennifer, Chapman, Martin, Sankar, Tejas, Lozano, Andres, Yeung, Robert, Damianou, Christakis, Papadopoulos, Nikolaos, Brokman, Omer, Zadicario, Eyal, Brenner, Ori, Castel, David, Wu, Shih-Ying, Grondin, Julien, Zheng, Wenlan, Heidmann, Marc, Karakatsani, Maria Eleni, Sánchez, Carlos J. Sierra, Ferrera, Vincent, Konofagou, Elisa E., Yiannakou, Marinos, Cho, HongSeok, Lee, Hwayoun, Han, Mun, Choi, Jong-Ryul, Lee, Taekwan, Ahn, Sanghyun, Chang, Yongmin, Park, Juyoung, Ellens, Nicholas, Partanen, Ari, Farahani, Keyvan, Airan, Raag, Carpentier, Alexandre, Canney, Michael, Vignot, Alexandre, Lafon, Cyril, Delattre, Jean-yves, Idbaih, Ahmed, Odéen, Henrik, Bolster, Bradley, Jeong, Eun Kee, Parker, Dennis L., Gaur, Pooja, Feng, Xue, Fielden, Samuel, Meyer, Craig, Werner, Beat, Grissom, William, Marx, Michael, Weber, Hans, Taviani, Valentina, Hargreaves, Brian, Tanaka, Jun, Kikuchi, Kentaro, Ishijima, Ayumu, Azuma, Takashi, Minamihata, Kosuke, Yamaguchi, Satoshi, Nagamune, Teruyuki, Sakuma, Ichiro, Takagi, Shu, Santin, Mathieu D., Marsac, Laurent, Maimbourg, Guillaume, Monfort, Morgane, Larrat, Benoit, François, Chantal, Lehéricy, Stéphane, Tanter, Mickael, Samiotaki, Gesthimani, Wang, Shutao, Acosta, Camilo, Feinberg, Eliza R., Kovacs, Zsofia I., Tu, Tsang-Wei, Papadakis, Georgios Z., Reid, William C., Hammoud, Dima A., Frank, Joseph A., Kovacs, Zsofia i., Kim, Saejeong, Jikaria, Neekita, Bresler, Michele, Qureshi, Farhan, Xia, Jingjing, Tsui, Po-Shiang, Liu, Hao-Li, Plata, Juan C., Sveinsson, Bragi, Salgaonkar, Vasant A., Adams, Matthew, Diederich, Chris, Ozhinsky, Eugene, Bucknor, Matthew D., Rieke, Viola, Mikhail, Andrew, Severance, Lauren, Negussie, Ayele H., Wood, Bradford, de Greef, Martijn, Schubert, Gerald, Ries, Mario, Poorman, Megan E., Dockery, Mary, Chaplin, Vandiver, Dudzinski, Stephanie O., Spears, Ryan, Caskey, Charles, Giorgio, Todd, Costa, Marcia M., Papaevangelou, Efthymia, Shah, Anant, Rivens, Ian, Box, Carol, Bamber, Jeff, ter Haar, Gail, Burks, Scott R., Nagle, Matthew, Nguyen, Ben, Milo, Blerta, Le, Nhan M., Song, Shaozhen, Zhou, Kanheng, Nabi, Ghulam, Huang, Zhihong, Ben-Ezra, Shmuel, Rosen, Shani, Mihcin, Senay, Strehlow, Jan, Karakitsios, Ioannis, Le, Nhan, Schwenke, Michael, Demedts, Daniel, Prentice, Paul, Haase, Sabrina, Preusser, Tobias, Melzer, Andreas, Mestas, Jean-Louis, Chettab, Kamel, Gomez, Gustavo Stadthagen, Dumontet, Charles, Werle, Bettina, Marquet, Fabrice, Bour, Pierre, Vaillant, Fanny, Amraoui, Sana, Dubois, Rémi, Ritter, Philippe, Haïssaguerre, Michel, Hocini, Mélèze, Bernus, Olivier, Quesson, Bruno, Livneh, Amit, Adam, Dan, Robin, Justine, Arnal, Bastien, Fink, Mathias, Pernot, Mathieu, Khokhlova, Tatiana D., Schade, George R., Wang, Yak-Nam, Kreider, Wayne, Simon, Julianna, Starr, Frank, Karzova, Maria, Maxwell, Adam, Bailey, Michael R., Lundt, Jonathan E., Allen, Steven P., Sukovich, Jonathan R., Hall, Timothy, Xu, Zhen, May, Philip, Lin, Daniel W., Constans, Charlotte, Deffieux, Thomas, Aubry, Jean-Francois, Park, Eun-Joo, Ahn, Yun Deok, Kang, Soo Yeon, Park, Dong-Hyuk, Lee, Jae Young, Vidal-Jove, J., Perich, E., Ruiz, A., Jaen, A., Eres, N., del Castillo, M. Alvarez, Myers, Rachel, Kwan, James, Coviello, Christian, Rowe, Cliff, Crake, Calum, Finn, Sean, Jackson, Edward, Pouliopoulos, Antonios, Li, Caiqin, Tinguely, Marc, Tang, Meng-Xing, Garbin, Valeria, Choi, James J., Folkes, Lisa, Stratford, Michael, Nwokeoha, Sandra, Li, Tong, Farr, Navid, D’Andrea, Samantha, Gravelle, Kayla, Chen, Hong, Lee, Donghoon, Hwang, Joo Ha, Tardoski, Sophie, Ngo, Jacqueline, Gineyts, Evelyne, Roux, Jean-Pau, Clézardin, Philippe, Conti, Allegra, Magnin, Rémi, Gerstenmayer, Matthieu, Lux, François, Tillement, Olivier, Mériaux, Sébastien, Penna, Stefania Della, Romani, Gian Luca, Dumont, Erik, Sun, Tao, Power, Chanikarn, Miller, Eric, Sapozhnikov, Oleg, Tsysar, Sergey, Yuldashev, Petr V., Svet, Victor, Li, Dongli, Pellegrino, Antonio, Petrinic, Nik, Siviour, Clive, Jerusalem, Antoine, Yuldashev, Peter V., Cunitz, Bryan W., Dunmire, Barbrina, Inserra, Claude, Guedra, Matthieu, Mauger, Cyril, Gilles, Bruno, Solovchuk, Maxim, Sheu, Tony W. H., Thiriet, Marc, Zhou, Yufeng, Neufeld, Esra, Baumgartner, Christian, Payne, Davnah, Kyriakou, Adamos, Kuster, Niels, Xiao, Xu, McLeod, Helen, Dillon, Christopher, Payne, Allison, Khokhova, Vera A., Sinilshchikov, Ilya, Andriyakhina, Yulia, Rybyanets, Andrey, Shvetsova, Natalia, Berkovich, Alex, Shvetsov, Igor, Shaw, Caroline J., Civale, John, Giussani, Dino, Lees, Christoph, Ozenne, Valery, Toupin, Solenn, Salgaonkar, Vasant, Kaye, Elena, Monette, Sebastien, Maybody, Majid, Srimathveeravalli, Govindarajan, Solomon, Stephen, Gulati, Amitabh, Bezzi, Mario, Jenne, Jürgen W., Lango, Thomas, Müller, Michael, Sat, Giora, Tanner, Christine, Zangos, Stephan, Günther, Matthias, Dinh, Au Hoang, Niaf, Emilie, Bratan, Flavie, Guillen, Nicolas, Souchon, Rémi, Lartizien, Carole, Crouzet, Sebastien, Rouviere, Olivier, Han, Yang, Payen, Thomas, Palermo, Carmine, Sastra, Steve, Olive, Kenneth, van Breugel, Johanna M., van den Bosch, Maurice A., Fellah, Benjamin, Le Bihan, Denis, Hernandez-Garcia, Luis, Cain, Charles A., Lyka, Erasmia, Elbes, Delphine, Li, Chunhui, Tamano, Satoshi, Jimbo, Hayato, Yoshizawa, Shin, Fujiwara, Keisuke, Itani, Kazunori, Umemura, Shin-ichiro, Stoianovici, Dan, Zaini, Zulfadhli, Takagi, Ryo, Zong, Shenyan, Watkins, Ron, Pascal-Tenorio, Aurea, Jones, Peter, Butts-Pauly, Kim, Bouley, Donna, Chen, Yazhu, Lin, Chung-Yin, Hsieh, Han-Yi, Wei, Kuo-Chen, Garnier, Camille, Renault, Gilles, Seifabadi, Reza, Wilson, Emmanuel, Eranki, Avinash, Kim, Peter, Lübke, Dennis, Huber, Peter, Georgii, Joachim, Dresky, Caroline V., Haller, Julian, Yarmolenko, Pavel, Sharma, Karun, Celik, Haydar, Li, Guofeng, Qiu, Weibao, Zheng, Hairong, Tsai, Meng-Yen, Chu, Po-Chun, Webb, Taylor, Vyas, Urvi, Walker, Matthew, Zhong, Jidan, Waspe, Adam C., Hodaie, Mojgan, Yang, Feng-Yi, Huang, Sin-Luo, Zur, Yuval, Assif, Benny, Aurup, Christian, Kamimura, Hermes, Carneiro, Antonio A., Rothlübbers, Sven, Schwaab, Julia, Houston, Graeme, Azhari, Haim, Weiss, Noam, Sosna, Jacob, Goldberg, S. Nahum, Barrere, Victor, Jang, Kee W., Lewis, Bobbi, Wang, Xiaotong, Suomi, Visa, Edwards, David, Larrabee, Zahary, Hananel, Arik, Rafaely, Boaz, Debbiny, Rasha Elaimy, Dekel, Carmel Zeltser, Assa, Michael, Menikou, George, Mouratidis, Petros, Pineda-Pardo, José A., de Pedro, Marta Del Álamo, Martinez, Raul, Hernandez, Frida, Casas, Silvia, Oliver, Carlos, Pastor, Patricia, Vela, Lidia, Obeso, Jose, Greillier, Paul, Zorgani, Ali, Catheline, Stefan, Solovov, Vyacheslav, Vozdvizhenskiy, Michael O., Orlov, Andrew E., Wu, Chueh-Hung, Sun, Ming-Kuan, Shih, Tiffany T., Chen, Wen-Shiang, Prieur, Fabrice, Pillon, Arnaud, Cartron, Valerie, Cebe, Patrick, Chansard, Nathalie, Lafond, Maxime, Seya, Pauline Muleki, Bera, Jean-Christophe, Boissenot, Tanguy, Fattal, Elias, Bordat, Alexandre, Chacun, Helene, Guetin, Claire, Tsapis, Nicolas, Maruyama, Kazuo, Unga, Johan, Suzuki, Ryo, Fant, Cécile, Rogez, Bernadette, Afadzi, Mercy, Myhre, Ola Finneng, Vea, Siri, Bjørkøy, Astrid, Yemane, Petros Tesfamichael, van Wamel, Annemieke, Berg, Sigrid, Hansen, Rune, Angelsen, Bjørn, and Davies, Catharina

Subjects
Meeting Abstracts
Published
2017

9. Comparison of Single Spot and Volume Ultrasound Sonications for Efficient Nanoparticle Delivery to Glioblastoma Model in Rats

Author

Conti, Allegra, Gerstenmayer, Matthieu, Geffroy, Françoise, Tillement, Olivier, Lux, François, Mériaux, Sébastien, Larrat, Benoit, Rayet, Béatrice, Service NEUROSPIN (NEUROSPIN), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
[SPI.ACOU]Engineering Sciences [physics]/Acoustics [physics.class-ph], [SPI.ACOU] Engineering Sciences [physics]/Acoustics [physics.class-ph], [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Settore FIS/07, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Background, Motivation and ObjectiveBrain tumors therapy is limited by the Blood-Tumor Barrier (BTB) and Blood-Brain Barrier (BBB), still intact in the infiltrative areas. Low intensity Focused Ultrasound (FUS) in conjunction with microbubbles is the only method allowing the local disruption of the BTB/BBB [Hynynen et al. 2001, Zhao et al. 2015]. Proper study of the influence of acousticscanning parameters (duty cycle, number of focal spots) on the amount of delivered nanoparticles is not available so far. Here, we compared two acoustic strategies to enhance the molecular concentration within brain tumors. The efficacy of the two methods is evaluated on the basis of absolute concentrations of delivered MR-contrast agents (CA) and on theirrates of uptake/clearance by the tumors.Statement of Contribution/Methods9L tumors were implanted in both striatum of Fischer rats (n=8): one tumor was sonicated and the other one was used as a control. A MR-guided motorized FUS system [Magnin et al. 2016] was used to target only one of the two tumors. A single point sonication at the tumor core (n=3) and a sonication at 8 vertices of a 3D trajectory covering the whole tumorvolume (n=5) were compared. Frequency, duty cycle, sonication time and estimated peak negative pressure were kept constant respectively to 1.5 MHz, 3%, 120 s and 1.2 MPa. Microbubbles administration was followed by FUS application and by the intravenous injection of a Gd-based MR-CA (AGuIX). Gd uptake and clearance inside the tumors wasimaged by acquiring dynamic 3D T1-maps within 1 hour allowing to reconstruct absolute CA-maps in the whole brain [Marty et al. 2012]. Tumors were manually segmented on T2-weighted anatomical images co-registered to the CA-maps, in order to follow the CA concentration time courses in tumors.Results/DiscussionFigure 1 shows the results obtained with 1 and 8 points sonications. With both methods, higher CA concentrations are delivered to sonicated tumors respect to the control ones. The single spot sonication appears to be more efficient, independently of the tumor size although not very efficient in large tumors (B). Choice of acoustic trajectory has a huge impact on drug delivery efficacy and needs to be optimized to each configuration. It seems to affect more the uptake rate than the clearance rate of the pharmacokinetics of tumors.

Published
2017

13. Characterization of the diffusion process of different Gadolinium-based nanoparticles within the brain tissue after ultrasound induced Blood-Brain Barrier permeabilization

Author

Conti, Allegra, primary, Magnin, Remi, additional, Gerstenmayer, Matthieu, additional, Lux, Francois, additional, Tillement, Olivier, additional, Meriaux, Sebastien, additional, Della Penna, Stefania, additional, Romani, Gian Luca, additional, Dumont, Erik, additional, Le Bihan, Denis, additional, and Larrat, Benoit, additional

Published
2016
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14. International Society for Therapeutic Ultrasound Conference 2016: Tel Aviv, Israel. 14-18 March, 2016

Author

Fowlkes, Brian, Ghanouni, Pejman, Sanghvi, Narendra, Coussios, Constantin, Lyon, Paul C., Gray, Michael, Mannaris, Christophoros, Victor, Marie de Saint, Stride, Eleanor, Cleveland, Robin, Carlisle, Robert, Wu, Feng, Middleton, Mark, Gleeson, Fergus, Aubry, Jean-Franҫois, Pauly, Kim Butts, Moonen, Chrit, Vortman, Jacob, Sharabi, Shirley, Daniels, Dianne, Last, David, Guez, David, Levy, Yoav, Volovick, Alexander, Grinfeld, Javier, Rachmilevich, Itay, Amar, Talia, Zibly, Zion, Mardor, Yael, Harnof, Sagi, Plaksin, Michael, Weissler, Yoni, Shoham, Shy, Kimmel, Eitan, Naor, Omer, Farah, Nairouz, Paeng, Dong-Guk, Xu, Zhiyuan, Snell, John, Quigg, Anders H., Eames, Matthew, Jin, Changzhu, Everstine, Ashli C., Sheehan, Jason P., Lopes, Beatriz S., Kassell, Neal, Looi, Thomas, Khokhlova, Vera, Mougenot, Charles, Hynynen, Kullervo, Drake, James, Slayton, Michael, Amodei, Richard C., Compton, Keegan, McNelly, Ashley, Latt, Daniel, Kearney, John, Melodelima, David, Dupre, Aurelien, Chen, Yao, Perol, David, Vincenot, Jeremy, Chapelon, Jean-Yves, Rivoire, Michel, Guo, Wei, Ren, Guoxin, Shen, Guofeng, Neidrauer, Michael, Zubkov, Leonid, Weingarten, Michael S., Margolis, David J., Lewin, Peter A., McDannold, Nathan, Sutton, Jonathan, Vykhodtseva, Natalia, Livingstone, Margaret, Kobus, Thiele, Zhang, Yong-Zhi, Schwartz, Michael, Huang, Yuexi, Lipsman, Nir, Jain, Jennifer, Chapman, Martin, Sankar, Tejas, Lozano, Andres, Yeung, Robert, Damianou, Christakis, Papadopoulos, Nikolaos, Brokman, Omer, Zadicario, Eyal, Brenner, Ori, Castel, David, Wu, Shih-Ying, Grondin, Julien, Zheng, Wenlan, Heidmann, Marc, Karakatsani, Maria Eleni, Sánchez, Carlos J. Sierra, Ferrera, Vincent, Konofagou, Elisa E., Yiannakou, Marinos, Cho, HongSeok, Lee, Hwayoun, Han, Mun, Choi, Jong-Ryul, Lee, Taekwan, Ahn, Sanghyun, Chang, Yongmin, Park, Juyoung, Ellens, Nicholas, Partanen, Ari, Farahani, Keyvan, Airan, Raag, Carpentier, Alexandre, Canney, Michael, Vignot, Alexandre, Lafon, Cyril, Delattre, Jean-yves, Idbaih, Ahmed, Odéen, Henrik, Bolster, Bradley, Jeong, Eun Kee, Parker, Dennis L., Gaur, Pooja, Feng, Xue, Fielden, Samuel, Meyer, Craig, Werner, Beat, Grissom, William, Marx, Michael, Weber, Hans, Taviani, Valentina, Hargreaves, Brian, Tanaka, Jun, Kikuchi, Kentaro, Ishijima, Ayumu, Azuma, Takashi, Minamihata, Kosuke, Yamaguchi, Satoshi, Nagamune, Teruyuki, Sakuma, Ichiro, Takagi, Shu, Santin, Mathieu D., Marsac, Laurent, Maimbourg, Guillaume, Monfort, Morgane, Larrat, Benoit, François, Chantal, Lehéricy, Stéphane, Tanter, Mickael, Samiotaki, Gesthimani, Wang, Shutao, Acosta, Camilo, Feinberg, Eliza R., Kovacs, Zsofia I., Tu, Tsang-Wei, Papadakis, Georgios Z., Reid, William C., Hammoud, Dima A., Frank, Joseph A., Kovacs, Zsofia i., Kim, Saejeong, Jikaria, Neekita, Bresler, Michele, Qureshi, Farhan, Xia, Jingjing, Tsui, Po-Shiang, Liu, Hao-Li, Plata, Juan C., Sveinsson, Bragi, Salgaonkar, Vasant A., Adams, Matthew, Diederich, Chris, Ozhinsky, Eugene, Bucknor, Matthew D., Rieke, Viola, Mikhail, Andrew, Severance, Lauren, Negussie, Ayele H., Wood, Bradford, de Greef, Martijn, Schubert, Gerald, Ries, Mario, Poorman, Megan E., Dockery, Mary, Chaplin, Vandiver, Dudzinski, Stephanie O., Spears, Ryan, Caskey, Charles, Giorgio, Todd, Costa, Marcia M., Papaevangelou, Efthymia, Shah, Anant, Rivens, Ian, Box, Carol, Bamber, Jeff, ter Haar, Gail, Burks, Scott R., Nagle, Matthew, Nguyen, Ben, Milo, Blerta, Le, Nhan M., Song, Shaozhen, Zhou, Kanheng, Nabi, Ghulam, Huang, Zhihong, Ben-Ezra, Shmuel, Rosen, Shani, Mihcin, Senay, Strehlow, Jan, Karakitsios, Ioannis, Le, Nhan, Schwenke, Michael, Demedts, Daniel, Prentice, Paul, Haase, Sabrina, Preusser, Tobias, Melzer, Andreas, Mestas, Jean-Louis, Chettab, Kamel, Gomez, Gustavo Stadthagen, Dumontet, Charles, Werle, Bettina, Marquet, Fabrice, Bour, Pierre, Vaillant, Fanny, Amraoui, Sana, Dubois, Rémi, Ritter, Philippe, Haïssaguerre, Michel, Hocini, Mélèze, Bernus, Olivier, Quesson, Bruno, Livneh, Amit, Adam, Dan, Robin, Justine, Arnal, Bastien, Fink, Mathias, Pernot, Mathieu, Khokhlova, Tatiana D., Schade, George R., Wang, Yak-Nam, Kreider, Wayne, Simon, Julianna, Starr, Frank, Karzova, Maria, Maxwell, Adam, Bailey, Michael R., Lundt, Jonathan E., Allen, Steven P., Sukovich, Jonathan R., Hall, Timothy, Xu, Zhen, May, Philip, Lin, Daniel W., Constans, Charlotte, Deffieux, Thomas, Aubry, Jean-Francois, Park, Eun-Joo, Ahn, Yun Deok, Kang, Soo Yeon, Park, Dong-Hyuk, Lee, Jae Young, Vidal-Jove, J., Perich, E., Ruiz, A., Jaen, A., Eres, N., del Castillo, M. Alvarez, Myers, Rachel, Kwan, James, Coviello, Christian, Rowe, Cliff, Crake, Calum, Finn, Sean, Jackson, Edward, Pouliopoulos, Antonios, Li, Caiqin, Tinguely, Marc, Tang, Meng-Xing, Garbin, Valeria, Choi, James J., Folkes, Lisa, Stratford, Michael, Nwokeoha, Sandra, Li, Tong, Farr, Navid, D’Andrea, Samantha, Gravelle, Kayla, Chen, Hong, Lee, Donghoon, Hwang, Joo Ha, Tardoski, Sophie, Ngo, Jacqueline, Gineyts, Evelyne, Roux, Jean-Pau, Clézardin, Philippe, Conti, Allegra, Magnin, Rémi, Gerstenmayer, Matthieu, Lux, François, Tillement, Olivier, Mériaux, Sébastien, Penna, Stefania Della, Romani, Gian Luca, Dumont, Erik, Sun, Tao, Power, Chanikarn, Miller, Eric, Sapozhnikov, Oleg, Tsysar, Sergey, Yuldashev, Petr V., Svet, Victor, Li, Dongli, Pellegrino, Antonio, Petrinic, Nik, Siviour, Clive, Jerusalem, Antoine, Yuldashev, Peter V., Cunitz, Bryan W., Dunmire, Barbrina, Inserra, Claude, Guedra, Matthieu, Mauger, Cyril, Gilles, Bruno, Solovchuk, Maxim, Sheu, Tony W. H., Thiriet, Marc, Zhou, Yufeng, Neufeld, Esra, Baumgartner, Christian, Payne, Davnah, Kyriakou, Adamos, Kuster, Niels, Xiao, Xu, McLeod, Helen, Dillon, Christopher, Payne, Allison, Khokhova, Vera A., Sinilshchikov, Ilya, Andriyakhina, Yulia, Rybyanets, Andrey, Shvetsova, Natalia, Berkovich, Alex, Shvetsov, Igor, Shaw, Caroline J., Civale, John, Giussani, Dino, Lees, Christoph, Ozenne, Valery, Toupin, Solenn, Salgaonkar, Vasant, Kaye, Elena, Monette, Sebastien, Maybody, Majid, Srimathveeravalli, Govindarajan, Solomon, Stephen, Gulati, Amitabh, Bezzi, Mario, Jenne, Jürgen W., Lango, Thomas, Müller, Michael, Sat, Giora, Tanner, Christine, Zangos, Stephan, Günther, Matthias, Dinh, Au Hoang, Niaf, Emilie, Bratan, Flavie, Guillen, Nicolas, Souchon, Rémi, Lartizien, Carole, Crouzet, Sebastien, Rouviere, Olivier, Han, Yang, Payen, Thomas, Palermo, Carmine, Sastra, Steve, Olive, Kenneth, van Breugel, Johanna M., van den Bosch, Maurice A., Fellah, Benjamin, Le Bihan, Denis, Hernandez-Garcia, Luis, Cain, Charles A., Lyka, Erasmia, Elbes, Delphine, Li, Chunhui, Tamano, Satoshi, Jimbo, Hayato, Yoshizawa, Shin, Fujiwara, Keisuke, Itani, Kazunori, Umemura, Shin-ichiro, Stoianovici, Dan, Zaini, Zulfadhli, Takagi, Ryo, Zong, Shenyan, Watkins, Ron, Pascal-Tenorio, Aurea, Jones, Peter, Butts-Pauly, Kim, Bouley, Donna, Chen, Yazhu, Lin, Chung-Yin, Hsieh, Han-Yi, Wei, Kuo-Chen, Garnier, Camille, Renault, Gilles, Seifabadi, Reza, Wilson, Emmanuel, Eranki, Avinash, Kim, Peter, Lübke, Dennis, Huber, Peter, Georgii, Joachim, Dresky, Caroline V., Haller, Julian, Yarmolenko, Pavel, Sharma, Karun, Celik, Haydar, Li, Guofeng, Qiu, Weibao, Zheng, Hairong, Tsai, Meng-Yen, Chu, Po-Chun, Webb, Taylor, Vyas, Urvi, Walker, Matthew, Zhong, Jidan, Waspe, Adam C., Hodaie, Mojgan, Yang, Feng-Yi, Huang, Sin-Luo, Zur, Yuval, Assif, Benny, Aurup, Christian, Kamimura, Hermes, Carneiro, Antonio A., Rothlübbers, Sven, Schwaab, Julia, Houston, Graeme, Azhari, Haim, Weiss, Noam, Sosna, Jacob, Goldberg, S. Nahum, Barrere, Victor, Jang, Kee W., Lewis, Bobbi, Wang, Xiaotong, Suomi, Visa, Edwards, David, Larrabee, Zahary, Hananel, Arik, Rafaely, Boaz, Debbiny, Rasha Elaimy, Dekel, Carmel Zeltser, Assa, Michael, Menikou, George, Mouratidis, Petros, Pineda-Pardo, José A., de Pedro, Marta Del Álamo, Martinez, Raul, Hernandez, Frida, Casas, Silvia, Oliver, Carlos, Pastor, Patricia, Vela, Lidia, Obeso, Jose, Greillier, Paul, Zorgani, Ali, Catheline, Stefan, Solovov, Vyacheslav, Vozdvizhenskiy, Michael O., Orlov, Andrew E., Wu, Chueh-Hung, Sun, Ming-Kuan, Shih, Tiffany T., Chen, Wen-Shiang, Prieur, Fabrice, Pillon, Arnaud, Cartron, Valerie, Cebe, Patrick, Chansard, Nathalie, Lafond, Maxime, Seya, Pauline Muleki, Bera, Jean-Christophe, Boissenot, Tanguy, Fattal, Elias, Bordat, Alexandre, Chacun, Helene, Guetin, Claire, Tsapis, Nicolas, Maruyama, Kazuo, Unga, Johan, Suzuki, Ryo, Fant, Cécile, Rogez, Bernadette, Afadzi, Mercy, Myhre, Ola Finneng, Vea, Siri, Bjørkøy, Astrid, Yemane, Petros Tesfamichael, van Wamel, Annemieke, Berg, Sigrid, Hansen, Rune, Angelsen, Bjørn, and Davies, Catharina

Published
2017
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15. Empirical and Theoretical Characterization of the Diffusion Process of Different Gadolinium-Based Nanoparticles within the Brain Tissue after Ultrasound-Induced Permeabilization of the Blood-Brain Barrier.

Author

Conti A, Magnin R, Gerstenmayer M, Tsapis N, Dumont E, Tillement O, Lux F, Le Bihan D, Mériaux S, Della Penna S, and Larrat B

Subjects
Algorithms, Animals, Blood-Brain Barrier radiation effects, Corpus Striatum metabolism, Diffusion, Extracellular Space, Male, Meglumine pharmacokinetics, Particle Size, Phantoms, Imaging, Rats, Rats, Sprague-Dawley, Blood-Brain Barrier diagnostic imaging, Capillary Permeability, Contrast Media pharmacokinetics, Corpus Striatum diagnostic imaging, Heterocyclic Compounds pharmacokinetics, Meglumine analogs & derivatives, Microbubbles, Nanoconjugates chemistry, Organometallic Compounds pharmacokinetics, Phospholipids pharmacokinetics, Sulfur Hexafluoride pharmacokinetics, Ultrasonic Waves
Abstract

Low-intensity focused ultrasound (FUS), combined with microbubbles, is able to locally, and noninvasively, open the blood-brain barrier (BBB), allowing nanoparticles to enter the brain. We present here a study on the diffusion process of gadolinium-based MRI contrast agents within the brain extracellular space after ultrasound-induced BBB permeabilization. Three compounds were tested (MultiHance, Gadovist, and Dotarem). We characterized their diffusion through in vivo experimental tests supported by theoretical models. Specifically, by estimation of the free diffusion coefficients from in vitro studies and of apparent diffusion coefficients from in vivo experiments, we have assessed tortuosity in the right striatum of 9 Sprague Dawley rats through a model correctly describing both vascular permeability as a function of time and diffusion processes occurring in the brain tissue. This model takes into account acoustic pressure, particle size, blood pharmacokinetics, and diffusion rates. Our model is able to fully predict the result of a FUS-induced BBB opening experiment at long space and time scales. Recovered values of tortuosity are in agreement with the literature and demonstrate that our improved model allows us to assess that the chosen permeabilization protocol preserves the integrity of the brain tissue., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2019 Allegra Conti et al.)

Published
2019
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