Blood-brain barrier disruption with focused ultrasound enhances delivery of dopamine transporter tracer (PE2I) into the brain

International audiencePE2I is one of the most selective ligands for dopamine transporter. However it is associated with blood-brain barrier (BBB) permeability limitations. The aim of this study was to investigate the use of ultrasound and microbubbles to increase its delivery through the BBB and by determining the optimal experimental conditions that achieve a transient and safe BBB disruption. First, we stablished the ultrasound conditions that achieved a transient BBB disruption in rats using a non-permeant marker, Evans blue. Hence SonoVue® (450μL/kg) and Evans blue (100mg/kg) were intravenously administered. BBB leakage was obtained using ultrasound insonation through the rat skull at 1.6MPa, PRF 1Hz, duty cycle 1%, burst 10ms during 120sec. BBB disruption was observed in all treated animals (N=4) by histological analysis. The same experimental conditions were applied to enhance brain uptake of PE2I. Biological samples were analyzed using a scintillation counter apparatus. The results showed 50% and 20% increase of 125I-PE2I uptake in the striatum and cerebral cortex, respectively, in the treated rats (N=5) versus control (N=4). Similar enhancements were observed using SonoVue® at half concentration. This innovative method provides a great potential for intracerebral delivery of molecular ligands that could be used for the therapy of brain diseases

Doxorubicin-liposomes loaded microbubbles for ultrasound-triggered doxorubicin delivery

International audienceDoxorubicin (Dox) is a potent chemotherapeutic whose severe side effects limit its clinical efficacy. Microbubble-assisted ultrasound has become a promising strategy for non-invasive local drug delivery to increase the drug concentration locally and to reduce systemic side effects. The aim of this study is to evaluate the effectiveness of administration of Dox-liposomes loaded on MB combined with ultrasound in human glioblastoma cells. Experiments were carried out with free Dox or Dox-loaded MBs on a cell suspension of U-87MG cells. Ultrasound waves were transmitted at 1MHz frequency with a pulse repetition period of 100µs, 40 cycles per pulse and for 30s. Cell viability was evaluated by Trypan blue assay 24h and 48h later. Using Dox alone, the cell viability was 63±3% and 26±2% at 24h and 48h later, respectively. The combination of ultrasound at 600 kPa and Dox-loaded MBs induced a 2.5-fold decrease of cell viability compared to the incubation of Dox-loaded MBs alone at 24h and 48h after treatment, respectively. At 24h, this combination was 3 times more efficient than the doxorubicin treatment alone. The conclusions drawn from this study show the potential of this strategy for a controlled, efficient, and safe drug delivery. Project funded by the EU Project SONODRUGS (NMP4-LA-2008-213706)

Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood–brain and blood–spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Mémoires reconfigurables à accès aléatoire et à semi-conducteurs

Universités : Université scientifique et médicale de Grenoble et Institut national polytechnique de Grenobl

From concept to early clinical trials: 30 years of microbubble-based ultrasound-mediated drug delivery research

International audienceUltrasound mediated drug delivery, a promising therapeutic modality, has evolved remarkably over the past three decades. Initially designed to enhance contrast in ultrasound imaging, microbubbles have emerged as a main vector for drug delivery, offering targeted therapy with minimized side effects. This review addresses the historical progression of this technology, emphasizing the pivotal role microbubbles play in augmenting drug extravasation and targeted delivery. We explore the complex mechanisms behind this technology, from stable and inertial cavitation to diverse acoustic phenomena, and their applications in medical fields. While the potential of ultrasound mediated drug delivery is undeniable, there are still challenges to overcome. Balancing therapeutic efficacy and safety and establishing standardized procedures are essential areas requiring attention. A multidisciplinary approach, gathering collaborations between researchers, engineers, and clinicians, is important for exploiting the full potential of this technology. In summary, this review highlights the potential of using ultrasound mediated drug delivery in improving patient care across various medical conditions

Therapeutic Ultrasound

International audienc

Software and Protocols in Rebus. A Distributed Real-Time Control System

International audienceREBUS is a robust and fault tolerant cooperation system for a local real time control microcomputer network. It is being developed at the LAAS in connexion with the industrial real time control system MODUMAT 800 of SCHLUMBERGER-EUROPE. Based on a general hardware architecture, the design of REBUS emphasizes, the aspects of cooperation and fault tolerance as required in local real time control networks and it is primarly concerned with the problems of specification, validation and implementation of some standard and specificic protocols. After a short presentation of the hardware architecture, the various software levels are described ; they include the operating system kernel of the processors, the line, network and transport layers, and the remote call mechanism. Finally, a tool, the observer, developed for protocol debugging and measure purposes is also presented

Second Harmonic and Subharmonic for Non-Linear Wideband Contrast Imaging Using a Capacitive Micromachined Ultrasonic Transducer Array

International audienc

Ultrastructural sonoporation bio-effects: Comparative study on two human cancer cell lines

Sonoporation increases transiently the cell membrane permeability, enabling the therapeutic compounds internalization into the cells. Several investigations reported heterogeneities in the permeabilization and transfection efficacy depending on the ultrasound (US) settings and cell type. Here, we compare the sonoporation effects on two human cell lines, glioblastoma and breast cancer using scanning electron microscopy (SEM). Adherent U-87 MG and MDA-MB-231 cells were insonated at 1 W/cm 2 , during 60 s at 10% or 20% duty cycle, in the presence of BR14 ® microbubbles, added at a microbubble-cell ratio of 5. SYTOX ® Green, a non-permeant fluorescent dye was used at 1µM, to quantify the membrane permeabilization using flow cytometry. The ultrastructural changes of the cell membrane morphology were monitored by SEM. Flow cytometry results show that the percentage of permeabilized U-87 MG cells reaches 60%, while this value doesn't exceed 40% for MDA-MB-231 cells. These results indicate that the percentage of permeabilized cells depends on the cell type. SEM observations were carried out to elucidate the differences in permeabilization rate between the two cell lines. The SEM analysis reveals that control cells show regular plasma membrane morphology. Their insonation in the presence of BR14 ® induce the formation of dark holes on their membrane surfaces (named here pore-like structures). However, the quantitative analysis of the SEM micrographs highlights noticeable differences in morphological changes postsonoporation between the two cell lines. Thus, the mean number of pore-like structures is more abundant on U-87 MG cell membrane than on MDA-MB-231 cell membrane (645 vs. 290). In addition, the mean size of pore-like structures depends on the cell line. Indeed, the mean size on MDA-MB-231 cells was 40 ± 1.2 nm (30-60 nm) while this value reached 80 ± 0.9 nm (10 to 160 nm) for U-87 MG cells. In conclusion, the study confirms that the pore-like structures observed post sonoporation are directly associated to the cell permeabilization rate. Moreover, the observed differences in the permeabilization levels between both cell lines could be attributed to the differences in the number and size of pore-like structures that were seen on the cell membrane. This difference may be due to the fibroblastic nature of the U-87 MG cells in comparison to MDA-MB-231 cells