Low-boiling-point perfluorocarbon nanodroplets for adaptable ultrasound-induced blood-brain barrier opening.

Low-boiling point perfluorocarbon nanodroplets (NDs) are valued as effective sonosensitive agents, encapsulating a liquid perfluorocarbon that would instantaneously vaporize at body temperature without the NDs shell. Those NDs have been explored for both therapeutic and diagnostic purposes. Here, phospholipid-shelled nanodroplets containing octafluoropropane (CF) or decafluorobutane (CF) formed by condensation of microbubbles were thoroughly characterized before blood-brain (BBB) permeabilization.

Magnetic resonance cavitation imaging for the monitoring of ultrasound therapies.

Focused ultrasound (FUS) is a promising non-invasive therapeutic approach that can be used to generate thermal and non-thermal bioeffects. Several non-thermal FUS therapies rely on FUS-induced oscillations of microbubbles (MBs), a phenomenon referred to as cavitation. Cavitation monitoring in real time is essential to ensure both the efficacy and the safety of FUS therapies.

CMUT for ultrafast passive cavitation detection during ultrasound-induced blood-brain barrier disruption: proof of concept study.

Cavitation dose monitoring plays a key role in ultrasound drug delivery to the brain. The use of capacitive micromachined ultrasonic transducer (CMUT) technology has a great potential for passive cavitation detection (PCD).Here, a circular (diameter 7 mm) CMUT centered at 5 MHz was designed to be inserted into a therapeutic transducer (1.

Efficient PD-L1 imaging of murine glioblastoma with FUS-aided immunoPET by leveraging FcRn-antibody interaction.

The passage of antibodies through the blood-brain barrier (BBB) and the blood-tumoral barrier (BTB) is determinant not only to increase the immune checkpoint inhibitors efficacy but also to monitor prognostic and predictive biomarkers such as the programmed death ligand 1 (PD-L1) via immunoPET. Although the involvement of neonatal Fc receptor (FcRn) in antibody distribution has been demonstrated, its function at the BBB remains controversial, while it is unknown at the BTB. In this context, we assessed FcRn's role by pharmacokinetic immunoPET imaging combined with focused ultrasounds (FUS) using unmodified and FcRn low-affinity IgGs targeting PD-L1 in a preclinical orthotopic glioblastoma model.

Anticancer drug delivery by focused ultrasound-mediated blood-brain/tumor barrier disruption for glioma therapy: From benchside to bedside.

The therapeutic management of gliomas remains particularly challenging. Brain tumors present multiple obstacles that make therapeutic innovation complex, mainly due to the presence of blood-tumor and blood-brain barriers (BTB and BBB, respectively) which prevent penetration of anticancer agents into the brain parenchyma. Focused ultrasound-mediated BBB disruption (FUS-BBBD) provides a physical method for non-invasive, local, and reversible BBB disruption.

Imaging the impact of blood-brain barrier disruption induced by focused ultrasound on P-glycoprotein function.

The P-glycoprotein (P-gp/ABCB1) is a major efflux transporter which impedes the brain delivery of many drugs across the blood-brain barrier (BBB). Focused ultrasound with microbubbles (FUS) enables BBB disruption, which immediate and delayed impact on P-gp function remains unclear. Positron emission tomography (PET) imaging using the radiolabeled substrate [C]metoclopramide provides a sensitive and translational method to study P-gp function at the living BBB.

Sonoporation-assisted micelle delivery in subcutaneous glioma-bearing mice evaluated by PET/fluorescent bi-modal imaging.

Tumor-specific drug delivery is a major challenge for the pharmaceutical industry. Nanocarrier systems have been widely investigated to increase and control drug delivery to the heterogeneous tumor microenvironment. Classically, the uptake of nanocarriers by solid tumor tissues is mainly mediated by the enhanced permeability and retention effect (EPR).

PLA2G12A as a Novel Biomarker for Colorectal Cancer with Prognostic Relevance.

Metastasis is the leading cause of colorectal cancer (CRC)-related deaths. Therefore, the identification of accurate biomarkers predictive of metastasis is needed to better stratify high-risk patients to provide preferred management and reduce mortality. In this study, we identified 13 new genes that modified circulating tumor cell numbers using a genome-wide genetic screen in a whole animal CRC model.

State of the art on microbubble cavitation monitoring and feedback control for blood-brain-barrier opening using focused ultrasound.

Focused ultrasound (FUS) is a non-invasive and highly promising method for targeted and reversible blood-brain barrier permeabilization. Numerous preclinical studies aim to optimize the localized delivery of drugs using this method in rodents and non-human primates. Several clinical trials have been initiated to treat various brain diseases in humans using simultaneous BBB permeabilization and drug injection.

Regulation of P-glycoprotein and Breast Cancer Resistance Protein Expression Induced by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption: A Pilot Study.

The blood-brain barrier (BBB) controls brain homeostasis; it is formed by vascular endothelial cells that are physically connected by tight junctions (TJs). The BBB expresses efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which limit the passage of substrate molecules from blood circulation to the brain. Focused ultrasound (FUS) with microbubbles can create a local and reversible detachment of the TJs.

Refining the delivery and therapeutic efficacy of cetuximab using focused ultrasound in a mouse model of glioblastoma: An Zr-cetuximab immunoPET study.

Introduction: Glioblastoma (GBM) is the most common and deadly form of primary brain tumor. Between 30 % and 60 % of GBM are characterized by overexpression of the Epidermal Growth Factor Receptor (EGFR). The anti-EGFR antibody Cetuximab (CTX) showed a favorable effect for EGFR colorectal cancer but failed to demonstrate efficacy for GBM.

Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model.

Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically.

Perfluorocarbon Nanodroplets as Potential Nanocarriers for Brain Delivery Assisted by Focused Ultrasound-Mediated Blood-Brain Barrier Disruption.

The management of brain diseases remains a challenge, particularly because of the difficulty for drugs to cross the blood-brain barrier. Among strategies developed to improve drug delivery, nano-sized emulsions (i.e.

[F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound.

Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood-brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [F]2-fluoro-2-deoxy-sorbitol ([F]FDS) was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity.

Ultrasound-Mediated Blood-Brain Barrier Opening Improves Whole Brain Gene Delivery in Mice.

Gene therapy represents a powerful therapeutic tool to treat diseased tissues and provide a durable and effective correction. The central nervous system (CNS) is the target of many gene therapy protocols, but its high complexity makes it one of the most difficult organs to reach, in part due to the blood-brain barrier that protects it from external threats. Focused ultrasound (FUS) coupled with microbubbles appears as a technological breakthrough to deliver therapeutic agents into the CNS.

Development of a multi-functional preclinical device for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) is one of the most common and aggressive malignant primary brain tumors in adults. The treatment of GBM is limited by the blood-brain barrier (BBB), which limits the diffusion of appropriate concentrations of therapeutic agents at the tumor site. Among experimental therapies, photo-thermal therapy (PTT) mediated by nanoparticles is a promising strategy.

Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound.

The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies.

Prognostic Factors Involved in the Epithelial-Mesenchymal Transition Process in Colorectal Cancer Have a Preponderant Role in Oxidative Stress: A Systematic Review and Meta-Analysis.

Epithelial-to-mesenchymal transition (EMT) is one of the most accepted mechanisms leading to metastasis, which is responsible for most of the cancer-related deaths. In order to identify EMT-related biomarkers able to predict clinical outcomes in colorectal cancer (CRC), a systematic review and meta-analysis of prognostic factors associated to overall survival (OS) and progression free survival (PFS) was conducted. The systematic literature search included studies from June 2014 to June 2019 available at PubMed and Scopus databases.

Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: An immunoPET study using Zr-cetuximab.

Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas.

A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures.

Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. The real-time control of the ultrasound dose delivered through the skull is necessary as the range of pressure for efficient and safe BBB opening is very narrow. Passive cavitation detection (PCD) is a method proposed to monitor the microbubble activity during ultrasound exposure.

Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [Tc]mebrofenin Imaging in Rats.

The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [Tc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [Tc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system.

Enhancing Nab-Paclitaxel Delivery Using Microbubble-Assisted Ultrasound in a Pancreatic Cancer Model.

A combination of microbubbles (MBs) and ultrasound (US) is an emerging method for noninvasive and targeted enhancement of anti-cancer drug uptake. This method showed an increase local drug extravasation in tumor tissue while reducing the systemic adverse effects in various tumor models. The present study aims to evaluate the effectiveness of this approach for Nab-paclitaxel delivery in a pancreatic tumor model.

Quantitative Ultrasound in Ex Vivo Fibrotic Rabbit Livers.

Liver fibrosis is the common result of chronic liver disease. Diagnosis and grading liver fibrosis for patient management is mainly based on blood tests and hepatic puncture-biopsy, which is particularly invasive. Quantitative ultrasound (QUS) techniques provide insight into tissue microstructure and are based on the frequency-based analysis of the signals from biologic tissues.

Ultrasound-Stimulated Phase-Change Contrast Agents for Transepithelial Delivery of Macromolecules, Toward Gastrointestinal Drug Delivery.

The gastrointestinal (GI) tract presents a notoriously difficult barrier for macromolecular drug delivery, especially for biologics. Herein, we demonstrate that ultrasound-stimulated phase change contrast agents (PCCAs) can transiently disrupt confluent colorectal adenocarcinoma monolayers and improve the transepithelial transport of a macromolecular model drug. With ultrasound treatment in the presence of PCCAs, we achieved a maximum of 44 ± 15% transepithelial delivery of 70-kDa fluorescein isothiocyanate-dextran, compared with negligible delivery through sham control monolayers.