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

Abstract

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. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD2 PET/CT imaging and post-mortem histological analysis, showing that tumor growth was not influenced by FUS. In conclusion, molecular imaging can be used to evaluate the time frame for systemic treatment combined with transient BBB opening and to test its efficacy over time.

Systemic and local immune responses to glioblastoma surgery help tailoring combinatory regimens

“…[99mTc]Tc-DTPA was administered via an intravenous injection of 50 µL of radioactive tracer (30 MBq) in isotonic and pyrogen-free solution using an insulin syringe (27G) 34 . Thirty minutes after injection, the SPECT/CT acquisition was done for 20 min under anesthesia with 1.5% vol% iso urane (IsoVet®, Laboratoire Osalia, Paris, France) using a NanoSPECT/CTplus® camera and the Nucline® 1.02 acquisition software (Mediso Medical Imaging System Ltd., Budapest, Hungary).…”

“…Multiparametric ow cytometry was used for immunophenotypic analysis of blood to evaluate the systemic immune landscape following surgery. Single-Photon Emission Computed Tomography (SPECT) imaging was performed post-surgery to evaluate BBB permeability via [99mTc]Tc-DTPA SPECT/CT 33 . Biphotonic imaging was used to unravel the complexity of the SMe at identi ed time frames, the morphology, spatial organization, and interaction of the immune cells around the resection cavity.…”

Non-Invasive Device-Mediated Drug Delivery to the Brain across the Blood–Brain Barrier

“…A variety of nanoparticles can be effectively evaluated through this system. Marie-Anne Estève demonstrates the transportation of imaging compounds into the brain through transient FUS-mediated BBB opening performed on healthy animals [ 50 ]. CNS imaging is increasingly recognized for its vital role in preventive medicine for neurodegenerative diseases such as AD in an aging society [ 51 ].…”