Journal Article

Temporary blood–brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma

Carpentier, Alexandre, Canney, Michael, Goli, Larissa, Bouchoux, Guillaume, Idbaih, Ahmed, Schmitt, Charlotte, Sottilini, Frédéric, Bouzidi, Amira, Sanson, Marc, Guehennec, Jeremy, Lemaire, Nolwenn, Verreault, Maïté, Delattre, Jean-Yves, Mokhtari, Karima, Goldwirt, Lauriane, Dréan, Antonin

2019

Overview

Introduction Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Few cytotoxic chemotherapies have been shown to be effective against GBM, due in part to the presence of the blood–brain barrier (BBB), which reduces the penetration of chemotherapies from the blood to the brain. Ultrasound-induced BBB opening (US-BBB) has been shown to increase the penetration of multiple chemotherapeutic agents in the brain in animal models. In the current study, the anti-tumor activity of carboplatin chemotherapy with and without US-BBB was investigated in several GBM mouse models. Methods First, the IC50 of two commercial (U87 and U251) and six patient-derived GBM cell lines (PDCL) to carboplatin was measured. Next, U87 was subcutaneously grafted to a nude mouse model to test the in vivo response of the tumor to carboplatin in the absence of the BBB. Lastly, nude mice bearing orthotopically xenografted GBM cell lines (U87 or a PDCL) were randomized to four experimental groups: (i) untreated, (ii) US-BBB alone, (iii) carboplatin alone and, (iv) carboplatin + US-BBB. Mice were treated once weekly for 4 weeks and monitored for toxicity, tumor growth, and survival. Results Carboplatin plus US-BBB enhanced survival (p = 0.03) and delayed tumor growth (p < 0.05) of GBM-bearing mice compared to carboplatin alone, with a 4.2-fold increase of carboplatin penetration in the brain, without evidence of significant neurological or systemic toxicity. Conclusions Carboplatin efficacy was enhanced in GBM mouse models with US-BBB and appears to be a promising chemotherapy for this approach.

• Publisher: Springer US,Springer Nature B.V,Springer Verlag
• Subject: Animal models / Animals / Antineoplastic Agents - pharmacokinetics / Antineoplastic Agents - pharmacology / Antitumor agents / Apoptosis / Blood-brain barrier / Blood-Brain Barrier - drug effects / Blood-Brain Barrier - metabolism / Blood-Brain Barrier - radiation effects / Brain cancer / Brain Neoplasms - drug therapy / Brain Neoplasms - metabolism / Brain Neoplasms - pathology / Cancer / Carboplatin / Carboplatin - pharmacokinetics / Carboplatin - pharmacology / Cell Proliferation / Chemotherapy / Cytotoxicity / Disease Models, Animal / Female / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - metabolism / Glioblastoma - pathology / Humans / Laboratory Investigation / Life Sciences / Medicine / Medicine & Public Health / Mice / Mice, Nude / Neurobiology / Neurology / Neurons and Cognition / Oncology / Pharmaceutical sciences / Pharmacology / Tissue Distribution / Tumor Cells, Cultured / Ultrasonic imaging / Ultrasonic Waves / Ultrasound / Xenograft Model Antitumor Assays / Xenografts