title: Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models.
abstract: Glioblastoma multiforme (GBM) is the most common and most aggressive malignant primary brain tumor in humans with a very poor prognosis. Chemotherapeutical treatment of GBMs is limited by the blood-brain barrier (BBB). This physical and metabolic barrier separates the blood from the brain parenchyma and prevents the entry of toxins but also of potentially useful chemotherapeutics from the blood into the brain. Microbubble-enhanced focused ultrasound (MB-FUS) has been proposed to disrupt locally and reversibly the BBB to facilitate diffusion of drugs from the micro vasculature into brain tissue. The present study investigates the feasibility and the safety of such an approach in two syngenic mouse models of GBM (GL261 and SMA-560). Local doxorubicin (DOX) concentration in MB-FUS sonicated normal brain tissue as well as in brain tumor tissue was increased as compared to the unsonicated control tissue in the contralateral hemisphere. Moreover, ultrasound mediated BBB disruption, in combination with DOX therapy, resulted in a significant increase of survival and in a slower disease progression in the two syngenic GBM mouse models. In conclusion, our results confirm that MB-ultrasound might ultimately be an effective technology to improve the therapy of GBM, and they provide for the first time evidence that combining MB-FUS with DOX treatment is effective in syngenic mouse models for GBM which can serve as preclinical models to study the impact of immune system on the therapeutic application of MB-FUS chemotherapy.
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Zurich, Switzerland; Oncology Department, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kovacs
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Werner
authors.affiliation: Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Anahita
authors.initials: A
authors.lastname: Rassi
authors.affiliation: Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.affiliation: Center for MR-Research, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors.forename: Ernst
authors.initials: E
authors.lastname: Martin-Fiori
authors.affiliation: Oncology Department, University Children's Hospital Zurich, Zurich, Switzerland; Experimental Infectious Diseases and Cancer Research, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland. Electronic address: michele.bernasconi@kispi.uzh.ch.
authors.forename: Michele
authors.initials: M
authors.lastname: Bernasconi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D045423:Microbubbles; D013010:Sonication
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
keywords: Blood–brain barrier; Focused ultrasound; Glioblastoma; Micro bubbles; Syngenic mouse cancer models