title: Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma.
abstract: The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the efficacy of chemotherapy. We report a new anti-invasive small molecule, Imipramine Blue (IB), which inhibits invasion of glioma in vitro when tested against several models. IB inhibits NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-mediated reactive oxygen species generation and alters expression of actin regulatory elements. In vivo, liposomal IB (nano-IB) halts invasion of glioma, leading to a more compact tumor in an aggressively invasive RT2 syngeneic astrocytoma rodent model. When nano-IB therapy was followed by liposomal doxorubicin (nano-DXR) chemotherapy, the combination therapy prolonged survival compared to nano-IB or nano-DXR alone. Our data demonstrate that nano-IB-mediated containment of diffuse glioma enhanced the efficacy of nano-DXR chemotherapy, demonstrating the promise of an anti-invasive compound as an adjuvant treatment for glioma.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Munson
authors.forename: Levi
authors.initials: L
authors.lastname: Fried
authors.forename: Sydney A
authors.initials: SA
authors.lastname: Rowson
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Bonner
authors.forename: Lohitash
authors.initials: L
authors.lastname: Karumbaiah
authors.forename: Begoña
authors.initials: B
authors.lastname: Diaz
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
authors.forename: Ulla G
authors.initials: UG
authors.lastname: Knaus
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.forename: Jack L
authors.initials: JL
authors.lastname: Arbiser
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Bellamkonda
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017024:Chemotherapy, Adjuvant; D004317:Doxorubicin / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D007099:Imipramine / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008081:Liposomes / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry; D009361:Neoplasm Invasiveness; D051381:Rats; D016896:Treatment Outcome
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin; D007099:Imipramine