title: Combined local blood-brain barrier opening and systemic methotrexate for the treatment of brain tumors.
abstract: Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood-brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)-HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA-HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA-HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.
authors: 1] The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel [3] School of Psychology, Interdisciplinary Center (IDC), Herzliya, Israel.
authors: Itzik
authors: I
authors: Cooper
authors: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: David
authors: D
authors: Last
authors: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: David
authors: D
authors: Guez
authors: 1] The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Shirley
authors: S
authors: Sharabi
authors: The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Shirin
authors: S
authors: Elhaik Goldman
authors: The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Irit
authors: I
authors: Lubitz
authors: 1] The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Dianne
authors: D
authors: Daniels
authors: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Sharona
authors: S
authors: Salomon
authors: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Gregory
authors: G
authors: Tamar
authors: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Tzur
authors: T
authors: Tamir
authors: The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel.
authors: Ronni
authors: R
authors: Mardor
authors: Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors: Mati
authors: M
authors: Fridkin
authors: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors: Yoram
authors: Y
authors: Shechter
authors: 1] The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel [2] Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors: Yael
authors: Y
authors: Mardor
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002460:Cell Line; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D005021:Ethylamines / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D012709:Serum Albumin / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry; D013552:Swine
chemical_list: D000964:Antimetabolites, Antineoplastic; D005021:Ethylamines; D012709:Serum Albumin; C041564:ethylamine; D008727:Methotrexate