title: Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor.
abstract: In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Yang
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Taigen
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: b Department of Neurological Surgery , University of California San Francisco , San Francisco , California , USA.
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.affiliation: b Department of Neurological Surgery , University of California San Francisco , San Francisco , California , USA.
authors.forename: Krystof
authors.initials: K
authors.lastname: Bankiewicz
authors.affiliation: a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018481:Convection; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016503:Drug Delivery Systems / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051381:Rats; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Brain tumor; convection-enhanced delivery; drug delivery; pre-surgical infusion; steroid