title: Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery.
abstract: Enhanced permeability in tumours is thought to result from malformed vascular walls with leaky cell-to-cell junctions. This assertion is backed by studies using electron microscopy and polymer casts that show incomplete pericyte coverage of tumour vessels and the presence of intercellular gaps. However, this gives the impression that tumour permeability is static amid a chaotic tumour environment. Using intravital confocal laser scanning microscopy we show that the permeability of tumour blood vessels includes a dynamic phenomenon characterized by vascular bursts followed by brief vigorous outward flow of fluid (named 'eruptions') into the tumour interstitial space. We propose that 'dynamic vents' form transient openings and closings at these leaky blood vessels. These stochastic eruptions may explain the enhanced extravasation of nanoparticles from the tumour blood vessels, and offer insights into the underlying distribution patterns of an administered drug.
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.|Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 113-0033, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Bioengineering, University of Utah, Utah 84112, USA.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Nichols
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Toh
authors.affiliation: Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Kanagawa 226-8503, Japan.
authors.forename: Takahiro
authors.identifier: http://orcid.org/0000-0002-0391-0478
authors.initials: T
authors.lastname: Nomoto
authors.affiliation: Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 113-8656, Japan.
authors.forename: Horacio
authors.initials: H
authors.lastname: Cabral
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.
authors.forename: R James
authors.initials: RJ
authors.lastname: Christie
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamada
authors.affiliation: Nikon Instech Company Limited, Tokyo 108-6290, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
authors.forename: Mitsunobu R
authors.identifier: http://orcid.org/0000-0003-1593-1855
authors.initials: MR
authors.lastname: Kano
authors.affiliation: Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Chiba 277-8577, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Polymer Chemistry Division, Chemical Resources Laboratory, Tokyo Institute of Technology, Kanagawa 226-8503, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nishiyama
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, 113-0033, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Utah 84112, USA.
authors.forename: You Han
authors.initials: YH
authors.lastname: Bae
authors.affiliation: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 113-8655, Japan.|Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 113-8656, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects*; D003198:Computer Simulation; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008955:Models, Cardiovascular; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D010316:Particle Size
chemical_list: D000970:Antineoplastic Agents