title: Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.
abstract: BACKGROUND
  The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED).
  
  
  METHODS
  The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls.
  
  
  RESULTS
  Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test,P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination.
  
  
  CONCLUSIONS
  CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol; Department of Neurosurgery, North Bristol NHS Trust.
authors.forename: W G
authors.initials: WG
authors.lastname: Singleton
authors.affiliation: Bristol Centre for Functional Nanomaterials, School of Physics, HH Wills Physics Laboratory.
authors.forename: A M
authors.initials: AM
authors.lastname: Collins
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol.
authors.forename: A S
authors.initials: AS
authors.lastname: Bienemann
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol.
authors.forename: C L
authors.initials: CL
authors.lastname: Killick-Cole
authors.affiliation: Brain Tumour Research Group, School of Clinical Sciences.
authors.forename: H R
authors.initials: HR
authors.lastname: Haynes
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol.
authors.forename: D J
authors.initials: DJ
authors.lastname: Asby
authors.affiliation: School of Chemistry, University of Bristol, Bristol, UK.
authors.forename: C P
authors.initials: CP
authors.lastname: Butts
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol.
authors.forename: M J
authors.initials: MJ
authors.lastname: Wyatt
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol; Department of Neurosurgery, North Bristol NHS Trust.
authors.forename: N U
authors.initials: NU
authors.lastname: Barua
authors.affiliation: Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol; Department of Neurosurgery, North Bristol NHS Trust.
authors.forename: S S
authors.initials: SS
authors.lastname: Gill
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D018481:Convection; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D000077767:Panobinostat; D020442:Poloxamer / Q000737:chemistry*; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D016019:Survival Analysis
chemical_list: D006877:Hydroxamic Acids; D007211:Indoles; D008823:Micelles; D020442:Poloxamer; D000077767:Panobinostat
keywords: HDAC inhibitor; convection enhanced delivery; glioma; micelle; panobinostat