title: Adjuvant chemotherapy for brain tumors delivered via a novel intra-cavity moldable polymer matrix.
abstract: BACKGROUND
  Polymer-based delivery systems offer innovative intra-cavity administration of drugs, with the potential to better target micro-deposits of cancer cells in brain parenchyma beyond the resected cavity. Here we evaluate clinical utility, toxicity and sustained drug release capability of a novel formulation of poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) microparticles.
  
  
  METHODS
  PLGA/PEG microparticle-based matrices were molded around an ex vivo brain pseudo-resection cavity and analyzed using magnetic resonance imaging and computerized tomography. In vitro toxicity of the polymer was assessed using tumor and endothelial cells and drug release from trichostatin A-, etoposide- and methotrexate-loaded matrices was determined. To verify activity of released agents, tumor cells were seeded onto drug-loaded matrices and viability assessed.
  
  
  RESULTS
  PLGA/PEG matrices can be molded around a pseudo-resection cavity wall with no polymer-related artifact on clinical scans. The polymer withstands fractionated radiotherapy, with no disruption of microparticle structure. No toxicity was evident when tumor or endothelial cells were grown on control matrices in vitro. Trichostatin A, etoposide and methotrexate were released from the matrices over a 3-4 week period in vitro and etoposide released over 3 days in vivo, with released agents retaining cytotoxic capabilities. PLGA/PEG microparticle-based matrices molded around a resection cavity wall are distinguishable in clinical scanning modalities. Matrices are non-toxic in vitro suggesting good biocompatibility in vivo. Active trichostatin A, etoposide and methotrexate can be incorporated and released gradually from matrices, with radiotherapy unlikely to interfere with release.
  
  
  CONCLUSIONS
  The PLGA/PEG delivery system offers an innovative intra-cavity approach to administer chemotherapeutics for improved local control of malignant brain tumors.
authors.affiliation: Division of Drug Delivery and Tissue Engineering, School of Pharmacy, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Cheryl V
authors.initials: CV
authors.lastname: Rahman
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Paul S
authors.initials: PS
authors.lastname: Morgan
authors.forename: Keith A
authors.initials: KA
authors.lastname: Langmack
authors.forename: Phil A
authors.initials: PA
authors.lastname: Clarke
authors.forename: Alison A
authors.initials: AA
authors.lastname: Ritchie
authors.forename: Donald C
authors.initials: DC
authors.lastname: Macarthur
authors.forename: Felicity R
authors.initials: FR
authors.lastname: Rose
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shakesheff
authors.forename: Richard G
authors.initials: RG
authors.lastname: Grundy
authors.lastname: Ruman Rahman
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D016503:Drug Delivery Systems; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012756:Sheep; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D005047:Etoposide