title: Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments.
abstract: OBJECTIVE
  The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression.
  
  
  METHODS
  Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg(-1)) or ethanolic lomustine (6.5 mg kg(-1)) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg(-1)) or ethanolic lomustine (daily 1.2 mg kg(-1) - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated.
  
  
  RESULTS
  The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes.
  
  
  CONCLUSIONS
  Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Funmilola A
authors.initials: FA
authors.lastname: Fisusi
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Adeline
authors.initials: A
authors.lastname: Siew
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Kar Wai
authors.initials: KW
authors.lastname: Chooi
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Omotunde
authors.initials: O
authors.lastname: Okubanjo
authors.affiliation: School of Physics, University of Exeter, Exeter, EX4 4QL, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Garrett
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Lalatsa
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Dolores
authors.initials: D
authors.lastname: Serrano
authors.affiliation: School of Physics, University of Exeter, Exeter, EX4 4QL, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Summers
authors.affiliation: School of Physics, University of Exeter, Exeter, EX4 4QL, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Moger
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Stapleton
authors.affiliation: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.|Nanomerics Ltd. Euro House, 1394 High Road, London, N20 9YZ, UK.
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Schätzlein
authors.affiliation: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK. Ijeoma.uchegbu@ucl.ac.uk.|Nanomerics Ltd. Euro House, 1394 High Road, London, N20 9YZ, UK. Ijeoma.uchegbu@ucl.ac.uk.
authors.forename: Ijeoma F
authors.initials: IF
authors.lastname: Uchegbu
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008130:Lomustine
keywords: glioblastoma multiforme; lomustine; molecular envelope technology (MET); myelosuppression; nanoparticles