title: In vivo evaluation of mucoadhesive nanoparticulate docetaxel for intravesical treatment of non-muscle-invasive bladder cancer.
abstract: OBJECTIVE
  The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy.
  
  
  METHODS
  Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C(8)/C(10) alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C(8/10)-MePEG-NH(2)) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofi-aventis), and DTX-loaded HPG-C(8/10)-MePEG and/or HPG-C(8/10)-MePEG-NH(2). Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed.
  
  
  RESULTS
  In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C(8/10)-MePEG-NH(2) (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C(8/10)-MePEG-NH(2) showed enhanced uptake of these nanoparticles in bladder tumor tissues.
  
  
  CONCLUSIONS
  Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer.
authors.affiliation: Faculty of Pharmaceutical Sciences, Departments of Urologic Sciences and Pathology & Laboratory Medicine and Chemistry, Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Clement
authors.initials: C
authors.lastname: Mugabe
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsui
authors.forename: Alan I
authors.initials: AI
authors.lastname: So
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Jennifer H E
authors.initials: JH
authors.lastname: Baker
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.forename: Irina
authors.initials: I
authors.lastname: Manisali
authors.forename: Richard
authors.initials: R
authors.lastname: Liggins
authors.forename: Donald E
authors.initials: DE
authors.lastname: Brooks
authors.forename: Helen M
authors.initials: HM
authors.lastname: Burt
mesh_terms: D000268:Adhesiveness; D000283:Administration, Intravesical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage; D009361:Neoplasm Invasiveness; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel