title: Paclitaxel incorporated in hydrophobically derivatized hyperbranched polyglycerols for intravesical bladder cancer therapy.
abstract: OBJECTIVE
  To develop paclitaxel incorporated into unimolecular micelles based on hydrophobically derivatized hyperbranched polyglycerols (dHPGs) for use as mucoadhesive intravesical agents against non-muscle-invasive bladder cancer.
  
  
  METHODS
  Two different types of dHPGs (HPG- C10-polyethylene glycol (PEG) and polyethyleneimine (PEI)-C18-HPG) were synthesized and paclitaxel was loaded into these using a solvent evaporation method. After physicochemical characterization of the resulting nanoparticles, four human bladder cancer cell lines were incubated with various concentrations of paclitaxel incorporated in dHPGs and the results were compared with those of paclitaxel formulated in Cremophor-EL (Taxol(R), Bristol-Myers-Squibb). In vivo, nude mice with orthotopic KU7-luc tumours were intravesically instilled with phosphate buffered saline, Taxol, or paclitaxel/HPG-C10-PEG.
  
  
  RESULTS
  dHPGs are mucoadhesive nanoparticles with hydrodynamic radii of <10 nm and incorporation of paclitaxel did not affect their size. The release profiles of paclitaxel from dHPGs were characterized by a rapid-release phase followed by a slower sustained-release phase. While the PEI-C18-HPG formulation released only approximately 40% of the initially incorporated paclitaxel, up to 80% was released from HPG-C10-PEG. Moreover, only paclitaxel/HPG-C10-PEG was stable in acidic urine. In vitro, all paclitaxel formulations potently decreased bladder cancer proliferation although paclitaxel/HPG-C10-PEG was slightly less cytotoxic than standard Taxol. By contrast, in vivo, the mucoadhesive HPG-C10-PEG formulation of paclitaxel was significantly more effective in reducing orthotopic tumour growth than Taxol and was well tolerated.
  
  
  CONCLUSIONS
  Intravesical administration of mucoadhesive nanoparticulate formulations of paclitaxel might be a promising approach for instillation therapy of patients with non-muscle-invasive bladder cancer.
authors.affiliation: Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Canada.
authors.forename: Clement
authors.initials: C
authors.lastname: Mugabe
authors.forename: Boris A
authors.initials: BA
authors.lastname: Hadaschik
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Kainthan
authors.forename: Donald E
authors.initials: DE
authors.lastname: Brooks
authors.forename: Alan I
authors.initials: AI
authors.lastname: So
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Helen M
authors.initials: HM
authors.lastname: Burt
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000737:chemistry; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D017239:Paclitaxel