title: In vitro and in vivo evaluation of intravesical docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols in an orthotopic model of bladder cancer.
abstract: The objective of this study was to evaluate the tolerability, to establish a dosing regimen, and to evaluate the efficacy of intravesical docetaxel (DTX) formulations in a mouse model of bladder cancer. DTX in commercial formulation (Taxotere, DTX in Tween 80) or loaded in hyperbranched polyglycerols (HPGs) was evaluated. The synthesis and characterization of HPGs with hydrophobic cores and derivatized with methoxy poly(ethylene glycol) in the shell and further functionalized with amine groups (HPG-C(8/10)-MePEG and HPG-C(8/10)-MePEG-NH(2)) is described. Intravesical DTX in either commercial or HPGs formulations (up to 1.0 mg/mL) was instilled in mice with orthotopic bladder cancer xenografts and was well tolerated with no apparent signs of local or systemic toxicities. Furthermore, a single dose of intravesical DTX (0.5 mg/mL) loaded in HPGs was significantly more effective in reducing the tumor growth in an orthotopic model of bladder cancer than the commercial formulation of Taxotere. In addition, DTX-loaded HPG-C(8/10)-MePEG-NH(2) was found to be more effective at lower instillation dose than DTX (0.2 mg/mL)-loaded HPG-C(8/10)-MePEG. Overall, our data show promising antitumor efficacy and safety in a recently validated orthotopic model of bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard intravesical therapy.
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, 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: Markus
authors.initials: M
authors.lastname: Heller
authors.forename: Magali
authors.initials: M
authors.lastname: Zeisser-Labouèbe
authors.forename: Lindsay
authors.initials: L
authors.lastname: Heller
authors.forename: Irina
authors.initials: I
authors.lastname: Chafeeva
authors.forename: Donald E
authors.initials: DE
authors.lastname: Brooks
authors.forename: Helen M
authors.initials: HM
authors.lastname: Burt
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002850:Chromatography, Gel; D004195:Disease Models, Animal; D000077143:Docetaxel; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D010316:Particle Size; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel