Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC, V6T 1Z3, Canada.
The present work describes the development, in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy.
Mucoadhesive formulations based on hyperbranched polyglycerols (HPGs), hydrophobically derivatized with C8/C10 alkyl chains in the core and modified with MePEG and amine groups in the shell (HPG-C8/10-MePEG-NH2) 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), DTX loaded HPG-C8/10-MePEG and/or HPG-C8/10-MePEG-NH2. Drug uptake was conducted using LC/MS/MS and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed.
In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX loaded HPG-C8/10-MePEG-NH2 (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-C8/10-MePEG-NH2 demonstrated enhanced uptake of these nanoparticles in bladder tumor tissues.
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.
Written by:
Mugabe C, Matsui Y, So AI, Gleave ME, Baker JH, Minchinton AI, Manisali I, Liggins R, Brooks DE, Burt HM.
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Reference: Clin Cancer Res. 2011 Feb 28. Epub ahead of print.
doi: 10.1158/1078-0432.CCR-10-2981
PubMed Abstract
PMID: 21357680
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