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Development of a nanoparticulate formulation of docetaxel for the treatment of non-muscle-invasive bladder cancer

University of British Columbia

Approximately 70-85% of bladder cancer patients present with non-muscle invasive bladder cancer (NMIBC). These patients are usually treated by surgical resection of bladder tumours followed by the intravesical administration of anticancer drugs such as mitomycin C (MMC), doxorubicin or gemcitabine. However the recurrence rate after 5 years remains high (70%) so that the development of more effective chemotherapeutic strategies is essential. We have previously shown that hyperbranched polyglycerol (HPG-C₈/₁₀-MePEG-NH₂) nanoparticulate carriers of docetaxel (DTX) offered an improved and effective formulation of the drug for intravesical delivery in mice. The present work describes the effect of concentration and exposure times of three HPG-C₈/₁₀-MePEG-NH₂’s with increasing degrees of amineation on ex vivo porcine bladder tissue morphology and the tissue depth uptake of DTX. The results demonstrated the exfoliation of porcine bladder tissues in a time and concentration-dependent manner. Exfoliation and DTX uptake was significantly enhanced upon treatment with medium or high-density HPG-C₈/₁₀-MePEG-NH₂’s, as compared to a commercially available DTX/polysorbate 80 formulation. Further studies on the local effect of the chemotherapeutic agents MMC, doxorubicin and gemcitabine, on ex vivo porcine bladder tissue showed that these drugs all caused exfoliation of urothelium and were well taken up by the bladder tissue with no additional effect of HPG-C₈/₁₀-MePEG-NH₂ pre-treatment. The exfoliating effect of these three drugs was shown to enhance the bladder tissue uptake of paclitaxel (PTX) or DTX when the bladder was exposed to combinations of taxanes with either MMC, doxorubicin or gemcitabine. Generally, the exfoliation effect of HPG-C₈/₁₀-MePEG-NH₂’s, MMC, doxorubicin and gemcitabine is attributed to an interaction of the positively charged amine groups on all these agents with the negatively charged mucosal surface. This binding may modulate tight junction protein function followed by exfoliation of the protective urothelial layer so that drugs may penetrate the exposed underlying tissue. In conclusion this thesis supports a novel role of DTX loaded-HPG-C₈/₁₀-MePEG-NH₂ nanoparticles as an improved drug delivery vehicle for the potential chemotherapeutic treatment of bladder cancer. Additionally, data suggests promising strategies for intravesical combination drug therapies, to enhance the uptake of taxanes with potential additive therapeutic effects for improved efficacy in the treatment of NMIBC.

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2015-09-30

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/50506

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/