UBC Theses and Dissertations
Bladder tissue distribution of paclitaxel and docetaxel from polymeric nanoparticles Tsallas, Antonia Theodora
Taxane based drugs are commonly used second-line adjuvant therapies for the treatment of superficial bladder cancer. However, the effectiveness of these drugs following intravesical instillation is limited, because of a short drug residence time and poor drug penetration into the bladder wall. The goals of this project were to use PTX and DTX loaded nanoparticulate formulations and investigate their bladder mucosal permeability and distribution characteristics in ex vivo isolated porcine bladders. PTX and DTX were loaded into nanoparticles of methoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) (MePEG-PDLLA), methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-PCL) and hydrophobically derivatized hyperbranched polyglycerol, HPG-C10-MePEG. In vitro drug release profiles of PTX and DTX loaded MePEG-PDLLA micelles (approx. 20 nm in size) demonstrated controlled and complete release of the drugs over 7 days. The penetration and distribution characteristics of PTX and DTX from nanoparticulate formulations (spiked with tritium labelled drugs) into freshly excised porcine bladder tissue were evaluated using Franz diffusion cells. Nanoparticle dispersions were instilled onto bladder tissue for 2 h. The tissues were frozen, sectioned and drugs quantified using liquid scintillation counting. The drug tissue levels were highest in the urothelium and then decreased exponentially with increasing tissue depth. Micellar formulations of MePEG-PDLLA showed higher bladder tissue uptake levels of PTX and DTX compared to control commercial formulations. Drug uptake levels did not differ significantly between concentrations of 0.5 and 1 mg/mL. However, DTX was present in bladder tissue at significantly higher concentrations than PTX. Micellar formulations of MePEG-PDLLA showed higher bladder tissue uptake levels of PTX compared to both MePEG-PCL copolymer formulations. The rapid and high levels of PTX and DTX penetration observed in bladder tissue using the MePEG-PDLLA micellar formulation of these drugs was likely due to the use of high concentrations of the drugs with these polymeric micelles, greater free drug released from the MePEG-PDLLA micelles and the ability to increase the contact of the formulation at the bladder wall surface allowing for improved partitioning of the drug into the tissues.
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