Tissue uptake of docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols and their effects on the morphology of the bladder urothelium

• Published in: Biomaterials Vol. 33; no. 2; pp. 692 - 703
• Main Authors: Mugabe, Clement, Raven, Peter A, Fazli, Ladan, Baker, Jennifer H.E, Jackson, John K, Liggins, Richard T, So, Alan I, Gleave, Martin E, Minchinton, Andrew I, Brooks, Donald E, Burt, Helen M
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2012
• Subjects: Advanced Basic Science; Animals; Bladder cancer; Chemistry, Pharmaceutical; Dentistry; Disease Models, Animal; Drug Delivery Systems; Exfoliation; Female; Glycerol - chemistry; Hydrophobic and Hydrophilic Interactions; Hydrophobically derivatized hyperbranched polyglycerols; Intravesical therapy; Male; Mice; Mice, Nude; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Mucoadhesive; Nanoparticles - chemistry; Polymers - chemistry; Swine; Taxoids - pharmacokinetics; Urinary Bladder - drug effects; Urinary Bladder - pathology; Urinary Bladder Neoplasms - drug therapy; Urothelium; Urothelium - drug effects; Urothelium - pathology; Intravesical therapy; Hydrophobically derivatized hyperbranched polyglycerols; Mucoadhesive; Bladder cancer; Exfoliation; Urothelium
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.09.081

Abstract Recently, we have reported that docetaxel (DTX) loaded, amine terminated hyperbranched polyglycerol (HPG-C8/10 -MePEG-NH2 ) nanoparticles significantly increased drug uptake in mouse bladder tissues and was the most effective formulation to significantly inhibit tumor growth in an orthotopic model of bladder cancer. The objective of this study was to investigate the effects of HPG-C8/10 -MePEG-NH2 nanoparticles on bladder urothelial morphology and integrity, DTX uptake and permeability in bladder tissue and the extent of bladder urothelial recovery following exposure to, and then washout of, HPG-C8/10 -MePEG-NH2 nanoparticles. HPG-C8/10 -MePEG-NH2 nanoparticles significantly increased the uptake of DTX in both isolated pig bladder as well as in live mouse bladder tissues. Furthermore, HPG-C8/10 -MePEG-NH2 nanoparticles were demonstrated to increase the permeability of the urinary bladder wall by causing changes to the urothelial barrier function and morphology through opening of tight junctions and exfoliation of the superficial umbrella cells. These data suggest that exfoliation may be triggered by an apoptosis mechanism, which was followed by a rapid recovery of the urothelium within 24 h post-instillation of HPG-C8/10 -MePEG-NH2 nanoparticles. HPG-C8/10 -MePEG-NH2 nanoparticles cause significant but rapidly recoverable changes in the bladder urothelial morphology, which we believe may make them suitable for increasing drug permeability of bladder tissue and intravesical drug delivery.