Tissue uptake of docetaxel loaded hydrophobically derivatized hyperbranched polyglycerols and their effects on the morphology of the bladder urothelium.
Recently, we have reported that docetaxel (DTX) loaded, amine terminated hyperbranched polyglycerol (HPG-C(8/10)-MePEG-NH(2)) 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-C(8/10)-MePEG-NH(2) 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-C(8/10)-MePEG-NH(2) nanoparticles. HPG-C(8/10)-MePEG-NH(2) nanoparticles significantly increased the uptake of DTX in both isolated pig bladder as well as in live mouse bladder tissues. Furthermore, HPG-C(8/10)-MePEG-NH(2) 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-C(8/10)-MePEG-NH(2) nanoparticles. HPG-C(8/10)-MePEG-NH(2) 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.
University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Clement
C
Mugabe
Peter A
PA
Raven
Ladan
L
Fazli
Jennifer H E
JH
Baker
John K
JK
Jackson
Richard T
RT
Liggins
Alan I
AI
So
Martin E
ME
Gleave
Andrew I
AI
Minchinton
Donald E
DE
Brooks
Helen M
HM
Burt
D000818:Animals; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D000077143:Docetaxel; D016503:Drug Delivery Systems; D005260:Female; D005990:Glycerol / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D013552:Swine; D043823:Taxoids / Q000493:pharmacokinetics*; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy; D019459:Urothelium / Q000187:drug effects* / Q000473:pathology
D011108:Polymers; D043823:Taxoids; D000077143:Docetaxel; C043941:polyglycerol; D005990:Glycerol