Published: March 01, 2011 r2011 American Chemical Society 949 dx.doi.org/10.1021/bm101316q | Biomacromolecules 2011, 12, 949–960 ARTICLE pubs.acs.org/Biomac In Vitro and In Vivo Evaluation of Intravesical Docetaxel Loaded Hydrophobically Derivatized Hyperbranched Polyglycerols in an Orthotopic Model of Bladder Cancer Clement Mugabe, † Yoshiyuki Matsui, ^ Alan I. So, ^,‡ Martin E. Gleave, ^,‡ Markus Heller, # Magali Zeisser-Labou  ebe, # Lindsay Heller, # Irina Chafeeva, § Donald E. Brooks, §,|| and Helen M. Burt* ,† † Faculty of Pharmaceutical Sciences, ‡ Department of Urologic Sciences, § Centre for Blood Research, and ) Departments of Pathology & Laboratory Medicine and Chemistry, University of British Columbia, Vancouver, BC, Canada ^ The Vancouver Prostate Centre, Vancouver, BC, Canada # The Centre for Drug Research and Development, Vancouver, BC, Canada b S Supporting Information ABSTRACT: The objective of this study was to evaluate the tolerability, to establish a dos- ing regimen, and to evaluate the efficacy of intravesical docetaxel (DTX) formulations in a mouse model of bladder cancer. DTX in commercial formulation (Taxotere, DTX in Tween 80) or loaded in hyperbranched poly- glycerols (HPGs) was evaluated. The synth- esis and characterization of HPGs with hy- drophobic cores and derivatized with methoxy poly(ethylene glycol) in the shell and further functionalized with amine groups (HPG-C 8/10 - MePEG and HPG-C 8/10 -MePEG-NH 2 ) is described. Intravesical DTX in either com- mercial or HPGs formulations (up to 1.0 mg/mL) was instilled in mice with orthoto- pic bladder cancer xenografts and was well tolerated with no apparent signs of local or systemic toxicities. Furthermore, a single dose of intravesical DTX (0.5 mg/mL) loaded in HPGs was significantly more effective in reducing the tumor growth in an orthotopic model of bladder cancer than the com- mercial formulation of Taxotere. In addition, DTX-loaded HPG-C 8/10 -MePEG-NH 2 was found to be more effective at lower instillation dose than DTX (0.2 mg/mL)-loaded HPG-C 8/10 -MePEG. Overall, our data show promising antitumor efficacy and safety in a recently validated orthotopic model of bladder cancer. Further research is warranted to evaluate its safety and efficacy in early phase clinical trials in patients refractory to standard intravesical therapy. ’ INTRODUCTION Following prostate, lung, and colon cancer, bladder cancer is the fourth most common malignancy in men in the Western world. 1 Approximately 70% of all newly diagnosed bladder tumors are non-muscle-invasive. 2 Current treatment options for non-muscle-invasive or “superficial”, bladder cancer following transurethral resection are of limited efficacy because up to 80% of patients develop recurrent tumors, of which 20-30% develop into more aggressive and potentially lethal tumors. 3,4 Treatment failure is thought to be in part due to the short dwell-time of intravesical drugs. Conventional formulations are typically maintained in the bladder for 2 h and urothelial drug exposure rarely lasts beyond the first voiding of urine after instillation. 5 Our approach to increase the dwell-time of intravesical drugs is to target mucins on the surface of the urothelium by exploiting the concept of mucoadhesion, which is an adhesive phenomenon occurring between certain types of polymers known as “mucoadhesive” polymers and the mucin-gel layer covering the bladder mucosa. The drug delivery systems we are currently developing are based on hydrophobically derivatized hyperbranched polyglcer- ols (HPGs), which are dendritic-like macromolecules, also termed “unimolecular micelles”, with a hydrophobic core and a hydro- philic shell connected by covalent bonds in a single molecule. 6 Received: November 5, 2010 Revised: January 14, 2011