In vivo Evaluation of Mucoadhesive Nanoparticulate Docetaxel for Intravesical Treatment of Non―Muscle-Invasive Bladder Cancer

• Published in: Clinical cancer research Vol. 17; no. 9; pp. 2788 - 2798
• Main Authors: MUGABE, Clement, MATSUI, Yoshiyuki, SO, Alan I, GLEAVE, Martin E, BAKER, Jennifer H. E, MINCHINTON, Andrew I, MANISALI, Irina, LIGGINS, Richard, BROOKS, Donald E, BURT, Helen M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2011
• Subjects: Adhesiveness; Administration, Intravesical; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Biological and medical sciences; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - pathology; Cell Line, Tumor; Female; Humans; Medical sciences; Mice; Mice, Nude; Mucous Membrane - drug effects; Mucous Membrane - metabolism; Mucous Membrane - pathology; Muscle, Smooth - pathology; Nanoparticles - administration & dosage; Neoplasm Invasiveness; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Taxoids - administration & dosage; Treatment Outcome; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays; Antineoplastic agent; Evaluation; Urinary system disease; Nanoparticle; Mucosa; Docetaxel; Urinary tract disease; Malignant tumor; Adhesion; In vivo; Treatment; Urinary system; Urinary bladder; Taxane derivatives; Microparticle; Bladder disease; Intravesical administration; Antimitotic; Non muscle invasive bladder cancer; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-2981

The present work describes the development and in vitro and in vivo evaluation of a mucoadhesive nanoparticulate docetaxel (DTX) formulation for intravesical bladder cancer therapy. Mucoadhesive formulations based on hyperbranched polyglycerols (HPG), hydrophobically derivatized with C(8)/C(10) alkyl chains in the core and modified with methoxy-polyethylene glycol (MePEG) and amine groups in the shell (HPG-C(8/10)-MePEG-NH(2)) were synthesized and DTX was loaded into these by a solvent evaporation method. Both low-grade (RT4, MGHU3) and high-grade (UMUC3) human urothelial carcinoma cell lines were treated with various concentrations of DTX formulations in vitro. KU7 cells that stably express firefly luciferase (KU7-luc) were inoculated in female nude mice by intravesical instillation and quantified using bioluminescence imaging. Mice with established KU7-luc tumors were given a single intravesical instillation with PBS, Taxotere (DTX from Sanofi-aventis), and DTX-loaded HPG-C(8/10)-MePEG and/or HPG-C(8/10)-MePEG-NH(2). Drug uptake was conducted using LC/MS-MS (liquid chromatography/tandem mass spectrometry) and tumor microenvironment and uptake of rhodamine labeled HPGs was assessed. In vitro, all DTX formulations potently inhibited bladder cancer proliferation. However, in vivo, DTX-loaded HPG-C(8/10)-MePEG-NH(2) (mucoadhesive DTX) was the most effective formulation to inhibit tumor growth in an orthotopic model of bladder cancer. Furthermore, mucoadhesive DTX significantly increased drug uptake in mouse bladder tissues. In addition, rhodamine labeled HPG-C(8/10)-MePEG-NH(2) showed enhanced uptake of these nanoparticles in bladder tumor tissues. Our data show promising in vivo antitumor efficacy and provide preclinical proof of principle for the intravesical application of mucoadhesive nanoparticulate DTX formulation in the treatment of bladder cancer.