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An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy
Ze Lu1, Teng-Kuang Yeh, Max Tsai
1College of Pharmacy and James Cancer Hospital, The Ohio State University, Columbus, Ohio 43210, USA.
Purpose:
The present report describes the development of paclitaxel-loaded gelatin nanoparticles for use in intravesical therapy of superficial bladder cancer. The commercial formulation of paclitaxel contains Cremophor, which forms micelles and thereby entraps the drug and reduces its partition across the urothelium.
Experimental Design:
Paclitaxel-loaded gelatin nanoparticles were prepared using the desolvation method, and their physicochemical and biological properties were characterized.
Results:
The size of the particles ranged from 600 to 1,000 nm and increased with the molecular weight of the gelatin polymer. Under optimal conditions, the yield was >80%, and the drug loading was 0.7%. Wide-angle X-ray diffraction analysis showed that the entrapped paclitaxel was present in an amorphous state, which has higher water solubility compared with the crystalline state. Identical, rapid drug release from nanoparticles was observed in PBS and urine, with approximately 90% released at 37 degrees C after 2 hours. Treatment with a protease (i.e., Pronase) rapidly degraded the nanoparticles, with half-lives of 23.8 minutes, 0.6 minute, and 0.4 minute in the presence of 0.01, 0.05, and 0.25 mg/mL Pronase, respectively. The paclitaxel-loaded nanoparticles were active against human RT4 bladder transitional cancer cells; the IC50 paclitaxel-equivalent concentrations were nearly identical to those of aqueous solutions of paclitaxel, i.e., approximately 30 nmol/L (equivalent to approximately 25 ng/mL) for 2-hour treatments and approximately 4 nmol/L for 96-hour treatments. In dogs given an intravesical dose of paclitaxel-loaded particles, the drug concentrations in the urothelium and lamina propria tissue layers, where Ta and T1 tumors would be located, were 7.4 +/- 4.3 mug/g (mean +/- SD; 3 dogs; 9 tissue sections), which were 2.6x the concentrations we reported for dogs treated with the Cremophor formulation.
Conclusions:
Paclitaxel-loaded gelatin nanoparticles represent a rapid release, biologically active paclitaxel formulation that can be used for intravesical bladder cancer therapy.
