Paclitaxel-loaded gelatin nanoparticles for intravesical bladder cancer therapy.
OBJECTIVE
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.


METHODS
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.
Lu
Ze
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College of Pharmacy and James Cancer Hospital, The Ohio State University, Columbus, Ohio 43210, USA.
Yeh
Teng-Kuang
TK
Tsai
Max
M
Au
Jessie L-S
JL
Wientjes
M Guill
MG
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005780:Gelatin / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008823:Micelles; D049329:Nanostructures / Q000737:chemistry*; D036103:Nanotechnology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols; D013997:Time Factors; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D014961:X-Ray Diffraction
D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; C022131:cremophor; D011092:Polyethylene Glycols; D005780:Gelatin; D017239:Paclitaxel