Paclitaxel-Loaded Gelatin Nanoparticles for Intravesical Bladder Cancer Therapy

Abstract

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 ϳ90% released at 37°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 IC 50 paclitaxel-equivalent concentrations were nearly identical to those of aqueous solutions of paclitaxel, i.e., ϳ30 nmol/L (equivalent to ϳ25 ng/mL) for 2-hour treatments and ϳ4 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 g/g (mean ؎ SD; 3 dogs; 9 tissue sections), which were 2.6؋ 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.

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

“…Sustained drug concentrations are achieved with prolonged PTX infusions 9 and various alternative drug delivery systems instead of Cremophor 1 , such as albumin-bound nanoparticles, 31 microspherical polymers, 32 cholesterol-rich nanoemulsions, 33 or gelatin nanoparticles 34 have been introduced. All these particles, including our PMBN, are intended to solubilize PTX to increase its bioavailability and to let the drug remain in the systemic circulation long enough to provide gradual accumulation in the required area.…”

Conventional Chemotherapeutic Drug Nanoparticles for Cancer Treatment

“…The paclitaxel-loaded nanoparticles were active against human RT4 bladder transitional cancer cells with IC 50 s nearly identical to those of the commercial solution of paclitaxel. In dogs given an intravesical dose of paclitaxel-loaded particles, drug concentrations in the urothelium and lamina propria tissue layers, where Ta and T1 tumors would be located, were 2.6-fold greater than those reported for dogs treated with the Cremophor EL formulation [115].…”

Current status of nanotechnology in urology

“…The paclitaxel-loaded gelatin nanoparticles for intravesical chemotherapy has shown much higher drug concentrations in the urothelium and lamina propria than with Cremophor formulation. 22 To further improve efficacy and to reduce side-effects, targeted intravesical chemotherapy has been explored. Bladder transitional cell carcinoma over-expresses the transferrin receptors on the surface of cells.…”