Long circulating nanoparticles of etoposide using PLGA-MPEG and PLGA-pluronic block copolymers: characterization, drug-release, blood-clearance, and biodistribution studies

摘要

The anti-leukemic drug, etoposide (ETO), has variable oral bioavailability ranging from 24–74% with a short terminal half-life of 1.5?h i.v. necessitating continuous infusion for 24–34?h for the treatment of leukemia. In the present study, etoposide-loaded PLGA-based surface-modified nanoparticles (NPs) with long circulation were designed as an alternative to continuous i.v. administration. PLGA-mPEG and PLGA-PLURONIC copolymers were synthesised and used to prepared ETO-loaded NPs by high-pressure homogenization. The mean particle size of ETO-loaded PLGA-MPEG nanoparticles was 94.02±3.4?nm, with an Entrapment Efficiency (EE) of 71.2% and zeta potential value of ?6.9±1.3?mV. ETO-loaded PLGA-pluronic nanoparticles had a mean particle size of 148.0±2.1?nm, an EE of 73.12±2.7%, and zeta potential value of ?21.5±1.6?mV. In vitro release of the pure drug was complete within 4?h, but was sustained up to 7 days from PLGA-mPEG nanoparticles and for 5 days from PLGA-pluronic nanoparticles. Release was first order and followed non-Fickian diffusion kinetics in both instances. ETO and ETO-loaded PLGA nanoparticles labeled with 99mTc were used in blood clearance studies in rats where the two coated NPs, 99mTc- ETO-PLGA-PLU NP and 99mTc- ETO-PLGA-mPEG NP, were found to be available in higher concentrations in the circulation as compared to the pure drug. Biodistribution studies in mice showed that ETO-loaded PLGA-MPEG NP and PLGA-PLURONIC NP had reduced uptake by the RES due to their steric barrier properties and were present in the circulation for a longer time. Moreover, the NPs had greater uptake in bone and brain where concentration of the free drug, ETO, was negligible. Drug delivered from these NPs could result in a single i.v. injection that would release the drug for a number of days, which would be potentially beneficial and in better control of leukemia therapy. Drug Dev Res 71: 228–239, 2010. ? 2010 Wiley-Liss, Inc.