Long Circulating Nanoparticles of Etoposide Using PLGA-MPEG and PLGA-Pluronic Block Copolymers: Characterization, Drug-Release, Blood-Clearance, and Biodistribution Studies

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 iv. 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. [TO-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. [TO and ETO-loaded PLGA nanoparticles labeled with Tc-99m were used in blood clearance studies in rats where the two coated NPs, Tc-99m-ETO-PLGA-PLU NP and Tc-99m-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 [TO-loaded PLGA-MPEG NP and PLGA-PLURONIC NP had reduced uptake by the RES clue 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, [TO, 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. (C) 2010 Wiley-Liss, Inc.