Incorporation of novel 1-alkylcarbonyloxymethyl prodrugs of 5-fluorouracil into poly(lactide-co-glycolide) nanoparticles

Incorporation of 1-alkylcarbonyloxymethylprodrugs of 5FU into poly(lactide-co-glycolide) nanoparticles using nanoprecipitation methods gave increased loading efficiencies over that obtained using the parent drug substance. SEM studies revealed spherical nanoparticles of around 200 nm in diameter, corresponding well with measurements made using photon correlation spectroscopy. The C-7 prodrug gave the best mean loading of 47.23%, which compared favourably to 3.68% loading achieved with 5FU. Loading efficiency was seen to follow the hydrophilic-lipophilic balance in the homologue series, where increases in lipophilicities alone were not good predictors of loading. Drug release, in terms of resultant 5FU concentration, was monitored using a flow-through dissolution apparatus. Cumulative drug release from nanoparticles loaded with the C-5 prodrug was linear over 6h, with approximately 14% of the total available 5FU dose released and with no evidence of a burst effect. The flux profile of the C-5-loaded nanoparticles showed an initial peak in flux in the first sampling interval, but became linear for the remainder of the release phase. C-7-loaded nanoparticles released considerably less (4% in 6 h) with a similar flux pattern to that seen with the C-5 prodrug. The C-9-loaded nanoparticles released less than 1% of the available 5FU over 6 h, with a similar zero-order profile. The C7 prodrug was deemed to be the prodrug of choice, achieving the highest loadings and releasing 5FU, following hydrolysis, in a zero-order fashion over a period of at least 6 h. Given the lack of burst effect and steady-state flux conditions, this nanoparticulate formulation offers a better dosing strategy for sustained intravenous use when compared to that arising from nanoparticles made by direct incorporation of 5FU. (c) 2007 Elsevier B.V. All rights reserved.