Enhanced brain targeting by synthesis of 3′,5′-dioctanoyl-5-fluoro-2′-deoxyuridine and incorporation into solid lipid nanoparticles

To overcome the limited access of the drug 5-fluoro-2'-deoxyuridine (FUdR) to the brain, 31,5'-dioctanoyl-5-fluoro-2'-deoxyuridine (DO-FUdR) was synthesized and incorporated into solid lipid nanoparticles (DO-FUdR-SLN). DO-FUdR-SLN were prepared by a thin-layer ultrasonication technique and a central composite design (CCD) was applied to optimize the formulation. The median particle size of DO-FUdR-SLN was 76 nm with drug loading of 29.02% and entrapment efficiency of 96.62%. The in vitro drug release was studied by a bulk-equilibrium reverse dialysis bag technique in phosphate-buffered saline (pH 7.4) containing 0.3% pancreatic enzyme at 37degreesC. The concentrations of FUdR in various organs were determined by reversed-phase high-performance liquid chromatography after intravenous administration of DO-FUdR-SLN, DO-FUdR or FUdR. The brain area under the concentration-time curve of DO-FUdR-SLN and DO-FUdR were 10.97- and 5.32-fold higher than that of FUdR, respectively. These results indicated that DO-FUdR-SLN had a good brain targeting efficiency in vivo. SLN can improve the ability of the drug to penetrate through the blood-brain barrier and is a promising drug targeting system for the treatment of central nervous system disorders. (C) 2002 Elsevier Science B.V. All rights reserved.