Solid lipid nanoparticles as drug carriers II.: Plasma stability and biodistribution of solid lipid nanoparticles containing the lipophilic prodrug 3′-azido-3′-deoxythymidine palmitate in mice

Solid lipid nanoparticles (SLNs) were prepared using trilaurin as the SLNs solid core and a mixture of neutral and negatively charged phospholipid. To produce SLNs with a poly(ethylene glycol) (PEG) coating, PEG was incorporated in SLNs using dipalmitoyIphosphatidylethanolamine-N-[poly(ethylene glycol)(2000)] (PE-PEG). 3'-azido-3'-deoxythymydine palmitate (AZT-P) with [H-3]-AZT-P as tracer were synthesized and incorporated in SLNs. Their subsequent retention in SLNs with and without PEG was determined after incubation in 50% bovine plasma. Biodistribution studies were performed in mice using free AZT-P, AZT-P incorporated in SLNs or AZT-P incorporated in PE-PEG coated SLNs (SLN-PE-PEG). The presence of PE-PEG significantly reduced the SLN zeta potential from -22 to -5 mV. Although AZT-P was rapidly released from SLNs during incubation in bovine plasma, the release rate was significantly slower in SLN-PE-PEG. AZT-P was rapidly removed from blood following i.v. injection in mice. The decrease in AZT-P blood level was biphasic and rapid, and the major excretory route of AZT-P was the kidney. Higher levels were observed after i.v. injection of AZT-P incorporated in SLNs. This effect was further increased using SLN-PE-PEG. Both SLN and SLN-PE-PEG incorporation of AZT-P significantly decreased the urinary excretion of AZT-P and increased the localization of AZT-P in the liver. The results obtained in this study indicate that using SLNs as a drug carrier increases the bioavailibility of incorporated AZT-P, and that the pharmacokinetic behaviour of the incorporated drug can be modified by changing the surface characteristics of SLNs by using the amphiphilic solvation enhancer PE-PEG. (C) 1998 Elsevier Science B.V. All rights reserved.