Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles

Docetaxel is used in the treatment of many types of cancer, but its entry into the brain is restricted by p-glycoprotein (p-gp) efflux. A potential drug–drug interaction exists between docetaxel and ketoconazole because both agents are metabolized hepatically by the cytochrome P-450 system, and ketoconazole can inhibit p-gp efflux of docetaxel at blood brain barrier. Hence, these two drugs were loaded in solid lipid nanoparticles (SLNPs) and surface of these NPs were modified with folic acid for brain targeting. These NPs were characterized for particle size, zeta potential, entrapment efficiency, in vitro drug release, cytotoxicity, and cell uptake in brain endothelial cell lines. Plasma and brain pharmacokinetics have shown increased brain uptake of docetaxel with surface-modified dual drug-loaded SLNPs. Brain permeation coefficient (Kin) of folate-grafted docetaxel and ketoconazole loaded SLNPs was 44 times higher than that of Taxotere. Hence, these NPs were suitable for the delivery of lipophilic anticancer drugs to the brain.From the Clinical EditorIn this paper, successful delivery of docetaxel and ketoconazole is reported using solid lipid nanoparticles surface modified with folic acid for brain targeting, which may pave the way to optimized clinical applications of lipophilic anticancer drugs to the brain.

Graphical AbstractDual drug-loaded folate-grafted solid lipid nanoparticles (NPs) were prepared using solvent emulsification and evaporation method. Docetaxel and ketoconazole were selected as drugs to incorporate in solid lipid NPs because those drugs have potential drug–drug interaction. These NPs showed about 20-fold increased uptake in brain endothelial cells in comparison with Taxotere. Rhodamine 123 and ketoconazole-loaded solid lipid NPs were used for microscopic images. In vivo studies in Wistar rats also resulted in increased brain uptake of docetaxel and these NPs showed 44-fold increase in brain permeation coefficient (Kin) value in comparison with Taxotere.Figure optionsDownload high-quality image (182 K)Download as PowerPoint slide