title: Increased brain uptake of docetaxel and ketoconazole loaded folate-grafted solid lipid nanoparticles.
abstract: 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 (K(in)) 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.
  
  
  BACKGROUND
  In 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.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Science Center, 1406 S.Coulter, Amarillo, TX 79106, USA. vvk282@gmail.com.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Venishetty
authors.forename: Rojarani
authors.initials: R
authors.lastname: Komuravelli
authors.forename: Madhusudana
authors.initials: M
authors.lastname: Kuncha
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Sistla
authors.forename: Prakash V
authors.initials: PV
authors.lastname: Diwan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D000077143:Docetaxel; D005492:Folic Acid / Q000737:chemistry*; D007654:Ketoconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D008055:Lipids; D043823:Taxoids; D000077143:Docetaxel; D005492:Folic Acid; D007654:Ketoconazole