title: Development of vorinostat-loaded solid lipid nanoparticles to enhance pharmacokinetics and efficacy against multidrug-resistant cancer cells.
abstract: OBJECTIVE
  To investigate whether delivery of a histone deacetylase inhibitor, vorinostat (VOR), by using solid lipid nanoparticles (SLNs) enhanced its bioavailability and effects on multidrug-resistant cancer cells.
  
  
  METHODS
  VOR-loaded SLNs (VOR-SLNs) were prepared by hot homogenization using an emulsification-sonication technique, and the formulation parameters were optimized. The cytotoxicity of the optimized formulation was evaluated in cancer cell lines (MCF-7, A549, and MDA-MB-231), and pharmacokinetic parameters were examined following oral and intravenous (IV) administration to rats.
  
  
  RESULTS
  VOR-SLNs were spherical, with a narrowly distributed average size of ~100 nm, and were physically stable for 3 months. Drug release showed a typical bi-phasic pattern in vitro, and was independent of pH. VOR-SLNs were more cytotoxic than the free drug in both sensitive (MCF-7 and A549) and resistant (MDA-MB-231) cancer cells. Importantly, SLN formulations showed prominent cytotoxicity in MDA-MB-231 cells at low doses, suggesting an ability to effectively counter the P-glycoprotein-related drug efflux pumps. Pharmacokinetic studies clearly demonstrated that VOR-SLNs markedly improved VOR plasma circulation time and decreased its elimination rate constant. The areas under the VOR concentration-time curve produced by oral and IV administration of VOR-SLNs were significantly greater than those produced by free drug administration. These in vivo results clearly highlighted the remarkable potential of SLNs to augment the bioavailability of VOR.
  
  
  CONCLUSIONS
  VOR-SLNs successfully enhanced the oral bioavailability, circulation half-life, and chemotherapeutic potential of VOR.
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan, 712-749, South Korea.
authors.forename: Tuan Hiep
authors.initials: TH
authors.lastname: Tran
authors.forename: Thiruganesh
authors.initials: T
authors.lastname: Ramasamy
authors.forename: Duy Hieu
authors.initials: DH
authors.lastname: Truong
authors.forename: Beom Soo
authors.initials: BS
authors.lastname: Shin
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055808:Drug Discovery / Q000379:methods; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008055:Lipids / Q000008:administration & dosage / Q000493:pharmacokinetics; D061986:MCF-7 Cells; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D006877:Hydroxamic Acids; D008055:Lipids; D000077337:Vorinostat