Development of vorinostat-loaded solid lipid nanoparticles to enhance pharmacokinetics and efficacy against multidrug-resistant cancer cells.

Abstract

PURPOSE:

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: Tuan Hiep Tran, Thiruganesh Ramasamy, Duy Hieu Truong, Beom Soo Shin, Han-Gon Choi, Chul Soon Yong, Jong Oh Kim
• Journal: Pharmaceutical research (Pharm Res) Vol. 31 Issue 8 Pg. 1978-88 (Aug 2014) ISSN: 1573-904X [Electronic] United States
• PMID: 24562809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Hydroxamic Acids
• Lipids
• Vorinostat

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Drug Carriers (administration & dosage, pharmacokinetics)
• Drug Discovery (methods)
• Drug Resistance, Multiple (drug effects, physiology)
• Drug Resistance, Neoplasm (drug effects, physiology)
• Female
• Humans
• Hydroxamic Acids (administration & dosage, pharmacokinetics)
• Lipids (administration & dosage, pharmacokinetics)
• MCF-7 Cells
• Male
• Nanoparticles (administration & dosage, metabolism)
• Rats
• Rats, Sprague-Dawley
• Treatment Outcome
• Vorinostat