title: Alpha-lipoic acid-stearylamine conjugate-based solid lipid nanoparticles for tamoxifen delivery: formulation, optimization, in-vivo pharmacokinetic and hepatotoxicity study.
abstract: OBJECTIVE
  This study was designed to demonstrate the potential of novel α-lipoic acid-stearylamine (ALA-SA) conjugate-based solid lipid nanoparticles in modulating the pharmacokinetics and hepatotoxicity of tamoxifen (TMX).
  
  
  METHODS
  α-lipoic acid-stearylamine bioconjugate was synthesized via carbodiimide chemistry and used as a lipid moiety for the generation of TMX-loaded solid lipid nanoparticles (TMX-SLNs). TMX-SLNs were prepared by solvent emulsification-diffusion method and optimized for maximum drug loading using rotatable central composite design. The optimized TMX-SLNs were stabilized using 10% w/w trehalose as cryoprotectant. In addition, pharmacokinetics and hepatotoxicity of freeze-dried TMX-SLNs were also evaluated in Sprague Dawley rats.
  
  
  RESULTS
  Initial characterization with transmission electron microscopy revealed spherical morphology with smooth surface having an average particle size of 261.08 ± 2.13 nm. The observed entrapment efficiency was 40.73 ± 2.83%. In-vitro release study showed TMX release was slow and pH dependent. Pharmacokinetic study revealed a 1.59-fold increase in relative bioavailability as compared to TMX suspension. A decrease in hepatotoxicity of TMX is evidenced by the histopathological evaluation of liver tissues.
  
  
  CONCLUSIONS
  α-lipoic acid-stearylamine conjugate-based SLNs have a great potential in enhancing the oral bioavailability of poorly soluble drugs like TMX. Moreover, this ALA-SA nanoparticulate system could be of significant value in long-term anticancer therapy with least side effects.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Ankit
authors.initials: A
authors.lastname: Dhaundiyal
authors.affiliation: Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Jena
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Sanjaya K
authors.initials: SK
authors.lastname: Samal
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Bhavin
authors.initials: B
authors.lastname: Sonvane
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Chand
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, S.A.S Nagar, Punjab, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000737:chemistry*; D000818:Animals; D001682:Biological Availability; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003451:Cryoprotective Agents / Q000737:chemistry; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D053758:Nanoparticles; D036103:Nanotechnology; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D013501:Surface-Active Agents / Q000737:chemistry; D013629:Tamoxifen / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D013678:Technology, Pharmaceutical / Q000379:methods; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D014199:Trehalose / Q000737:chemistry
chemical_list: D000588:Amines; D003451:Cryoprotective Agents; D004337:Drug Carriers; D004965:Estrogen Antagonists; D012997:Solvents; D013501:Surface-Active Agents; D013629:Tamoxifen; D008063:Thioctic Acid; D014199:Trehalose; C009317:stearylamine
keywords: bioavailability; hepatotoxicity; solid lipid nanoparticles; tamoxifen; α-lipoic acid