title: An oral formulation of efavirenz-loaded lactoferrin nanoparticles with improved biodistribution and pharmacokinetic profile.
abstract: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, is a drug that is frequently included in highly active antiretroviral therapy for treatment of HIV infection. Decreased bioavailability and increased toxicity limit its use. We report a formulation of efavirenz-loaded lactoferrin nanoparticles (lacto-EFV-nano) for oral delivery which exhibited significantly improved pharmacological properties coupled with reduced toxicity compared with its free form.
  
  
  
  Lacto-EFV-nano was prepared using the Sol-oil protocol and characterized using various sources of characterization. In vitro and in vivo studies were performed to test the stability, safety, efficacy, biodistribution and pharmacokinetics of lacto-EFV-nano.
  
  
  
  The nanoparticles prepared for the present study had an average size of 45-60 nm as revealed by field emission scanning electron microscope measurements. Further, dynamic light scattering data showed a hydrodynamic radius of 103 ± 5.3 nm, a zeta potential of -23 ± 1.2 mV and a polydispersity index of < 0.341. Lacto-EFV-nano was found to be stable as assessed using differential scanning calorimetry and Fourier-transform infrared spectroscopy. Cell viability studies showed that lacto-EFV-nano was at least 2-fold less toxic to peripheral blood mononuclear cells, Jurkat T cell and B16-F10 cell lines than free EFV. Furthermore, lacto-EFV-nano [50% inhibitory concentration (IC50) < 1.1 nM] showed > 2-fold enhanced anti-HIV-1 activity compared with free EFV (IC50= 2.56 nM). Lacto-EFV-nano exhibited improved oral bioavailability and an improved in vivo pharmacokinetic profile, with a > 3-4-fold increase in the area under the plasma concentration-time curve (AUC), a 6-7-fold increase in the area under the first moment curve (AUMC), a > 30% increase in the peak plasma concentration of the drug after oral administration (Cmax) and a 2-fold increase in the time to reach Cmax(Tmax) and the time required for the concentration of the drug to reach half of its original value (t1/2). Furthermore, lacto-EFV-nano did not show any organ-related toxicity. A significant decrease in the concentrations of various parameters, elevated concentrations of which are markers of reduced safety, were also observed in rats treated with lacto-EFV-nano.
  
  
  
  Compared with free EFV, lacto-EFV-nano is a promising oral nanoformulation with enhanced bioavailability and efficacy of EFV and improved safety.
authors.affiliation: Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lakshmi
authors.affiliation: Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Kondapi
mesh_terms: D000284:Administration, Oral; D000480:Alkynes; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes; D004337:Drug Carriers / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007781:Lactoferrin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects; D017208:Rats, Wistar
chemical_list: D000480:Alkynes; D000890:Anti-Infective Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004337:Drug Carriers; D007781:Lactoferrin; C098320:efavirenz
keywords: 
  HIV
  ; efavirenz; nanoparticles; pharmacokinetics