title: Optimization of novel tocopheryl acetate nanoemulsions for parenteral delivery of curcumin for therapeutic intervention of sepsis.
abstract: OBJECTIVE
  The objective of this study is to develop a nanostructured parenteral delivery system, laden with curcumin (CUR), for the therapeutic intervention of sepsis and associated pathologies.
  
  
  METHODS
  Nanoemulsions were fabricated using sonication and speed homogenization. Size and zeta potential were evaluated by dynamic light scattering and transmission electron microscopy analysis. Pharmacodynamic and pharmacokinetic studies were performed on a rat model of lipopolysaccharide (LPS)-induced sepsis.
  
  
  RESULTS
  The drug content of optimized nanoemulsion (F5) formulation (particle size 246 ± 08 nm, polydispersity index (PDI) of 0.120, zeta potential of -41.1 ± 1.2 mV) was found to be 1.25 mg/ml. In vitro release studies demonstrated that F5 was able to sustain the release of CUR for up to 24 h. Minimal hemolysis and cellular toxicity demonstrated its suitability for intravenous administration. Significant reduction of inflammatory mediator levels was mediated through enhanced uptake by in RAW 264.7 and THP-1 in absence/presence of LPS. Nanoemulsion resulted in an improvement of plasma concentration (AUCF5/AUC CUR = 8.80) and tissue distribution of CUR in rats leading to a reduction in LPS-induced lung and liver injury due to less neutrophil migration, reduced TNF-α levels and oxidative stress (demonstrated by levels of lipid peroxides as well as carbonylated proteins) as confirmed by histopathological studies.
  
  
  CONCLUSIONS
  The findings suggest that the therapeutic performance (i.e., reduction in oxidative damage in tissues) of CUR can be enhanced by employing tocol acetate nanoemulsions (via improving pharmacokinetics and tissue distribution) as a platform for drug delivery in sepsis-induced organ injury.
authors.affiliation: CSIR-Central Drug Research Institute, Pharmaceutics Division, Preclinical south PCS 002/011 , Jankipuram Extension, Sitapur Road, Lucknow, 226031 , India +91 9415753171 ; mishrapr@hotmail.com.
authors.forename: Prashant
authors.initials: P
authors.lastname: Shukla
authors.forename: Pankaj
authors.initials: P
authors.lastname: Dwivedi
authors.forename: Pramod Kumar
authors.initials: PK
authors.lastname: Gupta
authors.forename: Prabhat Ranjan
authors.initials: PR
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002460:Cell Line; D003474:Curcumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004655:Emulsions / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D005434:Flow Cytometry; D007263:Infusions, Parenteral; D008054:Lipid Peroxides / Q000378:metabolism; D008070:Lipopolysaccharides; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D053758:Nanoparticles / Q000737:chemistry; D011654:Pulmonary Edema / Q000097:blood / Q000188:drug therapy / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D014018:Tissue Distribution; D014815:Vitamins / Q000737:chemistry*; D024502:alpha-Tocopherol / Q000737:chemistry*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004337:Drug Carriers; D004655:Emulsions; D008054:Lipid Peroxides; D008070:Lipopolysaccharides; D014815:Vitamins; D024502:alpha-Tocopherol; D003474:Curcumin
keywords: carbonyl protein; cytokines; lipid peroxides; lipopolysaccharide; lung edema; myeloperoxidase; sepsis