Vitamin E succinate-grafted-chitosan/chitosan oligosaccharide mixed micelles loaded with C-DMSA for Hg2+ detection and detoxification in rat liver

Int J Nanomedicine. 2019 Aug 27:14:6917-6932. doi: 10.2147/IJN.S213084. eCollection 2019.

Abstract

Aim: To determine whether the use of a mixed polymeric micelle delivery system based on vitamin E succinate (VES)-grafted-chitosan oligosaccharide (CSO)/VES-grafted-chitosan (CS) mixed micelles (VES-g-CSO/VES-g-CS MM) enhances the delivery of C-DMSA, a theranostic fluorescent probe, for Hg2+ detection and detoxification in vitro and in vivo.

Methods: Mixed micelles self-assembled from two polymers, VES-g-CSO and VES-g-CS, were used to load C-DMSA and afforded C-DMSA@VES-g-CSO/VES-g-CS MM for cell and in vivo applications. Fluorescence microscopy was used to assess C-DMSA cellular uptake and Hg2+ detection in L929 cells. C-DMSA@VES-g-CSO/VES-g-CS MM was then administered intravenously. Hg2+ detection was assessed by fluorescence microscopy in terms of bio-distribution while detoxification efficacy in Hg2+-poisoned rat models was evaluated in terms of mercury contents in blood and in liver.

Results: The C-DMSA loaded mixed micelles, C-DMSA@VES-g-CSO/VES-g-CS MM, significantly enhanced cellular uptake and detoxification efficacy of C-DMSA in Hg2+ pretreated human L929 cells. Evidence from the reduction of liver coefficient, mercury contents in liver and blood, alanine transaminase and aspartate transaminase activities in Hg2+ poisoned SD rats treated with the mixed micelles strongly supported that the micelles were effective for Hg2+ detoxification in vivo. Furthermore, ex vivo fluorescence imaging experiments also supported enhanced Hg2+ detection in rat liver.

Conclusion: The mixed polymeric micelle delivery system could significantly enhance cell uptake and efficacy of a theranostic probe for Hg2+ detection and detoxification treatment in vitro and in vivo. Moreover, this nanoparticle drug delivery system could achieve targeted detection and detoxification in liver.

Keywords: C-DMSA; detection and detoxification; drug delivery system; mercury poisoning; micelles.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Cell Death / drug effects
  • Cell Line
  • Chitosan / chemical synthesis
  • Chitosan / chemistry*
  • Drug Liberation
  • Fluorescent Dyes / chemical synthesis
  • Fluorescent Dyes / chemistry
  • Humans
  • Inactivation, Metabolic / drug effects
  • Liver / metabolism*
  • Male
  • Mercury / analysis*
  • Mercury / blood
  • Mice, Inbred BALB C
  • Micelles*
  • Nanoparticles / chemistry
  • Oligosaccharides / chemical synthesis
  • Oligosaccharides / chemistry*
  • Rats, Sprague-Dawley
  • Succimer / chemical synthesis
  • Succimer / chemistry*
  • alpha-Tocopherol / chemical synthesis
  • alpha-Tocopherol / chemistry
  • alpha-Tocopherol / pharmacology*

Substances

  • Fluorescent Dyes
  • Micelles
  • Oligosaccharides
  • Chitosan
  • Succimer
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Mercury
  • alpha-Tocopherol