title: Effects of particle size and binding affinity for small interfering RNA on the cellular processing, intestinal permeation and anti-inflammatory efficacy of polymeric nanoparticles.
abstract: BACKGROUND
  Silencing of excessive secreted tumour necrosis factor (TNF)-α from macrophages might be an effective therapy of ulcerative colitis (UC), which acquires improvements on small interfering RNA (siRNA) delivery vectors. Thus, in the present study, the effects of particle size and binding affinity of four polymeric nanoparticles on siRNA delivery for the treatment of UC were evaluated.
  
  
  METHODS
  Galactosylated trimethyl chitosan-cysteine (GTC) nanoparticles of varying particle size and binding affinity for siRNA were prepared and TNF-α siRNA was encapsulated. Their cellular transport was investigated in murine macrophages and Caco-2 cell monolayers were utilized to analysis the intestinal permeation. Finally, in vivo anti-inflammatory efficacy was assessed in a mouse model of UC.
  
  
  RESULTS
  Although marginal effects of particle size on the in vitro gene silencing efficiency were detected, GTC nanoparticles with a particle size of 450 nm and stronger binding affinity for siRNA showed reduced intestinal epithelial permeability and enhanced in vivo anti-inflammatory efficacy compared to those with a particle size of 200 nm. By contrast, the delivery processes were significantly affected by the binding affinity for siRNA, where smaller GTC nanoparticles (200 nm) with moderate siRNA binding strength exhibited remarkable cytoplasmic distribution and sufficient intracellular release of siRNA, as well as a sustained in vitro and in vivo gene silencing effect.
  
  
  CONCLUSIONS
  Nanoparticles with a particle size of 450 nm or balanced binding affinity for siRNA might be preferable for the treatment of ulcerative colitis.
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Wenyue
authors.initials: W
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yin
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D020868:Gene Silencing; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D010446:Peptide Fragments / Q000235:genetics*; D010539:Permeability; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000893:Anti-Inflammatory Agents; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C076419:tumor necrosis factor (1-26)
keywords: anti-inflammatory therapy; binding affinity; particle size; polymeric nanoparticles; siRNA delivery