title: Ternary polymeric nanoparticles for oral siRNA delivery.
abstract: OBJECTIVE
  Poor stability and inefficient absorption in the intestinal tract are major barriers confronting oral delivery of siRNA. We aimed to uncover if ternary polymeric nanoparticles (cationic polymer/siRNA/anionic component) can overcome these obstacles through changing the formulation-related parameters.
  
  
  METHODS
  Ternary polymeric nanoparticles were prepared by ionic gelation of chitosan, N-trimethyl chitosan (TMC), or thiolated trimethyl chitosan (TTMC) with tripolyphosphate (TPP) or hyaluronic acid (HA), and siRNA was simultaneously encapsulated. Structural stabilities and siRNA protection of these nanoparticles were assessed in simulated intestinal milieu. Their transport across ex vivo rat ileum, macrophage uptake, in vitro gene silencing, and in vivo biodistribution after oral administration were investigated.
  
  
  RESULTS
  Ternary polymeric nanoparticles formed by TTMC, siRNA, and TPP (TTMC/siRNA/TPP nanoparticles) showed suitable structural stability and siRNA protection in the intestinal tract, good permeability across ex vivo rat ileum, superior cellular uptake and gene silencing efficiency in Raw 264.7 cells, and high systemic biodistribution after oral administration.
  
  
  CONCLUSIONS
  TTMC/siRNA/TPP nanoparticles demonstrated efficient gene silencing in vitro and systemic biodistribution in vivo, therefore, they were expected to be potential vehicles for oral siRNA delivery.
authors: State Key Laboratory of Genetic Engineering Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, 200433, China.
authors: Jing
authors: J
authors: Zhang
authors: Chunbai
authors: C
authors: He
authors: Cui
authors: C
authors: Tang
authors: Chunhua
authors: C
authors: Yin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D011122:Polyphosphates / Q000737:chemistry / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; C118071:N-trimethyl chitosan chloride; D011122:Polyphosphates; D034741:RNA, Small Interfering; D013438:Sulfhydryl Compounds; D006820:Hyaluronic Acid; D048271:Chitosan; C005692:triphosphoric acid