title: Novel stable cytokine delivery system in physiological pH solution: chitosan oligosaccharide/heparin nanoparticles.
abstract: BACKGROUND
  Cell therapy is a promising strategy for tissue regeneration. Key to this strategy is mobilization and recruitment of exogenous or autologous stem/progenitor cells by cytokines. However, there is no effective cytokine delivery system available for clinic application, in particular for myocardial regeneration. The aim of this study was to develop a novel cytokine delivery system that is stable in solution at physiological pH.
  
  
  METHODS
  Four groups of self-assembled chitosan oligosaccharide/heparin (CSO/H) nanoparticles were prepared with various volume ratios of chitosan oligosaccharide to heparin (5:2, 5:4, 4:15, 1:5) and characterized by laser diffraction, particle size analysis, and transmission electron microscopy. The encapsulation efficiency and loading content of two cytokines, ie, stromal cell-derived factor (SDF)-1α and vascular endothelial growth factor (VEGF) were quantified using an enzyme-linked immunosorbent assay. The biological activity of the loaded SDF-1α and VEGF was evaluated using the transwell migration assay and MTT assay. The dispersion profiles for the cytokine-loaded nanoparticles were quantified using fluorescence molecular tomography.
  
  
  RESULTS
  CSO/H nanoparticles were prepared successfully in solution with physiological pH. The particle sizes in the four treatment groups were in the range of 96.2-210.5 nm and the zeta potential ranged from -29.4 mV to 24.2 mV. The loading efficiency in the CSO/H nanoparticle groups with the first three ratios was more than 90%. SDF-1α loaded into CSO/H nanoparticles retained its migration activity and VEGF loaded into CSO/H nanoparticles continued to show proliferation activity. The in vivo dispersion test showed that the CSO/H nanoparticles enabled to VEGF to accumulate locally for a longer period of time.
  
  
  CONCLUSIONS
  CSO/H nanoparticles have a high cytokine loading capacity and allow cytokines to maintain their bioactivity for longer, are stable in an environment with physiological pH, and may be a promising cytokine delivery system for tissue regeneration.
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Dengpu
authors.initials: D
authors.lastname: Deng
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Changwei
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Zhongkui
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Zhongshi
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Tang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D048271:Chitosan / Q000737:chemistry*; D016207:Cytokines / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D006493:Heparin / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D012996:Solutions; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D054377:Chemokine CXCL12; D016207:Cytokines; D012996:Solutions; D042461:Vascular Endothelial Growth Factor A; D006493:Heparin; D048271:Chitosan
keywords: chitosan oligosaccharide; cytokine delivery system; nanoparticles; physiological pH; stromal cell-derived factor-1α; vascular endothelial growth factor