title: Safety assessment of thiolated polymers: effect on ciliary beat frequency in human nasal epithelial cells.
abstract: OBJECTIVE
  The aim of this study was to investigate the nasal safety of gel formulations of thiolated polymers (thiomers) by assessing their effect on ciliary beat frequency (CBF) in human nasal epithelial cells.
  
  
  METHODS
  Poly(acrylic acid) 450 kDa-cysteine (PAA-cys) and alginate-cysteine (alg-cys) were synthesized by covalent attachment of L-cysteine to the polymeric backbone. The cationic polymer chitosan-thiobutylamidine (chito-TBA) was synthesized by attaching iminothiolane to chitosan. CBF using was measured by a photometric system. CBF was measured before incubating the cells with test gels, during incubation and after washing out the polymeric test gels to evaluate reversibility of cilio-inhibition. The influence of viscosity on CBF was determined by using hydroxyethylcellulose (HEC)-gels of various concentrations.
  
  
  RESULTS
  Ciliary beating was observed to be affected by viscosity, but cilia were still beating in the presence of a HEC-gel displaying an apparent viscosity of 25 Pa.s. In case of thiolated polymers and their unmodified control, a concentration-dependent decrease in CBF could be observed. PAA-cys, alg-cys, chito-TBA and their corresponding unmodified controls exhibited a moderate cilio-inhibitory effect, followed by a partial recovery of CBF when used at a concentration of 1%. Alg-cys 2% and chito-TBA 2% (m/v) gels exhibited severe cilio-inhibition, which was partially reversible. L-cysteine and reduced glutathione led to mild cilio-inhibition at concentrations of 3% (m/v).
  
  
  CONCLUSIONS
  Taking into account that dilution after application and cilio-modifying effects is usually more pronounced under in vitro conditions, thiomers can be considered as suitable excipients for nasal drug delivery systems.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Innsbruck, Austria.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Palmberger
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Anja
authors.initials: A
authors.lastname: Vetter
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000281:Administration, Intranasal; D000464:Alginates / Q000009:adverse effects; D001672:Biocompatible Materials / Q000009:adverse effects*; D048271:Chitosan / Q000009:adverse effects; D002923:Cilia / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects*; D020723:Glucuronic Acid / Q000009:adverse effects; D006603:Hexuronic Acids / Q000009:adverse effects; D006801:Humans; D009297:Nasal Mucosa / Q000187:drug effects*; D011108:Polymers / Q000009:adverse effects*; D013438:Sulfhydryl Compounds / Q000009:adverse effects*
chemical_list: D000464:Alginates; D001672:Biocompatible Materials; D006603:Hexuronic Acids; D011108:Polymers; D013438:Sulfhydryl Compounds; D020723:Glucuronic Acid; D048271:Chitosan