title: Epithelial toxicity of alkylglycoside surfactants.
abstract: Alkylglycoside surfactants have been proposed as drug delivery excipients with the potential to enhance mucosal drug absorption of therapeutic macromolecules. Previous work reported their drug absorption-promoting potential by demonstrating that several compounds within this class of surfactants improve mucosal absorption of peptides, proteins and other macromolecules. However, detailed investigation of their toxicity has not been conducted. Using Calu-3 epithelial cell layers as a model of the airway mucosa, and liposomes as models of cell membranes, this work investigates the cytotoxicity of dodecylmaltoside, tridecylmaltoside and tetradecylmaltoside, as representative alkylglycosides. A combination of different toxicity assays and other tests indicating cell membrane disruption were used to assess cytotoxicity. The alkylglycosides tested induced a dramatic reduction in cell viability, cell membrane and liposome-disruptive effects, as well as abrogation of transepithelial electrical resistance that did not recover completely. Importantly, these phenomena were noted at concentrations markedly lower than those typically used in the literature studies demonstrating the absorption-enhancing properties of alkylglycosides. This work therefore demonstrates that alkylglycosides exhibit significant toxicity towards airway epithelial cells, most likely resulting from a membrane-damaging effect, highlighting a need for further evaluation of their safety as absorption-enhancing excipients.
authors.affiliation: Division of Drug Delivery and Tissue Engineering, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Driton.Vllasaliu@nottingham.ac.uk
authors.forename: Driton
authors.initials: D
authors.lastname: Vllasaliu
authors.forename: Saif
authors.initials: S
authors.lastname: Shubber
authors.forename: Robyn
authors.initials: R
authors.lastname: Fowler
authors.forename: Martin
authors.initials: M
authors.lastname: Garnett
authors.forename: Cameron
authors.initials: C
authors.lastname: Alexander
authors.forename: Snow
authors.initials: S
authors.lastname: Stolnik
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000473:pathology; D002463:Cell Membrane Permeability; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004847:Epithelial Cells / Q000187:drug effects* / Q000473:pathology; D005960:Glucosides / Q000633:toxicity; D006027:Glycosides / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008081:Liposomes; D008320:Maltose / Q000031:analogs & derivatives / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000473:pathology; D013501:Surface-Active Agents / Q000737:chemistry / Q000633:toxicity*
chemical_list: D005960:Glucosides; D006027:Glycosides; D008081:Liposomes; D010713:Phosphatidylcholines; D013501:Surface-Active Agents; C459187:tetradecyl maltoside; D008320:Maltose; C040358:dodecyl maltoside; D002784:Cholesterol; D007770:L-Lactate Dehydrogenase