Effects of lipid membrane composition on the distribution of biocidal guanidine oligomer with solid supported lipid membranes

Polyhexamethylene guanidine (PHMG) is a cationic antimicrobial oligomer that has been used prevalently over the past few decades. However, due to the lack of inhalation toxicity assessment of PHMG, it has caused severe health damage, including fatal lung fibrosis, after being used as one of the major active ingredients of humidifier disinfectants in Korea. Because the first step of the entry of PHMG into airway is its association with cell membranes, the distribution of PHMG between lipid membranes and water is very important to know the depositional flux in the respiratory systems and related toxic mechanisms. We developed a quantitative method to determine the distribution constant (Klipw) of PHMG between solid supported lipid membranes and water and evaluated the effects of lipid membrane compositions on the Klipw of PHMG. PHMG accumulated into anionic lipid membranes rapidly compared to into cationic or zwitterionic lipid membranes, suggesting fast adsorption of PHMG onto anionic lipid head groups. Klipw values with anionic/zwitterionic lipid mixtures were higher than Klipw values with anionic lipids only, potentially due to the later phase separation after preferential interaction between PHMG and anionic lipids in lipid mixtures. In addition, Klipw values increased with increasing single acyl chain lipid content in unsaturated lipids and decreasing cholesterol content. These results imply that changes in lipid spontaneous curvature and lipid bilayer packing density also affect the membrane distribution of PHMG.