From model membranes to cell lines: Evaluating the safety of antifungal polycations using Langmuir monolayers

Polycations are promising antifungal agents for various applications owing to their broad-spectrum antimicrobial activity; however, their interactions with mammalian membranes and the mechanisms underlying their cytotoxicity remain insufficiently understood. To gain insight into these topics in this study the interactions of two polycation families, poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and poly(3-methacrylamidopropyl trimethylammonium chloride) (PMAPTAC), differing in chemical structure and molecular weight, which have previously been reported to exhibit antifungal activity, were investigated. The lipid Langmuir monolayers reflecting the composition of keratinocyte and fibroblast membranes, complemented by cytotoxicity studies on HaCaT keratinocytes and WS1 fibroblasts were used. PDMAEMA polymers affected all studied lipid monolayers more strongly than PMAPTAC, reducing molecular packing, and causing morphological alterations. The lower-molecular-weight PDMAEMA9k produced the greatest changes in membrane organization and displayed enhanced selectivity toward keratinocyte and fibroblast membrane models. Importantly, ceramides consistently attenuated polymer-induced perturbations, indicating their protective role in limiting polymer-membrane interactions. Cell-based studies demonstrated that, at concentrations corresponding to antifungal activity, none of the investigated polymers exhibited significant cytotoxicity toward studied skin cells lines. At higher concentrations, the higher-molecular-weight PDMAEMA66k caused a greater reduction in cell viability. This phenomenon, as reported in the literature it is complex in its nature, and the primary contributing factor may vary even among different types of mammalian cells however, there are no studies showing a link between these mechanisms and the membrane. Overall, Langmuir membrane models provide a valuable platform for evaluating polymer-membrane interactions and considering biological responses. The combined physicochemical and biological results indicate that the investigated polycations, particularly PDMAEMA derivatives, represent promising antifungal candidates with favorable safety profiles, while highlighting the need for further studies on the complex mechanisms underlying their cytotoxicity.