Abstract
BackgroundThe need for woman-controlled, cheap, safe, effective, easy-to-use and easy-to-store topical applications for prophylaxis against sexually transmitted infections (STIs) makes surfactant-containing formulations an interesting option that requires a more fundamental knowledge concerning surfactant toxicology and structure-activity relationships.Methodology/Principal FindingsWe report in vitro effects of surfactant concentration, exposure time and structure on the viability of mammalian cell types typically encountered in the vagina, namely, fully polarized and confluent epithelial cells, confluent but non-polarized epithelial-like cells, dendritic cells, and human sperm. Representatives of the different families of commercially available surfactants – nonionic (Triton X-100 and monolaurin), zwitterionic (DDPS), anionic (SDS), and cationic (CnTAB (n = 10 to 16), C12PB, and C12BZK) – were examined. Triton X-100, monolaurin, DDPS and SDS were toxic to all cell types at concentrations around their critical micelle concentration (CMC) suggesting a non-selective mode of action involving cell membrane destabilization and/or destruction. All cationic surfactants were toxic at concentrations far below their CMC and showed significant differences in their toxicity toward polarized as compared with non-polarized cells. Their toxicity was also dependent on the chemical nature of the polar head group. Our results suggest an intracellular locus of action for cationic surfactants and show that their structure-activity relationships could be profitably exploited for STI prophylaxis in vaginal gel formulations. The therapeutic indices comparing polarized epithelial cell toxicity to sperm toxicity for all surfactants examined, except C12PB and C12BZK, does not justify their use as contraceptive agents. C12PB and C12BZK are shown to have a narrow therapeutic index recommending caution in their use in contraceptive formulations.Conclusions/SignificanceOur results contribute to understanding the mechanisms involved in surfactant toxicity, have a predictive value with regard to their safety, and may be used to design more effective and less harmful surfactants for use in topical applications for STI prophylaxis.
Highlights
Transmitted infections (STIs) are a major public-health problem worldwide
The first criterion to be considered in the evaluation of the safety of topical vaginal microbicides is their toxicity to the cervicovaginal mucosa
Earlier studies identified vaginal columnar epithelial cells as the most important site of damage caused by the surfactants Nonoxynol-9 [10,20] and C31G [19] in humans
Summary
Transmitted infections (STIs) are a major public-health problem worldwide. Direct treatment costs and serious collateral perinatal damage caused by STIs represent hefty financial and social burdens, in developing countries [1]. Topical applications (such as vaginal gels) with microbicidal and spermicidal activity, that can be used by women without the need for consent of a male partner [5] are one possible answer to the problem These topical applications should be highly effective, non-disruptive of the integrity of the vaginal epithelial barrier, should not induce mucosal inflammation, not interfere with the innate immune response nor alter vaginal flora, and, for the poorer regions of the world, be cheap, stable, easy to store and easy to use. The need for woman-controlled, cheap, safe, effective, easy-to-use and easy-to-store topical applications for prophylaxis against sexually transmitted infections (STIs) makes surfactant-containing formulations an interesting option that requires a more fundamental knowledge concerning surfactant toxicology and structure-activity relationships
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