Cellular delivery: thiol-mediated uptake of vesicles, diselenolane-mediated uptake and activation of cell-penetrating peptides

Since their discovery, cell-penetrating peptides (CPPs) has been developed as a powerful drug delivery system. In order to increase their cellular penetration and cytoplasmic delivery, pyrenebutyrate has been added on cells to increase electrostatic and potential cation-π interactions with positive CPPs such as polyarginine. In order to increase the stabilization of the whole interaction, polarized π-surfaces with carboxylic function and different alkyl tails were tested along with perfluorinated fatty acids. Those new activators were tested first on model membrane and the most promising probes were tested on HeLa Kyoto cells. In a second project and following the discovery of increased uptake with strained cyclic disulfide by the thiol-mediated uptake in the Matile group and their ability to deliver peptides, we decided to investigate other cargoes such as liposomes and polymersomes. Therefore new transporters containing an alkyl chain, a positive charge and a thiol-responsive head were synthesized and the delivery of vesicles of different composition and size were tested on cells. Following the results with disulfides, we decided to investigate cyclic diselenides. Their thiol sensitivity was demonstrated and their potency as cellular transporter was evaluated using fluorophores.