Drug loading strategies for discotic amphiphile supramolecular polymers in water

(08) BTA-based supramolecular polymers are interesting systems for medical applications because of their high dynamicity and stimuli responsiveness in water [1]. Recently, IBEC developed a new class of BTA-based supramolecular polymers which showed responsiveness to temperature, salt concentration, pH, and light [2]. This versatility makes this new class of self-assembled fibers appealing for drug delivery purposes. In this work, we explored two strategies to incorporate different biologically active ligands into these polymers and demonstrate their employability as light-driven drug delivery systems. In the first strategy, we used a co-assembly approach in which two new discotic BTAazo- monomers assemble forming the final helicoidal supramolecular fibers. In the second one, we decided to cage Photoiperoxo [3], a potent photoswitchable derivative of the mAChR agonist Iperoxo [3]. Here, the interaction is based on the stacking between the azobenzene units of the ligand and the monomers. From the first approach, we obtained satisfying co-assemby results which were evaluated by transmission electron microscopy. Remarkably, the second system showed light-dependent biological effects in calcium imaging experiments on cells overexpressing M1 mAChRs. While caged Photoiperoxo did not evoke significant changes, UV pre-illuminated fibers caused an increase in intracellular calcium levels because of the activation of M1 mAChRs by the uncaged ligand. These results suggest that the new class of BTA-based supramolecular polymers [2] can potentially be used as light-driven drug delivery system for small, planar and amphiphilic drugs. References [1] Kantekin, S.; de Greef, T.F.A.; Palmans, A.R.A. Chemical Society Reviews. 2012, 41, 6125-6137. [2] Fuentes E.; Gerth M.; Berrocal J.A.; Matera C.; Gorostiza P.; Voets I.K.; Pujals S.; Albertazzi L. J Am Chem Soc. 2020, 142, 10069-10078. [3] Agnetta, L.; Bermudez, M.; Riefolo, F.; Matera, C.; Claro, E.; Messerer, R.; Littmann, T.; Wolber, G.; Holzgrabe, U.; Decker, M. Journal of Medicinal Chemistry. 2019, 62, 3009-3020.