Discotic amphiphile supramolecular polymers for drug release and cellular activation with light

The limited efficacy shown by drug delivery systems so far prompts to develop new molecular approaches to release drugs in a controlled and selective manner and with lower adverse effects. Light is a privileged stimulus for delivery because it can be applied in sharp spatiotemporal patterns and is orthogonal to most biological processes in animals. Supramolecular polymers form molecular nanostructures whose robustness, versatility, and responsivity to different stimuli have generated wide interest in materials chemistry, energy, and medicine1. However, their application as drug delivery vehicles has received little attention. We have built supramolecular polymers based on discotic amphiphiles that self-assemble in linear nanostructures in water2,3. They can integrate diverse amphiphilic bioligands and release them upon illumination, acutely producing functional effects in physiological conditions. We devised two strategies for drug incorporation into the photoswitchable nanofibers. In the first one, discotic monomers with and without conjugated bioligands were co-assembled in helicoidal supramolecular fibers and evaluated by transmission electron microscopy and circular dichroism. In the second approach, we integrated Iperoxo-azo4, a potent agonist of muscarinic receptors into the discotic polymer by means of noncovalent stacking interactions and showed that it can be released on demand with light ex situ and in situ, rapidly activating the target receptor in living cells and triggering intracellular responses. These novel discotic supramolecular polymers can be used as light-driven drug delivery systems for small, planar, and amphiphilic drugs. References: (1)​Cantekin, S.; de Greef, T. F. A.; Palmans, A. R. A. Benzene-1,3,5-Tricarboxamide: A Versatile Ordering Moiety for Supramolecular Chemistry. Chem Soc Rev 2012, 41 (18), 6125–6137. https://doi.org/10.1039/c2cs35156k. (2)​Fuentes, E.; Gerth, M.; Berrocal, J. A.; Matera, C.; Gorostiza, P.; Voets, I. K.; Pujals, S.; Albertazzi, L. An Azobenzene-Based Single-Component Supramolecular Polymer Responsive to Multiple Stimuli in Water. J Am Chem Soc 2020, 142 (22), 10069–10078. https://doi.org/10.1021/jacs.0c02067. (3)​Fuentes, E.; Gabaldón, Y.; Collado, M.; Dhiman, S.; Berrocal, J. A.; Pujals, S.; Albertazzi, L. Supramolecular Stability of Benzene-1,3,5-Tricarboxamide Supramolecular Polymers in Biological Media: Beyond the Stability–Responsiveness Trade-Off. J Am Chem Soc 2022, 144 (46), 21196–21205. https://doi.org/10.1021/jacs.2c08528. (4)​Agnetta, L.; Bermudez, M.; Riefolo, F.; Matera, C.; Claro, E.; Messerer, R.; Littmann, T.; Wolber, G.; Holzgrabe, U.; Decker, M. Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties. J Med Chem 2019, 62 (6), 3009–3020. https://doi.org/10.1021/acs.jmedchem.8b01822.