Interaction of model antibiotics with calixarene-based micellar aggregates: an ITC study

The employment of drug delivery systems (DDSs) for the entrapment of target molecules is an emerging strategy used to improve the therapeutic efficacy of a drug. For example, old generation antibiotics may benefit from the interaction with suitable nanocarriers for overcoming problems associated with antibiotic resistance [1]. Polycationic calixarene derivatives able to self-assemble in nanoaggregates are promising novel nanocontainers for the delivery of antibiotics to bacteria due to their ability to establish electrostatic interactions with the negatively charged bacterial membranes [2]. In particular, a polycationic calix[4]arene amphiphile, CholineC4dod, bearing choline groups and dodecyl aliphatic chains at the cavity upper and lower rim respectively, proved to be a promising nanocarrier for drug delivery [3]. Despite the general interest in the study of drug-micelle interactions, a quantitative analysis of the species, binding affinity as well as thermodynamic parameters for the recognition/inclusion of a drug with(in) micellar assemblies has rarely been addressed. However, the determination of the strength and nature of these interactions is crucial for the design of novel medicines as well as for the modification or selection of suitable shuttles for target-oriented drug delivery. The present work deals with the study of the binding features of polycationic calix[4]arene derivatives (CholineC4dod, MedeaC4dod and MedeaC4prop) with ofloxacin, chloramphenicol or tetracycline (Figure 1) in neutral aqueous solution for investigating the capability of micellar aggregates to recognize and host three old generation antibiotics. These molecules were selected as models of antibiotics affected by the onset of resistance phenomena with the aim of offering a contribution to the design and development of effective DDSs for the repurposing of old-fashioned drugs. The examination of solution equilibria and the determination of the binding parameters in neutral aqueous solution were carried out using nano-isothermal titration calorimetry, an invaluable technique for determining both stability constant and enthalpy change values for host-guest complex formation [4] and/or self-organization of surfactants into micelles by a single experiment [5,6]. ITC experiments provided key information on the forces driving the molecular recognition processes: the formation of the chloramphenicol-micelle adduct was found to be enthalpically driven, whereas entropy drives the formation of the adducts with both ofloxacin and tetracycline. The picture obtained by ITC results about the positioning of the antibiotics within the micellar backbone was also supported by NMR experiments [7]. Figure 1. (A) From left to right: MedeaC4prop, MedeaC4dod, CholineC4dod; (B) from left to right: ofloxacin, tetracycline hydrochloride, chloramphenicol. References: [1] R. K. Kobayashi, G. Nakazato, Frontiers in Microbiology 2020, 11, 1421-1423. [2] I. Di Bari, R. Picciotto, G. Granata, A. R. Blanco, G. M. L. Consoli, S. Sortino, Organic and Biomolecular Chemistry 2016, 14(34), 8047-8052. [3] G. Granata, S. Petralia, G. Forte, S. Conoci, G. M. L. Consoli, Materials Science and Engineering: C 2020, 111, 110842-110850. [4] C. Bonaccorso, R. Migliore, M. A. Volkova, G. Arena, C. Sgarlata, Thermochimica Acta 2017, 656, 47-52. [5] W. Loh, C. Brinatti, K. C. Tam, Biochimica et Biophysica Acta 2016, 1860(5), 999-1016. [6] R. Migliore, PhD Thesis, University of Catania, 2019. [7] R. Migliore, G. Granata, A. Rivoli, G. M. L. Consoli, C. Sgarlata, Frontiers in Chemistry 2021, 8, 626467.