Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers

Fernández-García, Raquel, Muñoz-García, Juan C., Wallace, Matthew, Fabian, Laszlo, González-Burgos, Elena, Gómez-Serranillos, M. Pilar, Raposo, Rafaela, Bolás-Fernández, Francisco, Ballesteros, M. Paloma, Healy, Anne Marie, Khimyak, Yaroslav Z. and Serrano, Dolores R. (2022) Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers. Journal of Controlled Release, 341. pp. 716-732. ISSN 0168-3659

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Abstract

Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell apoptosis and therefore efficacy. At the same time, the interaction can also take place with cell components from mammalian cells, leading to toxicity. AmB was selected as a model antifungal drug due to the complexity of its supramolecular chemical structure which can self-assemble in three different aggregation states in aqueous media: monomer, oligomer (also known as dimer) and poly-aggregate. The interplay between AmB self-assembly and its efficacy or toxicity against fungal or mammalian cells is not yet fully understood. To the best of our knowledge, this is the first report that investigates the role of excipients in the supramolecular chemistry of AmB and the impact on its biological activity and toxicity. The monomeric state was obtained by complexation with cyclodextrins resulting in the most toxic state, which was attributed to the greater production of highly reactive oxygen species upon disruption of mammalian cell membranes, a less specific mechanism of action compared to the binding to the ergosterol located in fungal cell membranes. The interaction between AmB and sodium deoxycholate resulted in the oligomeric and poly-aggregated forms which bound more selectively to the ergosterol of fungal cell membranes. NMR combined with XRD studies elucidated the interaction between drug and excipient to achieve the AmB aggregation states, and ultimately, their diffusivity across membranes. A linear correlation between particle size and the efficacy/toxicity ratio was established allowing to modulate the biological effect of the drug and hence, to improve pharmacological regimens. However, particle size is not the only factor modulating the biological response but also the equilibrium of each state which dictates the fraction of free monomeric form available. Tuning the aggregation state of AmB formulations is a promising strategy to trigger a more selective response against fungal cells and to reduce the toxicity in mammalian cells.

Item Type: Article
Additional Information: Funding Information: R. Fernández-García acknowledges Boehringer Ingelheim Fonds for her travel grant to perform solid-state characterisation at Trinity College Dublin and Erasmus + programme Key Action 1 (KA1) for her scholarship to perform NMR experiments at University of East Anglia. A.M. Healy acknowledges Science Foundation Ireland grants co-funded under the European Regional Development Fund (SFI/12/RC/2275 and SFI/12/RC/2275_P2). M. Wallace thanks the Royal Commission for the Exhibition of 1851 for a Research Fellowship and the Royal Society for a Research Grant: RGS\R1\191336. This work was also supported by a UKRI Future Leaders Fellowship to M. Wallace (MR/T044020/1). The Engineering and Physical Sciences Research Council (EPSRC) is acknowledged for provision of financial support (EP/N033337/1) for J.C. Muñoz-García and Y.Z. Khimyak. We are grateful for the use of the University of East Anglia (UEA) Faculty of Science NMR facility. This study has been partially funded by a Research Grant [year 2021, ID: 16306] from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) to D.R. Serrano.
Uncontrolled Keywords: aggregation states,amphotericin b,dimer,monomer,nmr,oligomer,poly-aggregate,ros,self-assembly,supramolecular chemistry,pharmaceutical science ,/dk/atira/pure/subjectarea/asjc/3000/3003
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 21 Dec 2021 13:30
Last Modified: 04 Jan 2022 09:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/82761
DOI: 10.1016/j.jconrel.2021.12.019

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