Person:
Ballesteros Papantonakis, María De La Paloma

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First Name
María De La Paloma
Last Name
Ballesteros Papantonakis
URI
https://hdl.handle.net/20.500.14352/77542
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Farmacia Galénica y Tecnología Alimentaria
Area
Farmacia y Tecnología Farmaceútica
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Author: González Burgos, Elena María × Subject: 615 ×

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    Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers
    (Journal of Controlled Release, 2021) Raquel Fernández-García; Juan C. Muñoz-García; Matthew Wallace; Laszlo Fabian; González Burgos, Elena María; Gómez-Serranillos Cuadrado, María Pilar; Raposo González, Rafaela; Bolas Fernández, Francisco; Ballesteros Papantonakis, María De La Paloma; Anne Marie Healy; Yaroslav Z. Khimyak; Serrano López, Dolores Remedios
    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 polyaggregated 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.