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

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dc.contributor.authorRaquel Fernández-García
dc.contributor.authorJuan C. Muñoz-García
dc.contributor.authorMatthew Wallace
dc.contributor.authorLaszlo Fabian
dc.contributor.authorGonzález Burgos, Elena María
dc.contributor.authorGómez-Serranillos Cuadrado, María Pilar
dc.contributor.authorRaposo González, Rafaela
dc.contributor.authorBolas Fernández, Francisco
dc.contributor.authorBallesteros Papantonakis, María De La Paloma
dc.contributor.authorAnne Marie Healy
dc.contributor.authorYaroslav Z. Khimyak
dc.contributor.authorSerrano López, Dolores Remedios
dc.date.accessioned2024-01-12T12:53:49Z
dc.date.available2024-01-12T12:53:49Z
dc.date.issued2021-12-20
dc.description.abstractAntifungal 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.
dc.description.departmentDepto. de Farmacia Galénica y Tecnología Alimentaria
dc.description.facultyFac. de Farmacia
dc.description.facultyInstituto Universitario de Farmacia Industrial
dc.description.refereedTRUE
dc.description.sponsorshipEuropean Regional Development Fund
dc.description.sponsorshipEuropean Society of Clinical Microbiology an Infection Diseases (ESCMID)
dc.description.sponsorshipEngineering and Physical Sciences Research Council
dc.description.statuspub
dc.identifier.citationFernández-García R, Muñoz-García JC, Wallace M, Fabian L, González-Burgos E, Gómez-Serranillos MP, et al. Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers. Journal of Controlled Release 2022;341:716–32. https://doi.org/10.1016/j.jconrel.2021.12.019.
dc.identifier.doi10.1016/j.jconrel.2021.12.019
dc.identifier.issn0168-3659
dc.identifier.officialurlhttps://doi.org/10.1016/j.jconrel.2021.12.019
dc.identifier.urihttps://hdl.handle.net/20.500.14352/92797
dc.journal.titleJournal of Controlled Release
dc.language.isoeng
dc.page.final732
dc.page.initial716
dc.publisherElsevier
dc.relation.projectIDinfo:eu-repo/grantAgreement/16306
dc.relation.projectIDinfo:eu-repo/grantAgreement/SFI/12/RC/2275
dc.relation.projectIDinfo:eu-repo/grantAgreement/SFI/ 12/RC/2275_P2
dc.relation.projectIDinfo:eu-repo/grantAgreement/RGS\R1\191336
dc.relation.projectIDinfo:eu-repo/grantAgreement/MR/T044020/1
dc.relation.projectIDinfo:eu-repo/grantAgreement/EP/N033337/1
dc.rights.accessRightsrestricted access
dc.subject.cdu615
dc.subject.keywordSelf-assembling
dc.subject.keywordAggregation-states
dc.subject.keywordAmphotericin B
dc.subject.keywordSupramolecular chemistry
dc.subject.keywordOligomer
dc.subject.keywordDimer
dc.subject.keywordPoly-aggregate
dc.subject.keywordMonomer
dc.subject.keywordNMR
dc.subject.keywordROS
dc.subject.ucmFarmacia
dc.subject.unesco32 Ciencias Médicas
dc.titleSelf-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers
dc.typejournal article
dc.type.hasVersionAM
dc.volume.number341
dspace.entity.typePublication
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