Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers
Chemicals and CAS Registry Numbers amphotericin B 1397-89-3, 30652-87-0 deoxycholate sodium 302-95-4 ergosterol 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4 gamma cyclodextrin 17465-86-0 sodium dihydrogen phosphate 7558-80-7, 7632-05-5 deoxycholic acid 83-44-3 Amphotericin B Antifungal Agents Deoxychol...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/394812 |
| Acceso en línea: | http://hdl.handle.net/10261/394812 https://api.elsevier.com/content/abstract/scopus_id/85121557127 |
| Access Level: | acceso abierto |
| Palabra clave: | Supramolecular chemistry Aggregation states Amphotericin B NMR Oligomer Poly-aggregate ROS Self-assembly |
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Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| title |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| spellingShingle |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers Fernández-García, Raquel Supramolecular chemistry Aggregation states Amphotericin B NMR Oligomer Poly-aggregate ROS Self-assembly |
| title_short |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| title_full |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| title_fullStr |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| title_full_unstemmed |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| title_sort |
Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomers |
| dc.creator.none.fl_str_mv |
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 Serrano, Dolores R |
| author |
Fernández-García, Raquel |
| author_facet |
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 Serrano, Dolores R |
| author_role |
author |
| author2 |
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 Serrano, Dolores R |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Boehringer Ingelheim Fonds Trinity College Dublin University of East Anglia Science Foundation Ireland European Commission Royal Society (UK) UK Research and Innovation Engineering and Physical Sciences Research Council (UK) European Society of Clinical Microbiology and Infectious Diseases Fernández-García, Raquel [0000-0001-5505-2615] Muñoz-García, Juan C. [0000-0003-2246-3236] Wallace, Matthew [0000-0002-5751-1827] Fabian, Laszlo [0000-0002-2087-4501] González-Burgos, Elena [0000-0003-2119-8768] Gómez-Serranillos, M Pilar [0000-0002-9178-3420] Raposo, Rafaela [0000-0002-2941-9767] Bolás-Fernández, Francisco [0000-0001-8062-2974] Ballesteros, M Paloma [0009-0003-9917-2506] Healy, Anne Marie [0000-0001-5093-9786] Khimyak, Yaroslav Z [0000-0003-0424-4128] Serrano, Dolores R [0000-0002-0475-8420] |
| dc.subject.none.fl_str_mv |
Supramolecular chemistry Aggregation states Amphotericin B NMR Oligomer Poly-aggregate ROS Self-assembly |
| topic |
Supramolecular chemistry Aggregation states Amphotericin B NMR Oligomer Poly-aggregate ROS Self-assembly |
| description |
Chemicals and CAS Registry Numbers amphotericin B 1397-89-3, 30652-87-0 deoxycholate sodium 302-95-4 ergosterol 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4 gamma cyclodextrin 17465-86-0 sodium dihydrogen phosphate 7558-80-7, 7632-05-5 deoxycholic acid 83-44-3 Amphotericin B Antifungal Agents Deoxycholic Acid Ergosterol Phospholipids |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2025 2025 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Postprint info:eu-repo/semantics/acceptedVersion |
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article |
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acceptedVersion |
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http://hdl.handle.net/10261/394812 https://api.elsevier.com/content/abstract/scopus_id/85121557127 |
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http://hdl.handle.net/10261/394812 https://api.elsevier.com/content/abstract/scopus_id/85121557127 |
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Inglés |
| language_invalid_str_mv |
Inglés |
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#PLACEHOLDER_PARENT_METADATA_VALUE# #PLACEHOLDER_PARENT_METADATA_VALUE# SFI/12/RC/2275 SFI/12/RC/2275_P2 https://doi.org/10.1016/j.jconrel.2021.12.019 No |
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info:eu-repo/semantics/openAccess |
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openAccess |
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aplication/pdf |
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Elsevier BV |
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Elsevier BV |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Consejo Superior de Investigaciones Científicas (CSIC) |
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1869409115818688512 |
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Self-assembling, supramolecular chemistry and pharmacology of amphotericin B: Poly-aggregates, oligomers and monomersFernández-García, RaquelMuñoz-García, Juan C.Wallace, MatthewFabian, LaszloGonzález-Burgos, ElenaGómez-Serranillos, M PilarRaposo, RafaelaBolás-Fernández, FranciscoBallesteros, M PalomaHealy, Anne MarieKhimyak, Yaroslav ZSerrano, Dolores RSupramolecular chemistryAggregation statesAmphotericin BNMROligomerPoly-aggregateROSSelf-assemblyChemicals and CAS Registry Numbers amphotericin B 1397-89-3, 30652-87-0 deoxycholate sodium 302-95-4 ergosterol 23637-22-1, 2418-45-3, 3992-98-1, 57-87-4 gamma cyclodextrin 17465-86-0 sodium dihydrogen phosphate 7558-80-7, 7632-05-5 deoxycholic acid 83-44-3 Amphotericin B Antifungal Agents Deoxycholic Acid Ergosterol PhospholipidsAntifungal 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.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.Peer reviewedElsevier BVBoehringer Ingelheim FondsTrinity College DublinUniversity of East AngliaScience Foundation IrelandEuropean CommissionRoyal Society (UK)UK Research and InnovationEngineering and Physical Sciences Research Council (UK)European Society of Clinical Microbiology and Infectious DiseasesFernández-García, Raquel [0000-0001-5505-2615]Muñoz-García, Juan C. [0000-0003-2246-3236]Wallace, Matthew [0000-0002-5751-1827]Fabian, Laszlo [0000-0002-2087-4501]González-Burgos, Elena [0000-0003-2119-8768]Gómez-Serranillos, M Pilar [0000-0002-9178-3420]Raposo, Rafaela [0000-0002-2941-9767]Bolás-Fernández, Francisco [0000-0001-8062-2974]Ballesteros, M Paloma [0009-0003-9917-2506]Healy, Anne Marie [0000-0001-5093-9786]Khimyak, Yaroslav Z [0000-0003-0424-4128]Serrano, Dolores R [0000-0002-0475-8420]202520252022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionaplication/pdfhttp://hdl.handle.net/10261/394812https://api.elsevier.com/content/abstract/scopus_id/85121557127reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#SFI/12/RC/2275SFI/12/RC/2275_P2https://doi.org/10.1016/j.jconrel.2021.12.019Noinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3948122026-05-22T06:33:51Z |
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15,811543 |