A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model

Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent pro...

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Autores: Pallarès, Victor, Unzueta, Ugutz, Falgàs, Aïda, Aviñó, Anna, Núñez, Yáiza, García-León, Annabel, Sánchez-García, Laura, Serna, Naroa, Gallardo, Alberto, Alba-Castellón, Lorena, Álamo, Patricia, Sierra, Jorge, Cedó, Lídia, Eritja Casadellà, Ramón, Villaverde, Antonio, Vázquez, Esther, Casanova, Isolda, Mangues, Ramon
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/255384
Acceso en línea:http://hdl.handle.net/10261/255384
Access Level:acceso abierto
Palabra clave:Acute myeloid leukemia
Ara-C prodrug
CXCR4
Multivalency
Targeted drug delivery
Targeted protein nanoparticle
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oai_identifier_str oai:digital.csic.es:10261/255384
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
title A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
spellingShingle A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
Pallarès, Victor
Acute myeloid leukemia
Ara-C prodrug
CXCR4
Multivalency
Targeted drug delivery
Targeted protein nanoparticle
title_short A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
title_full A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
title_fullStr A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
title_full_unstemmed A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
title_sort A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
dc.creator.none.fl_str_mv Pallarès, Victor
Unzueta, Ugutz
Falgàs, Aïda
Aviñó, Anna
Núñez, Yáiza
García-León, Annabel
Sánchez-García, Laura
Serna, Naroa
Gallardo, Alberto
Alba-Castellón, Lorena
Álamo, Patricia
Sierra, Jorge
Cedó, Lídia
Eritja Casadellà, Ramón
Villaverde, Antonio
Vázquez, Esther
Casanova, Isolda
Mangues, Ramon
author Pallarès, Victor
author_facet Pallarès, Victor
Unzueta, Ugutz
Falgàs, Aïda
Aviñó, Anna
Núñez, Yáiza
García-León, Annabel
Sánchez-García, Laura
Serna, Naroa
Gallardo, Alberto
Alba-Castellón, Lorena
Álamo, Patricia
Sierra, Jorge
Cedó, Lídia
Eritja Casadellà, Ramón
Villaverde, Antonio
Vázquez, Esther
Casanova, Isolda
Mangues, Ramon
author_role author
author2 Unzueta, Ugutz
Falgàs, Aïda
Aviñó, Anna
Núñez, Yáiza
García-León, Annabel
Sánchez-García, Laura
Serna, Naroa
Gallardo, Alberto
Alba-Castellón, Lorena
Álamo, Patricia
Sierra, Jorge
Cedó, Lídia
Eritja Casadellà, Ramón
Villaverde, Antonio
Vázquez, Esther
Casanova, Isolda
Mangues, Ramon
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Eritja Casadellà, Ramón [0000-0001-5383-9334]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Acute myeloid leukemia
Ara-C prodrug
CXCR4
Multivalency
Targeted drug delivery
Targeted protein nanoparticle
topic Acute myeloid leukemia
Ara-C prodrug
CXCR4
Multivalency
Targeted drug delivery
Targeted protein nanoparticle
description Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4+ AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4+ AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4+ leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/255384
url http://hdl.handle.net/10261/255384
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Biomaterials
https://doi.org/10.1016/j.biomaterials.2021.121258
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869410440491040768
spelling A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse modelPallarès, VictorUnzueta, UgutzFalgàs, AïdaAviñó, AnnaNúñez, YáizaGarcía-León, AnnabelSánchez-García, LauraSerna, NaroaGallardo, AlbertoAlba-Castellón, LorenaÁlamo, PatriciaSierra, JorgeCedó, LídiaEritja Casadellà, RamónVillaverde, AntonioVázquez, EstherCasanova, IsoldaMangues, RamonAcute myeloid leukemiaAra-C prodrugCXCR4MultivalencyTargeted drug deliveryTargeted protein nanoparticleCurrent therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4+ AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4+ AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4+ leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.This work was supported by Instituto de Salud Carlos III (ISCIII, Co-funding from FEDER) [PI18/00650, PIE15/00028, PI15/00378 and EU COST Action CA 17 140 to R.M.; FIS PI17/01246 and RD16/0011/0028 to J.S.; and PI20/00400 to U·U.]; Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (grant BIO2016-76063-R, AEI/FEDER, UE) to A.V.; (grant PID2019-105416RB-I00) to E.V.; CIBER-BBN [CB06/01/1031 and 4NanoMets to R.M., VENOM4CANCER to A.V., NANOREMOTE to E.V. and NANOLINK to U·U.]; AGAUR [2017 FI_B 00680 to A.F., 2018 FI_B2_00051 to L.S.G.; 2017-SGR-865 to R.M., 2017-SGR-1395 to J.S. and 2017SGR-229 to A.V.]; Josep Carreras Leukemia Research Institute [P/AG to R.M.]; La Marató TV3 [201 941-30-31-32 to J.S. and A.V.]; a grant from the Cellex Foundation, Barcelona [to J.S.]; a grant from La Generalitat de Catalunya (PERIS) [SLT002/16/00433to J.S.]; a grant from the Generalitat de Catalunya CERCA Programme. U.U. is supported by Miguel Servet fellowship (CP19/00028) from Instituto de Salud Carlos III co-funded by Fondo Social Europeo (ESF investing in your future). Finally, A.V. received an ICREA ACADEMIA Award supported by the Catalan Government. We are also indebted to the ISCIII Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) and its ICTS Nanbiosis Platform for their funding. The bioluminescent follow-up of cancer cells and toxicity studies has been performed in the ICTS-141007 Nanbiosis Platform, using its CIBER-BBN Nanotoxicology Unit (http://www.nanbiosis.es/portfolio/u18-nanotoxicology-unit/). Protein production has been partially performed by the ICTS “NANBIOSIS”, more specifically by the Protein Production Platform of CIBER-BBN/IBB (http://www.nanbiosis.es/unit/u1-protein-production-platform-ppp/). Finally, we are very grateful to Servei de Microscopia from UAB for their excellent confocal and electron microscopy services and especially to Alejandro Sánchez-Chardi for its excellent support and contribution in TEM and FESEM images.Peer reviewedElsevierEritja Casadellà, Ramón [0000-0001-5383-9334]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/255384reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésBiomaterialshttps://doi.org/10.1016/j.biomaterials.2021.121258Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2553842026-05-22T06:33:51Z
score 15,81155

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