Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Aïda Falgàs,1– 3 Victor Pallarès,1– 3 Ugutz Unzueta,1– 4 Yáiza Núñez,1,2 Jorge Sierra,2,5 Alberto Gallardo,1 Lorena Alba-Castellón,1,2 Maria Antonia Mangues,3,6 Patricia Álamo,1&nd...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Falgàs A, Pallarès V, Unzueta U, Núñez Y, Sierra J, Gallardo A, Alba-Castellón L, Mangues MA, Álamo P, Villaverde A, Vázquez E, Mangues R, Casanova I
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	nanomedicine targeted drug delivery mmae dlbcl Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/ad15fac8734d44d5b70ee95f4190a782
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ad15fac8734d44d5b70ee95f4190a782
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	nanomedicine targeted drug delivery mmae dlbcl Medicine (General) R5-920
spellingShingle	nanomedicine targeted drug delivery mmae dlbcl Medicine (General) R5-920 Falgàs A Pallarès V Unzueta U Núñez Y Sierra J Gallardo A Alba-Castellón L Mangues MA Álamo P Villaverde A Vázquez E Mangues R Casanova I Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
description	Aïda Falgàs,1– 3 Victor Pallarès,1– 3 Ugutz Unzueta,1– 4 Yáiza Núñez,1,2 Jorge Sierra,2,5 Alberto Gallardo,1 Lorena Alba-Castellón,1,2 Maria Antonia Mangues,3,6 Patricia Álamo,1– 3 Antonio Villaverde,3,4,7 Esther Vázquez,3,4,7 Ramon Mangues,1– 3 Isolda Casanova1– 3 1Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 2Josep Carreras Leukaemia Research Institute (IJC), Barcelona, 08916, Spain; 3CIBER de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, 28029, Spain; 4Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, 08193, Spain; 5Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 6Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 7Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Barcelona, 08193, SpainCorrespondence: Esther VázquezInstitute of Biotechnology and Biomedicine (IBB) and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona and CIBER-BBN, Barcelona, SpainTel +34 935812148Email Esther.Vazquez@uab.esRamon ManguesBiomedical Research Institute Sant Pau (IIB-Sant Pau), Josep Carreras Leukaemia Research Institute (IJC) and CIBER-BBN, Barcelona, SpainTel +34 935537918Email RMangues@santpau.catBackground and Purpose: Around 40– 50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4+) and associated with poor prognosis.Methods: The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4+ DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4+ DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs.Results: We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4+ DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4+ DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs.Conclusion: T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4+ DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4+ DLBCL patients.Keywords: nanomedicine, targeted drug delivery, MMAE, DLBCL
format	article
author	Falgàs A Pallarès V Unzueta U Núñez Y Sierra J Gallardo A Alba-Castellón L Mangues MA Álamo P Villaverde A Vázquez E Mangues R Casanova I
author_facet	Falgàs A Pallarès V Unzueta U Núñez Y Sierra J Gallardo A Alba-Castellón L Mangues MA Álamo P Villaverde A Vázquez E Mangues R Casanova I
author_sort	Falgàs A
title	Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
title_short	Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
title_full	Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
title_fullStr	Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
title_full_unstemmed	Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells
title_sort	specific cytotoxic effect of an auristatin nanoconjugate towards cxcr4+ diffuse large b-cell lymphoma cells
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/ad15fac8734d44d5b70ee95f4190a782
work_keys_str_mv	AT falgasa specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT pallaresv specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT unzuetau specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT nunezy specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT sierraj specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT gallardoa specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT albacastellonl specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT manguesma specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT alamop specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT villaverdea specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT vazqueze specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT manguesr specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells AT casanovai specificcytotoxiceffectofanauristatinnanoconjugatetowardscxcr4diffuselargebcelllymphomacells
_version_	1718385293425377280
spelling	oai:doaj.org-article:ad15fac8734d44d5b70ee95f4190a7822021-12-02T16:00:18ZSpecific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells1178-2013https://doaj.org/article/ad15fac8734d44d5b70ee95f4190a7822021-03-01T00:00:00Zhttps://www.dovepress.com/specific-cytotoxic-effect-of-an-auristatin-nanoconjugate-towards-cxcr4-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Aïda Falgàs,1– 3 Victor Pallarès,1– 3 Ugutz Unzueta,1– 4 Yáiza Núñez,1,2 Jorge Sierra,2,5 Alberto Gallardo,1 Lorena Alba-Castellón,1,2 Maria Antonia Mangues,3,6 Patricia Álamo,1– 3 Antonio Villaverde,3,4,7 Esther Vázquez,3,4,7 Ramon Mangues,1– 3 Isolda Casanova1– 3 1Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 2Josep Carreras Leukaemia Research Institute (IJC), Barcelona, 08916, Spain; 3CIBER de Bioingeniería Biomateriales y Nanomedicina (CIBER-BBN), Madrid, 28029, Spain; 4Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, 08193, Spain; 5Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 6Department of Pharmacy, Hospital de la Santa Creu i Sant Pau, Barcelona, 08025, Spain; 7Institute of Biotechnology and Biomedicine (IBB), Universitat Autònoma de Barcelona, Barcelona, 08193, SpainCorrespondence: Esther VázquezInstitute of Biotechnology and Biomedicine (IBB) and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona and CIBER-BBN, Barcelona, SpainTel +34 935812148Email Esther.Vazquez@uab.esRamon ManguesBiomedical Research Institute Sant Pau (IIB-Sant Pau), Josep Carreras Leukaemia Research Institute (IJC) and CIBER-BBN, Barcelona, SpainTel +34 935537918Email RMangues@santpau.catBackground and Purpose: Around 40– 50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4+) and associated with poor prognosis.Methods: The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4+ DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4+ DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs.Results: We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4+ DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4+ DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs.Conclusion: T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4+ DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4+ DLBCL patients.Keywords: nanomedicine, targeted drug delivery, MMAE, DLBCLFalgàs APallarès VUnzueta UNúñez YSierra JGallardo AAlba-Castellón LMangues MAÁlamo PVillaverde AVázquez EMangues RCasanova IDove Medical Pressarticlenanomedicinetargeted drug deliverymmaedlbclMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 1869-1888 (2021)

Specific Cytotoxic Effect of an Auristatin Nanoconjugate Towards CXCR4+ Diffuse Large B-Cell Lymphoma Cells

Ejemplares similares