Home > Articles > Published articles > T22-PE24-H6 Nanotoxin Selectively Kills CXCR4-High Expressing AML Patient Cells In Vitro and Potently Blocks Dissemination In Vivo |
Date: | 2023 |
Abstract: | Despite advances in the development of targeted therapies for acute myeloid leukemia (AML), most patients relapse. For that reason, it is still necessary to develop novel therapies that improve treatment effectiveness and overcome drug resistance. We developed T22-PE24-H6, a protein nanoparticle that contains the exotoxin A from the bacterium Pseudomonas aeruginosa and is able to specifically deliver this cytotoxic domain to CXCR4 + leukemic cells. Next, we evaluated the selective delivery and antitumor activity of T22-PE24-H6 in CXCR4 + AML cell lines and BM samples from AML patients. Moreover, we assessed the in vivo antitumor effect of this nanotoxin in a disseminated mouse model generated from CXCR4 + AML cells. T22-PE24-H6 showed a potent, CXCR4-dependent antineoplastic effect in vitro in the MONO-MAC-6 AML cell line. In addition, mice treated with nanotoxins in daily doses reduced the dissemination of CXCR4 + AML cells compared to buffer-treated mice, as shown by the significant decrease in BLI signaling. Furthermore, we did not observe any sign of toxicity or changes in mouse body weight, biochemical parameters, or histopathology in normal tissues. Finally, T22-PE24-H6 exhibited a significant inhibition of cell viability in CXCR4 high AML patient samples but showed no activity in CXCR4 low samples. These data strongly support the use of T22-PE24-H6 therapy to benefit high-CXCR4-expressing AML patients. |
Grants: | Instituto de Salud Carlos III PI21/00150 Instituto de Salud Carlos III PI18/00650 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-865 Instituto de Salud Carlos III PI20/00400 Instituto de Salud Carlos III PI17/01246 Instituto de Salud Carlos III PI20/01621 Ministerio de Economía y Competitividad RD16/0011/0028 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1395 Fundació la Marató de TV3 20194103132 Agencia Estatal de Investigación BIO2016-76063-R Agencia Estatal de Investigación PID2019-105416RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229 Instituto de Salud Carlos III CP19/00028 Instituto de Salud Carlos III FI18/00268 |
Note: | Altres ajuts: EU COST Action CA 17140; CERCA Programme/Generalitat de Catalunya; ICREA Academia |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Acute myeloid leukemia ; CXCR4 ; Targeted nanoparticle ; Disseminated AML mouse model |
Published in: | Pharmaceutics, Vol. 15, Issue 3 (March 2023) , art. 727, ISSN 1999-4923 |
17 p, 7.3 MB |