학술논문
T22-PE24-H6 Nanotoxin Selectively Kills CXCR4-High Expressing AML Patient Cells In Vitro and Potently Blocks Dissemination In Vivo.
Document Type
Academic Journal
Author
Núñez Y; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; Garcia-León A; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Falgàs A; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Serna N; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Sánchez-García L; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Garrido A; Department of Hematology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.; Sierra J; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; Department of Hematology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.; Gallardo A; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Department of Pathology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.; Unzueta U; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Vázquez E; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Villaverde A; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.; Mangues R; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Casanova I; Institut d'Investigació Biomèdica Sant Pau (IIB SANT PAU), 08041 Barcelona, Spain.; Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain.; CIBER Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain.
Source
Publisher: MDPI Country of Publication: Switzerland NLM ID: 101534003 Publication Model: Electronic Cited Medium: Print ISSN: 1999-4923 (Print) Linking ISSN: 19994923 NLM ISO Abbreviation: Pharmaceutics Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1999-4923
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.