An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination
Abstract Background Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated...
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2020-04-01
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Series: | Journal of Hematology & Oncology |
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Online Access: | http://link.springer.com/article/10.1186/s13045-020-00863-9 |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Victor Pallarès Ugutz Unzueta Aïda Falgàs Laura Sánchez-García Naroa Serna Alberto Gallardo Gordon A. Morris Lorena Alba-Castellón Patricia Álamo Jorge Sierra Antonio Villaverde Esther Vázquez Isolda Casanova Ramon Mangues |
spellingShingle |
Victor Pallarès Ugutz Unzueta Aïda Falgàs Laura Sánchez-García Naroa Serna Alberto Gallardo Gordon A. Morris Lorena Alba-Castellón Patricia Álamo Jorge Sierra Antonio Villaverde Esther Vázquez Isolda Casanova Ramon Mangues An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination Journal of Hematology & Oncology Acute myeloid leukemia CXCR4 Targeted nanoparticle Auristatin nanoconjugate Leukemic stem cells Disseminated AML mouse model |
author_facet |
Victor Pallarès Ugutz Unzueta Aïda Falgàs Laura Sánchez-García Naroa Serna Alberto Gallardo Gordon A. Morris Lorena Alba-Castellón Patricia Álamo Jorge Sierra Antonio Villaverde Esther Vázquez Isolda Casanova Ramon Mangues |
author_sort |
Victor Pallarès |
title |
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination |
title_short |
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination |
title_full |
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination |
title_fullStr |
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination |
title_full_unstemmed |
An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination |
title_sort |
auristatin nanoconjugate targeting cxcr4+ leukemic cells blocks acute myeloid leukemia dissemination |
publisher |
BMC |
series |
Journal of Hematology & Oncology |
issn |
1756-8722 |
publishDate |
2020-04-01 |
description |
Abstract Background Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups. Results T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model. Conclusions A novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy. |
topic |
Acute myeloid leukemia CXCR4 Targeted nanoparticle Auristatin nanoconjugate Leukemic stem cells Disseminated AML mouse model |
url |
http://link.springer.com/article/10.1186/s13045-020-00863-9 |
work_keys_str_mv |
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doaj-87ebec6b3f454f2189fdb0bc4e4136902020-11-25T02:02:14ZengBMCJournal of Hematology & Oncology1756-87222020-04-0113111910.1186/s13045-020-00863-9An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia disseminationVictor Pallarès0Ugutz Unzueta1Aïda Falgàs2Laura Sánchez-García3Naroa Serna4Alberto Gallardo5Gordon A. Morris6Lorena Alba-Castellón7Patricia Álamo8Jorge Sierra9Antonio Villaverde10Esther Vázquez11Isolda Casanova12Ramon Mangues13Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauBiomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauBiomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauCIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauDepartment of Chemical Sciences, School of Applied Sciences, University of HuddersfieldBiomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauBiomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauJosep Carreras Research InstituteCIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)CIBER en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN)Biomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauBiomedical Research Institute Sant Pau (IIB-Sant Pau), Hospital de la Santa Creu i Sant PauAbstract Background Current acute myeloid leukemia (AML) therapy fails to eliminate quiescent leukemic blasts in the bone marrow, leading to about 50% of patient relapse by increasing AML burden in the bone marrow, blood, and extramedullar sites. We developed a protein-based nanoparticle conjugated to the potent antimitotic agent Auristatin E that selectively targets AML blasts because of their CXCR4 receptor overexpression (CXCR4+) as compared to normal cells. The therapeutic rationale is based on the involvement of CXCR4 overexpression in leukemic blast homing and quiescence in the bone marrow, and the association of these leukemic stem cells with minimal residual disease, dissemination, chemotherapy resistance, and lower patient survival. Methods Monomethyl Auristatin E (MMAE) was conjugated with the CXCR4 targeted protein nanoparticle T22-GFP-H6 produced in E. coli. Nanoconjugate internalization and in vitro cell viability assays were performed in CXCR4+ AML cell lines to analyze the specific antineoplastic activity through the CXCR4 receptor. In addition, a disseminated AML animal model was used to evaluate the anticancer effect of T22-GFP-H6-Auristatin in immunosuppressed NSG mice (n = 10/group). U of Mann-Whitney test was used to consider if differences were significant between groups. Results T22-GFP-H6-Auristatin was capable to internalize and exert antineoplastic effects through the CXCR4 receptor in THP-1 and SKM-1 CXCR4+ AML cell lines. In addition, repeated administration of the T22-GFP-H6-Auristatin nanoconjugate (9 doses daily) achieves a potent antineoplastic activity by internalizing specifically in the leukemic cells (luminescent THP-1) to selectively eliminate them. This leads to reduced involvement of leukemic cells in the bone marrow, peripheral blood, liver, and spleen, while avoiding toxicity in normal tissues in a luminescent disseminated AML mouse model. Conclusions A novel nanoconjugate for targeted drug delivery of Auristatin reduces significantly the acute myeloid leukemic cell burden in the bone marrow and blood and blocks its dissemination to extramedullar organs in a CXCR4+ AML model. This selective drug delivery approach validates CXCR4+ AML cells as a target for clinical therapy, not only promising to improve the control of leukemic dissemination but also dramatically reducing the severe toxicity of classical AML therapy.http://link.springer.com/article/10.1186/s13045-020-00863-9Acute myeloid leukemiaCXCR4Targeted nanoparticleAuristatin nanoconjugateLeukemic stem cellsDisseminated AML mouse model |