An Auristatin nanoconjugate targeting CXCR4+ leukemic cells blocks acute myeloid leukemia dissemination

Autor: Pallarès, Victor, Unzueta Elorza, Ugutz, Falgàs, Aïda, Sánchez García, Laura, Serna, Naroa, Gallardo, Alberto, Morris, Gordon A., Alba-Castellón, Lorena, Álamo, Patricia, Sierra, Jorge, Villaverde Corrales, Antonio, Vázquez Gómez, Esther, Casanova Rigat, Isolda, Mangues, Ramon, Universitat Autònoma de Barcelona
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Cancer Research
medicine.medical_specialty
Receptors
CXCR4
Myeloid
Antineoplastic Agents
Nanoconjugates
CXCR4
lcsh:RC254-282
Auristatin nanoconjugate
chemistry.chemical_compound
Mice
Drug Delivery Systems
Mice
Inbred NOD
Internal medicine
Cell Line
Tumor
hemic and lymphatic diseases
medicine
Animals
Humans
Aminobenzoates
Neoplasm Invasiveness
Molecular Biology
Targeted nanoparticle
Leukemic stem cells
Hematology
Acute myeloid leukemia
business.industry
lcsh:RC633-647.5
Research
Myeloid leukemia
lcsh:Diseases of the blood and blood-forming organs
Disseminated AML mouse model
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Minimal residual disease
Leukemia
Myeloid
Acute
medicine.anatomical_structure
Oncology
Monomethyl auristatin E
chemistry
Cancer research
Female
Bone marrow
Stem cell
business
Oligopeptides
Zdroj: Dipòsit Digital de Documents de la UAB
Universitat Autònoma de Barcelona
Journal of Hematology & Oncology, Vol 13, Iss 1, Pp 1-19 (2020)
Journal of Hematology & Oncology
r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname
ISSN: 1756-8722
Popis: 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.
Databáze: OpenAIRE
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