Antineoplastic effect of a diphtheria toxin-based nanoparticle targeting acute myeloid leukemia cells overexpressing CXCR4
Por:
Pallares, V, Nunez, Y, Sanchez-Garcia, L, Falgas, A, Serna, N, Unzueta, U, Gallardo, A, Alba-Castellon, L, Alamo, P, Sierra, J, Villaverde, A, Vazquez, E, Casanova, I, Mangues, R
Publicada:
10 jul 2021
Ahead of Print:
1 may 2021
Resumen:
Nanomedicine has opened an opportunity to improve current clinical practice by enhancing the selectivity in the delivery of antitumor drugs to specific cancer cells. These new strategies are able to bypass toxicity on normal cells increasing the effectiveness of current anticancer treatments. In acute myeloid leukemia (AML) current chemotherapy treatments generate a relevant toxic impact in normal cells and severe side effects or even patient death. In this study, we have designed a self-assembling protein nanoparticle, T22-DITOX-H6, which incorporates a ligand (T22) targeting CXCR4-overexpressing (CXCR4+) cells, and a potent cytotoxic diphtheria toxin domain. CXCR4 is overexpressed in AML leukemic cells and associates with poor prognosis, being, therefore, a relevant clinical target. We demonstrate here that T22-DITOX-H6 induces apoptosis in CXCR4+ leukemic cells through CXCR4-dependent internalization. In addition, repeated T22-DITOX-H6 treatment (10 mu g/ dose per 10 doses, intravenously injected) in a disseminated AML mouse model (NSG mice intravenously injected with THP-1-Luci cells, n = 10 per group) potently blocks the dissemination of AML cells in bone marrow, spleen and liver of treated mice, without inducing toxicity in healthy tissues. In conclusion, our strategy of selectively ablating CXCR4 positive leukemic cells by administering the T22-DITOX-H6 nanoparticle could be a promising treatment, especially in patients undergoing AML relapse after chemotherapy, in which leukemic cells overexpress CXCR4.
Filiaciones:
Pallares, V:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Nunez, Y:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Sanchez-Garcia, L:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Falgas, A:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Serna, N:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Unzueta, U:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Gallardo, A:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona, Spain
Alba-Castellon, L:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
Alamo, P:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Sierra, J:
Josep Carreras Res Inst, Barcelona 08041, Spain
Univ Autonoma Barcelona, Dept Hematol, Hosp Santa Creu & St Pau, Barcelona, Spain
Villaverde, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Vazquez, E:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain
Casanova, I:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
Mangues, R:
Hosp Santa Creu & Sant Pau, Biomed Res Inst St Pau IIB St Pau, Barcelona, Spain
Josep Carreras Res Inst, Barcelona 08041, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Barcelona, Spain
|