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
ISSN: 01683659





JOURNAL OF CONTROLLED RELEASE
Editorial
ELSEVIER, RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS, Países Bajos
Tipo de documento: Article
Volumen: 335 Número:
Páginas: 117-129
WOS Id: 000669785100001
ID de PubMed: 34004204

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