A multivalent Ara-C-prodrug nanoconjugate achieves selective ablation of leukemic cells in an acute myeloid leukemia mouse model
Por:
Pallares, V, Unzueta, U, Falgas, A, Avino, A, Nunez, Y, Garcia-Leon, A, Sanchez-Garcia, L, Serna, N, Gallardo, A, Alba-Castellon, L, Alamo, P, Sierra, J, Cedo, L, Eritja, R, Villaverde, A, Vazquez, E, Casanova, I, Mangues, R
Publicada:
1 ene 2022
Ahead of Print:
1 nov 2021
Resumen:
Current therapy in acute myeloid leukemia (AML) is based on chemotherapeutic drugs administered at high doses, lacking targeting selectivity and displaying poor therapeutic index because of severe adverse effects. Here, we develop a novel nanoconjugate that combines a self-assembled, multivalent protein nanoparticle, targeting the CXCR4 receptor, with an Oligo-Ara-C prodrug, a pentameric form of Ara-C, to highly increase the delivered payload to target cells. This 13.4 nm T22-GFP-H6-Ara-C nanoconjugate selectively eliminates CXCR4(+) AML cells, which are protected by its anchoring to the bone marrow (BM) niche, being involved in AML progression and chemotherapy resistance. This nanoconjugate shows CXCR4-dependent internalization and antineoplastic activity in CXCR4(+) AML cells in vitro. Moreover, repeated T22-GFP-H6-Ara-C administration selectively eliminates CXCR4(+) leukemic cells in BM, spleen and liver. The leukemic dissemination blockage induced by T22-GFP-H6-Ara-C is significantly more potent than buffer or Oligo-Ara-C-treated mice, showing no associated on-target or off-target toxicity and, therefore, reaching a highly therapeutic window. In conclusion, T22-GFP-H6-Ara-C exploits its 11 ligands-multivalency to enhance target selectivity, while the Oligo-Ara-C prodrug multimeric form increases 5-fold its payload. This feature combination offers an alternative nanomedicine with higher activity and greater tolerability than current intensive or non-intensive chemotherapy for AML patients.
Filiaciones:
Pallares, V:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Unzueta, U:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Falgas, A:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Avino, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
CSIC, Inst Adv Chem Catalonia IQAC, Barcelona 08034, Spain
Nunez, Y:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
Garcia-Leon, A:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
Sanchez-Garcia, L:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Univ Autonoma Barcelona, Inst Biotechnol & Biomed IBB, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Serna, N:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Univ Autonoma Barcelona, Inst Biotechnol & Biomed IBB, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Gallardo, A:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona 08025, Spain
Alba-Castellon, L:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
Alamo, P:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Sierra, J:
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
Hosp Santa Creu & Sant Pau, Dept Hematol, Barcelona 08025, Spain
Cedo, L:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
CIBER Diabet & Enfermedades Metab Asociadas CIBER, Madrid 28029, Spain
Eritja, R:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
CSIC, Inst Adv Chem Catalonia IQAC, Barcelona 08034, Spain
Villaverde, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Univ Autonoma Barcelona, Inst Biotechnol & Biomed IBB, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Vazquez, E:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Univ Autonoma Barcelona, Inst Biotechnol & Biomed IBB, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Casanova, I:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Mangues, R:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08916, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Madrid 28029, Spain
Green Published, All Open Access, Hybrid Gold, Green
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