The Diphtheria Toxin Translocation Domain Impairs Receptor Selectivity in Cancer Cell-Targeted Protein Nanoparticles
Por:
Volta-Duran, E, Sanchez, JM, Parlade, E, Serna, N, Vazquez, E, Unzueta, U, Villaverde, A
Publicada:
1 dic 2022
Resumen:
Protein-based materials intended as nanostructured drugs or drug carriers are progressively gaining interest in nanomedicine, since their structure, assembly and cellular interactivity can be tailored by recruiting functional domains. The main bottleneck in the development of deliverable protein materials is the lysosomal degradation that follows endosome maturation. This is especially disappointing in the case of receptor-targeted protein constructs, which, while being highly promising and in demand in precision medicines, enter cells via endosomal/lysosomal routes. In the search for suitable protein agents that might promote endosome escape, we have explored the translocation domain (TD) of the diphtheria toxin as a functional domain in CXCR4-targeted oligomeric nanoparticles designed for cancer therapies. The pharmacological interest of such protein materials could be largely enhanced by improving their proteolytic stability. The incorporation of TD into the building blocks enhances the amount of the material detected inside of exposed CXCR4(+) cells up to around 25-fold, in absence of cytotoxicity. This rise cannot be accounted for by endosomal escape, since the lysosomal degradation of the new construct decreases only moderately. On the other hand, a significant loss in the specificity of the CXCR4-dependent cellular penetration indicates the unexpected role of the toxin segment as a cell-penetrating peptide in a dose-dependent and receptor-independent fashion. These data reveal that the diphtheria toxin TD displayed on receptor-targeted oligomeric nanoparticles partially abolishes the exquisite receptor specificity of the parental material and it induces nonspecific internalization in mammalian cells.
Filiaciones:
Volta-Duran, E:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Sanchez, JM:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Univ Nacl Cordoba, Inst Invest Biol & Tecnol IIBYT, CONICET, Ave Velez Sarsfield 1611,X5016GCA, Cordoba, Argentina
Parlade, E:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Serna, N:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Univ Autonoma Barcelona, Nanoligent SL, Campus Univ, Barcelona 08193, Spain
Vazquez, E:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Unzueta, U:
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
Inst Invest Biomed St Pau IIB St PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst, Barcelona 08025, Spain
Villaverde, A:
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Barcelona 08193, Spain
Inst Salud Carlos III, CIBER Bioingn, Biomat & Nanomed CIBER BBN, Barcelona 08193, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona 08193, Spain
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