TY - JOUR
T1 - A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity
AU - Sánchez-García, Laura
AU - Sala, Rita
AU - Serna, Naroa
AU - Álamo, Patricia
AU - Parladé, Eloi
AU - Alba-Castellón, Lorena
AU - Voltà-Durán, Eric
AU - Sánchez-Chardi, Alejandro
AU - Unzueta, Ugutz
AU - Vázquez, Esther
AU - Mangues, Ramón
AU - Villaverde, Antonio
N1 - Publisher Copyright:
© 2020 Acta Materialia Inc.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4+ colorectal cancer (at 300 μg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 μg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles. This fact leads to a potent and faster destruction of tumor tissues when compared to individual pro-apoptotic factors. The analysis and interpretation of the boosted effect, from both the structural and functional sides, offers clues for the design of more efficient nanomedicines and theragnostic agents in oncology based on precise cocktails of human proteins. Statement of significance: Several human pro-apoptotic peptides (namely BAK, BAX and PUMA) have been engineered as self-assembling protein nanoparticles targeted to the tumoral marker CXCR4. The systemic administration of the same final amounts of those materials as single drugs, or as combinations of two or three of them, shows disparate intensities of antitumoral effects in a mouse model of human colorectal cancer, which are boosted in the triple combination on a non-additive basis. The superiority of the combined administration of pro-apoptotic agents, acting at different levels of the apoptotic cascade, opens a plethora of possibilities for the development of effective and selective cancer therapies based on the precise cocktailing of pro-apoptotic nanoparticulate agents.
AB - A functional 29 amino acid-segment of the helix α5 from the human BAX protein has been engineered for production in recombinant bacteria as self-assembling, GFP-containing fluorescent nanoparticles, which are targeted to the tumoral marker CXCR4. These nanoparticles, of around 34 nm in diameter, show a moderate tumor biodistribution and limited antitumoral effect when systemically administered to mouse models of human CXCR4+ colorectal cancer (at 300 μg dose). However, if such BAX nanoparticles are co-administered in cocktail with equivalent nanoparticulate versions of BAK and PUMA proteins at the same total protein dose (300 μg), protein biodistribution and stability in tumor is largely improved, as determined by fluorescence profiles. This fact leads to a potent and faster destruction of tumor tissues when compared to individual pro-apoptotic factors. The analysis and interpretation of the boosted effect, from both the structural and functional sides, offers clues for the design of more efficient nanomedicines and theragnostic agents in oncology based on precise cocktails of human proteins. Statement of significance: Several human pro-apoptotic peptides (namely BAK, BAX and PUMA) have been engineered as self-assembling protein nanoparticles targeted to the tumoral marker CXCR4. The systemic administration of the same final amounts of those materials as single drugs, or as combinations of two or three of them, shows disparate intensities of antitumoral effects in a mouse model of human colorectal cancer, which are boosted in the triple combination on a non-additive basis. The superiority of the combined administration of pro-apoptotic agents, acting at different levels of the apoptotic cascade, opens a plethora of possibilities for the development of effective and selective cancer therapies based on the precise cocktailing of pro-apoptotic nanoparticulate agents.
KW - Cancer
KW - Colorectal cancer
KW - Drug cocktail
KW - Drug delivery
KW - Human proteins
KW - Nanomedicine
KW - Nanoparticles
KW - Pro-apoptotic factors
KW - Pro-apoptotic peptide
KW - Recombinant protein
KW - Targeted drug delivery
UR - http://www.scopus.com/inward/record.url?scp=85087479206&partnerID=8YFLogxK
U2 - 10.1016/j.actbio.2020.06.033
DO - 10.1016/j.actbio.2020.06.033
M3 - Article
C2 - 32603867
AN - SCOPUS:85087479206
SN - 1742-7061
VL - 113
SP - 584
EP - 596
JO - Acta Biomaterialia
JF - Acta Biomaterialia
ER -