A refined cocktailing of pro-apoptotic nanoparticles boosts anti-tumor activity

Laura Sánchez-García, Rita Sala, Naroa Serna, Patricia Álamo, Eloi Parladé, Lorena Alba-Castellón, Eric Voltà-Durán, Alejandro Sánchez-Chardi, Ugutz Unzueta, Esther Vázquez*, Ramón Mangues, Antonio Villaverde

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)584-596
Number of pages13
JournalActa Biomaterialia
Volume113
DOIs
Publication statusPublished - 1 Sep 2020

Keywords

  • Cancer
  • Colorectal cancer
  • Drug cocktail
  • Drug delivery
  • Human proteins
  • Nanomedicine
  • Nanoparticles
  • Pro-apoptotic factors
  • Pro-apoptotic peptide
  • Recombinant protein
  • Targeted drug delivery

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