Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness

Giulio Fracasso, Elisabetta Falvo, Gianni Colotti, Francesco Fazi, Tiziano Ingegnere, Adriana Amalfitano, Giovanni Battista Doglietto, Sergio Alfieri, Alberto Boffi, Veronica Morea, Giamaica Conti, Elisa Tremante, Patrizio Giacomini, Alessandro Arcovito, Pierpaolo Ceci

Research output: Contribution to journalArticle

Abstract

Human ferritin heavy chain (HFt) has been demonstrated to possess considerable potential for targeted delivery of drugs and diagnostic agents to cancer cells. Here, we report the development of a novel HFt-based genetic construct (HFt-MP-PAS) containing a short peptide linker (MP) between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). The peptide linker contains a matrix-metalloproteinases (MMPs) cleavage site that permits the protective PAS shield to be removed by tumor-driven proteolytic cleavage within the tumor microenvironment. For the first time HFt-MP-PAS ability to deliver doxorubicin to cancer cells, subcellular localization, and therapeutic efficacy on a xenogeneic mouse model of a highly refractory to conventional chemotherapeutics type of cancer were evaluated. HFt-MP-PAS-DOXO performance was compared with the novel albumin-based drug delivery system INNO-206, currently in phase III clinical trials. The results of this work provide solid evidence indicating that the stimuli-sensitive, long-circulating HFt-MP-PAS nanocarriers described herein have the potential to be exploited in cancer therapy.

Original languageEnglish
Pages (from-to)10-18
Number of pages9
JournalJournal of Controlled Release
Volume239
DOIs
Publication statusPublished - Oct 10 2016

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Keywords

  • Drug-delivery
  • Ferritin
  • Nuclear localization
  • Pancreatic cancer
  • PASylation
  • Protein-cage nanocarrier

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Fracasso, G., Falvo, E., Colotti, G., Fazi, F., Ingegnere, T., Amalfitano, A., Doglietto, G. B., Alfieri, S., Boffi, A., Morea, V., Conti, G., Tremante, E., Giacomini, P., Arcovito, A., & Ceci, P. (2016). Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness. Journal of Controlled Release, 239, 10-18. https://doi.org/10.1016/j.jconrel.2016.08.010