The presence of glutamate residues on the PAS sequence of the stimuli-sensitive nano-ferritin improves in vivo biodistribution and mitoxantrone encapsulation homogeneity

Elisabetta Falvo, Francesca Malagrinò, Alessandro Arcovito, Francesco Fazi, Gianni Colotti, Elisa Tremante, Patrizio Di Micco, Aldo Braca, Roberta Opri, Alessandro Giuffrè, Giulio Fracasso, Pierpaolo Ceci

Research output: Contribution to journalArticlepeer-review

Abstract

A genetically engineered human ferritin heavy chain (HFt)-based construct has been recently shown by our group to efficiently entrap and deliver doxorubicin to cancer cells. This construct, named HFt-MP-PAS, contained a tumor-selective sequence (MP) responsive to proteolytic cleavage by tumor proteases (MMPs), located between each HFt subunit and an outer shielding polypeptide sequence rich in proline (P), serine (S) and alanine (A) residues (PAS). HFt-MP-PAS displayed excellent therapeutic efficacy in xenogenic pancreatic and head and neck cancer models in vivo, leading to a significant increase in overall animal survivals. Here we report a new construct obtained by the genetic insertion of two glutamate residues in the PAS sequence of HFt-MP-PAS. Such new construct, named HFt-MP-PASE, is characterized by improved performances as drug biodistribution in a xenogenic pancreatic cancer model in vivo. Moreover, HFt-MP-PASE efficiently encapsulates the anti-cancer drug mitoxantrone (MIT), and the resulting MIT-loaded nanoparticles proved to be more soluble and monodispersed than the HFt-MP-PAS counterparts. Importantly, in vitro MIT-loaded HFt-MP-PASE kills several cancer cell lines of different origin (colon, breast, sarcoma and pancreas) at least as efficiently as the free drug. Finally, our MIT loaded protein nanocages allowed in vivo an impressive incrementing of the drug accumulation in the tumor with respect to the free drug.

Original languageEnglish
Pages (from-to)177-185
Number of pages9
JournalJournal of Controlled Release
Volume275
DOIs
Publication statusPublished - Apr 10 2018

Keywords

  • Cancer
  • Drug-delivery
  • Drug-encapsulation
  • Mitoxantrone
  • Pasylated ferritin
  • Protein-cage nanocarrier

ASJC Scopus subject areas

  • Pharmaceutical Science

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