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

doi:10.1016/j.jconrel.2016.08.010

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

J Control Release. 2016 Oct 10:239:10-8. doi: 10.1016/j.jconrel.2016.08.010. Epub 2016 Aug 12.

Authors

Affiliations

¹ Department of Medicine, University of Verona, 37134 Verona, Italy.
² Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy.
³ Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, "Sapienza" University, 00161 Rome, Italy.
⁴ Oncogenomics and Epigenetics, Regina Elena National Cancer Institute, 00144 Rome, Italy.
⁵ Institute of Biochemistry and Clinical Biochemistry, Catholic University, 00168 Rome, Italy.
⁶ Digestive Surgery Division, Department of Surgical Sciences, Catholic University, 00168 Rome, Italy.
⁷ Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy; Department of Biochemical Sciences "A. Rossi-Fanelli", "Sapienza" University, 00185 Rome, Italy; Center for Life Nano Science at "Sapienza" University, Italian Institute of Technology (IIT), 00161 Rome, Italy.
⁸ Department of Neurological and Movement Sciences, University of Verona, 37134 Verona, Italy.
⁹ Institute of Biochemistry and Clinical Biochemistry, Catholic University, 00168 Rome, Italy. Electronic address: alessandro.arcovito@unicatt.it.
¹⁰ Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy. Electronic address: pierpaolo.ceci@cnr.it.

PMID: 27524282
DOI: 10.1016/j.jconrel.2016.08.010

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.

Keywords: Doxorubicin (PubChem CID: 31703); Drug-delivery; Ferritin; INNO-206 (PubChem CID: 9810709); Nuclear localization; PASylation; Pancreatic cancer; Protein-cage nanocarrier.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibiotics, Antineoplastic / administration & dosage
Apoferritins / administration & dosage*
Cell Line, Tumor
Cell Proliferation / drug effects
Doxorubicin / administration & dosage*
Drug Carriers / administration & dosage
Drug Delivery Systems / methods*
Female
Humans
Mice
Mice, Nude
Nanoparticles / administration & dosage*
Xenograft Model Antitumor Assays / methods

Substances

Antibiotics, Antineoplastic
Drug Carriers
Doxorubicin
Apoferritins