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

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

Author information

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.

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

PMID:
27524282
DOI:
10.1016/j.jconrel.2016.08.010
[Indexed for MEDLINE]

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