title: Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness.
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.
authors.affiliation: Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.affiliation: Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Falvo
authors.affiliation: Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Colotti
authors.affiliation: Department of Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology & Medical Embryology, "Sapienza" University, 00161 Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazi
authors.affiliation: Oncogenomics and Epigenetics, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Ingegnere
authors.affiliation: Institute of Biochemistry and Clinical Biochemistry, Catholic University, 00168 Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Amalfitano
authors.affiliation: Digestive Surgery Division, Department of Surgical Sciences, Catholic University, 00168 Rome, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Doglietto
authors.affiliation: Digestive Surgery Division, Department of Surgical Sciences, Catholic University, 00168 Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Alfieri
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Boffi
authors.affiliation: Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Morea
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona, 37134 Verona, Italy.
authors.forename: Giamaica
authors.initials: G
authors.lastname: Conti
authors.affiliation: Oncogenomics and Epigenetics, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tremante
authors.affiliation: Oncogenomics and Epigenetics, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Giacomini
authors.affiliation: Institute of Biochemistry and Clinical Biochemistry, Catholic University, 00168 Rome, Italy. Electronic address: alessandro.arcovito@unicatt.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Arcovito
authors.affiliation: Institute of Molecular Biology and Pathology, CNR - National Research Council of Italy, 00185 Rome, Italy. Electronic address: pierpaolo.ceci@cnr.it.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Ceci
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D001052:Apoferritins / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage*; D004337:Drug Carriers / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D004317:Doxorubicin; D001052:Apoferritins
keywords: Doxorubicin (PubChem CID: 31703); Drug-delivery; Ferritin; INNO-206 (PubChem CID: 9810709); Nuclear localization; PASylation; Pancreatic cancer; Protein-cage nanocarrier