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Int. J. Mol. Sci. 2017, 18(7), 1555; doi:10.3390/ijms18071555

Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model

1
Department of Medical, Oral and Biotechnological Sciences and CeSI-Met Centro Scienze dell’Invecchiamento e Medicina Traslazionale, Universita “G. d’Annunzio” di Chieti-Pescara, Chieti 66100, Italy
2
Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome 00185, Italy
3
Department of Medicine, University of Verona, Verona 37134, Italy
4
Department of Biochemical Sciences “A. Rossi Fanelli”, Sapienza University of Rome, Rome 00185, Italy
*
Authors to whom correspondence should be addressed.
Received: 23 June 2017 / Revised: 14 July 2017 / Accepted: 15 July 2017 / Published: 18 July 2017
(This article belongs to the Collection Bioactive Nanoparticles)
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Abstract

Doxorubicin is employed alone or in combination for the treatment of several hematological and solid malignancies; despite its efficacy, there are associated cardiotoxicity limits both in its application in patients with heart disease risk factors and also in its long-term use. HFt-MP-PAS40 is a genetically engineered human ferritin heavy chain (HFt)-based construct able to efficiently entrap and deliver doxorubicin to cancer cells. HF-MP-PAS contains a short motif sequence (defined as MP) responsive to proteolytic cleavage by tumor matrix metalloproteases (MMPs), located between each HFt subunit and a masking polypeptide sequence rich in proline (P), alanine (A), and serine (S) residues (PAS). This carrier displayed excellent therapeutic efficacy in a xenogenic pancreatic cancer model in vivo, leading to a significant increase in overall animal survival in treated mice. Herein, we describe the HFt-MP-PAS40-Dox efficacy against squamous cell carcinomas of the head and neck (HNSCC) with the goal of validating the application of our nano-drug for the treatment of different solid tumors. In addition, a tolerability study in healthy mice was also performed. The results indicate that HFt-MP-PAS40-Dox produced increased anti-tumor effects both in vitro and in vivo in comparison to the free drug in several HNSCC cell lines. In the acute toxicity studies, the maximum tolerated dose (MTD) of HFt-MP-PAS40-Dox was about 3.5 higher than the free drug: 25 mg/kg versus 7 mg/kg doxorubicin equivalents. Importantly, evaluation of heart tissues provided evidence that doxorubicin is less cardio-toxic when encapsulated inside the ferritin carrier. In conclusion, HFt-MP-PAS40-Dox may be administered safely at higher doses compared with the free drug, resulting in superior efficacy to control HNSCC malignancies. View Full-Text
Keywords: pasylated ferritin; stimuli-sensitive peptides; doxorubicin; drug-delivery; head and neck cancer pasylated ferritin; stimuli-sensitive peptides; doxorubicin; drug-delivery; head and neck cancer
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Damiani, V.; Falvo, E.; Fracasso, G.; Federici, L.; Pitea, M.; De Laurenzi, V.; Sala, G.; Ceci, P. Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model. Int. J. Mol. Sci. 2017, 18, 1555.

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