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. 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

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Selective Delivery of Doxorubicin by Novel Stimuli-Sensitive Nano-Ferritins Overcomes Tumor Refractoriness

Giulio Fracasso et al. J Control Release. .

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.

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