TY - JOUR
T1 - Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness
AU - Fracasso, Giulio
AU - Falvo, Elisabetta
AU - Colotti, Gianni
AU - Fazi, Francesco
AU - Ingegnere, Tiziano
AU - Amalfitano, Adriana
AU - Doglietto, Giovanni
AU - Alfieri, Sergio
AU - Boffi, Alberto
AU - Morea, Veronica
AU - Conti, Giamaica
AU - Tremante, Elisa
AU - Giacomini, Patrizio
AU - Arcovito, Alessandro
AU - Ceci, Pierpaolo
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Doxorubicin (PubChem CID: 31703)
KW - Drug-delivery
KW - Ferritin
KW - INNO-206 (PubChem CID: 9810709)
KW - Nuclear localization
KW - PASylation
KW - Pancreatic cancer
KW - Protein-cage nanocarrier
KW - Doxorubicin (PubChem CID: 31703)
KW - Drug-delivery
KW - Ferritin
KW - INNO-206 (PubChem CID: 9810709)
KW - Nuclear localization
KW - PASylation
KW - Pancreatic cancer
KW - Protein-cage nanocarrier
UR - https://publicatt.unicatt.it/handle/10807/84231
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84982144525&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84982144525&origin=inward
U2 - 10.1016/j.jconrel.2016.08.010
DO - 10.1016/j.jconrel.2016.08.010
M3 - Article
SN - 0168-3659
VL - 239
SP - 10-18-18
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - August
ER -
