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

Giulio Fracasso; Elisabetta Falvo; Gianni Colotti; Francesco Fazi; Tiziano Ingegnere; Adriana Amalfitano; Giovanni Doglietto; Sergio Alfieri; Alberto Boffi; Veronica Morea; Giamaica Conti; Elisa Tremante; Patrizio Giacomini; Alessandro Arcovito; Pierpaolo Ceci

doi:10.1016/j.jconrel.2016.08.010

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

Giulio Fracasso
, Elisabetta Falvo
, Gianni Colotti
, Francesco Fazi
, Tiziano Ingegnere
, Adriana Amalfitano
, Giovanni Doglietto
, Sergio Alfieri
, Alberto Boffi
, Veronica Morea
, Giamaica Conti
, Elisa Tremante
, Patrizio Giacomini
, Alessandro Arcovito^*
, Pierpaolo Ceci

^*Corresponding author

University of Verona
Institute for Polymers
University of Rome La Sapienza
IRCCS Istituti fisioterapici ospitalieri - Istituto Regina Elena

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

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.

Original language	English
Pages (from-to)	10-18-18
Journal	Journal of Controlled Release
Volume	239
Issue number	August
DOIs	https://doi.org/10.1016/j.jconrel.2016.08.010
Publication status	Published - 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Pharmaceutical Science

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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10.1016/j.jconrel.2016.08.010

Cite this

Fracasso, G., Falvo, E., Colotti, G., Fazi, F., Ingegnere, T., Amalfitano, A., Doglietto, G., Alfieri, S., Boffi, A., Morea, V., Conti, G., Tremante, E., Giacomini, P., Arcovito, A., & Ceci, P. (2016). Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness. Journal of Controlled Release, 239(August), 10-18-18. https://doi.org/10.1016/j.jconrel.2016.08.010

@article{021c9b87d7874862860152965f2c44b6,

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.",

keywords = "Doxorubicin (PubChem CID: 31703), Drug-delivery, Ferritin, INNO-206 (PubChem CID: 9810709), Nuclear localization, PASylation, Pancreatic cancer, Protein-cage nanocarrier, Doxorubicin (PubChem CID: 31703), Drug-delivery, Ferritin, INNO-206 (PubChem CID: 9810709), Nuclear localization, PASylation, Pancreatic cancer, Protein-cage nanocarrier",

author = "Giulio Fracasso and Elisabetta Falvo and Gianni Colotti and Francesco Fazi and Tiziano Ingegnere and Adriana Amalfitano and Giovanni Doglietto and Sergio Alfieri and Alberto Boffi and Veronica Morea and Giamaica Conti and Elisa Tremante and Patrizio Giacomini and Alessandro Arcovito and Pierpaolo Ceci",

year = "2016",

doi = "10.1016/j.jconrel.2016.08.010",

language = "English",

volume = "239",

pages = "10--18--18",

journal = "Journal of Controlled Release",

issn = "0168-3659",

publisher = "Elsevier B.V.",

number = "August",

}

Fracasso, G, Falvo, E, Colotti, G, Fazi, F, Ingegnere, T, Amalfitano, A, Doglietto, G, Alfieri, S, Boffi, A, Morea, V, Conti, G, Tremante, E, Giacomini, P, Arcovito, A & Ceci, P 2016, 'Selective delivery of doxorubicin by novel stimuli-sensitive nano-ferritins overcomes tumor refractoriness', Journal of Controlled Release, vol. 239, no. August, pp. 10-18-18. https://doi.org/10.1016/j.jconrel.2016.08.010

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

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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 -

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

Abstract

UN SDGs

All Science Journal Classification (ASJC) codes

Keywords

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