Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts

Elena Gazzano, Ilaria Buondonno, Alessandro Marengo, Barbara Rolando, Konstantin Chegaev, Joanna Kopecka, Simona Saponara, Matteo Sorge, Claudia Maria Hattinger, Alberto Gasco, Roberta Fruttero, Mara Brancaccio, Massimo Serra, Barbara Stella, Elias Fattal, Silvia Arpicco, Chiara Riganti

Research output: Contribution to journalArticle

Abstract

Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.

Original languageEnglish
Pages (from-to)29-39
Number of pages11
JournalCancer Letters
Volume456
DOIs
Publication statusE-pub ahead of print - Apr 29 2019

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P-Glycoprotein
Osteosarcoma
Hyaluronic Acid
Heterografts
Liposomes
Doxorubicin
Endoplasmic Reticulum
Pharmaceutical Preparations
Endoplasmic Reticulum Stress
Ubiquitination
liposomal doxorubicin
Neoplasms
Proteins

Keywords

  • Endoplasmic reticulum stress
  • Liposomal doxorubicin
  • Osteosarcoma
  • P-glycoprotein
  • Protein sulfhydration

Cite this

Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts. / Gazzano, Elena; Buondonno, Ilaria; Marengo, Alessandro; Rolando, Barbara; Chegaev, Konstantin; Kopecka, Joanna; Saponara, Simona; Sorge, Matteo; Hattinger, Claudia Maria; Gasco, Alberto; Fruttero, Roberta; Brancaccio, Mara; Serra, Massimo; Stella, Barbara; Fattal, Elias; Arpicco, Silvia; Riganti, Chiara.

In: Cancer Letters, Vol. 456, 29.04.2019, p. 29-39.

Research output: Contribution to journalArticle

Gazzano, E, Buondonno, I, Marengo, A, Rolando, B, Chegaev, K, Kopecka, J, Saponara, S, Sorge, M, Hattinger, CM, Gasco, A, Fruttero, R, Brancaccio, M, Serra, M, Stella, B, Fattal, E, Arpicco, S & Riganti, C 2019, 'Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts', Cancer Letters, vol. 456, pp. 29-39. https://doi.org/10.1016/j.canlet.2019.04.029
Gazzano, Elena ; Buondonno, Ilaria ; Marengo, Alessandro ; Rolando, Barbara ; Chegaev, Konstantin ; Kopecka, Joanna ; Saponara, Simona ; Sorge, Matteo ; Hattinger, Claudia Maria ; Gasco, Alberto ; Fruttero, Roberta ; Brancaccio, Mara ; Serra, Massimo ; Stella, Barbara ; Fattal, Elias ; Arpicco, Silvia ; Riganti, Chiara. / Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts. In: Cancer Letters. 2019 ; Vol. 456. pp. 29-39.
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abstract = "Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx{\circledR} against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx{\circledR}. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.",
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T1 - Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts

AU - Gazzano, Elena

AU - Buondonno, Ilaria

AU - Marengo, Alessandro

AU - Rolando, Barbara

AU - Chegaev, Konstantin

AU - Kopecka, Joanna

AU - Saponara, Simona

AU - Sorge, Matteo

AU - Hattinger, Claudia Maria

AU - Gasco, Alberto

AU - Fruttero, Roberta

AU - Brancaccio, Mara

AU - Serra, Massimo

AU - Stella, Barbara

AU - Fattal, Elias

AU - Arpicco, Silvia

AU - Riganti, Chiara

N1 - Copyright © 2019 Elsevier B.V. All rights reserved.

PY - 2019/4/29

Y1 - 2019/4/29

N2 - Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.

AB - Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.

KW - Endoplasmic reticulum stress

KW - Liposomal doxorubicin

KW - Osteosarcoma

KW - P-glycoprotein

KW - Protein sulfhydration

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DO - 10.1016/j.canlet.2019.04.029

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VL - 456

SP - 29

EP - 39

JO - Cancer Letters

JF - Cancer Letters

SN - 0304-3835

ER -