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 journalArticlepeer-review

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
Early online dateApr 29 2019
DOIs
Publication statusPublished - Aug 2019

Keywords

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

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