title: GSH-targeted nanosponges increase doxorubicin-induced toxicity "in vitro" and "in vivo" in cancer cells with high antioxidant defenses.
abstract: Several reports indicate that chemo-resistant cancer cells become highly adapted to intrinsic oxidative stress by up-regulating their antioxidant systems, which causes an increase of intracellular GSH content. Doxorubicin is one of the most widely used drugs for tumor treatment, able to kill cancer cells through several mechanisms. However, doxorubicin use is limited by its toxicity and cancer resistance. Therefore, new therapeutic strategies able to reduce doses and to overcome chemo-resistance are needed. A new class of glutathione-responsive cyclodextrin nanosponges (GSH-NS), is able to release anticancer drugs preferentially in cells having high GSH content. Doxorubicin-loaded GSH-NS, in the cancer cells with high GSH content, inhibited clonogenic growth, cell viability, topoisomerase II activity and induced DNA damage with higher effectiveness than free drug. Moreover, GSH-NS reduced the development of human tumor in xenograft models more than free drug. These characteristics indicate that GSH-NS can be a suitable drug delivery carrier for future applications in cancer therapy.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Daga
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ullio
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Argenziano
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Cavalli
authors.affiliation: Department of Chemistry - University of Turin, Via Pietro Giuria 7, 10125 Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trotta
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferretti
authors.affiliation: Department of Drug Science and Technology, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Zara
authors.affiliation: Department of Health Sciences, University of Eastern Piedmont'A Avogadro', Via Solaroli 17, 28100 Novara, Italy.
authors.forename: Casimiro L
authors.initials: CL
authors.lastname: Gigliotti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Ciamporcero
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, Biochemistry, Human Health Medical School University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Corti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. Electronic address: stefania.pizzimenti@unito.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pizzimenti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Barrera
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D004317:Doxorubicin; D005978:Glutathione
keywords: Doxorubicin; GSH-targeted nanosponges; Prostate and colon cancer cells; Toxic effects