TY - JOUR
T1 - Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin
T2 - Evaluation of toxicity and transport mechanisms in the liver
AU - Daga, Martina
AU - de Graaf, Inge A.M.
AU - Argenziano, Monica
AU - Barranco, Ana Sofia Martinez
AU - Loeck, Maximillian
AU - Al-Adwi, Yehya
AU - Cucci, Marie Angele
AU - Caldera, Fabrizio
AU - Trotta, Francesco
AU - Barrera, Giuseppina
AU - Casini, Angela
AU - Cavalli, Roberta
AU - Pizzimenti, Stefania
N1 - Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/6
Y1 - 2020/6
N2 - The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance.
AB - The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance.
KW - Doxorubicin
KW - Glutathione-responsive nanosponges
KW - HepG2 cells
KW - Hepatotoxicity
KW - Rat precision-cut liver slices
KW - β-Cyclodextrin
UR - http://www.scopus.com/inward/record.url?scp=85080151012&partnerID=8YFLogxK
U2 - 10.1016/j.tiv.2020.104800
DO - 10.1016/j.tiv.2020.104800
M3 - Article
C2 - 32084521
AN - SCOPUS:85080151012
SN - 0887-2333
VL - 65
JO - Toxicology in Vitro
JF - Toxicology in Vitro
M1 - 104800
ER -