Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver

Martina Daga, Inge A. M. de Graaf, Monica Argenziano, Ana Sofia Martinez Barranco, Maximillian Loeck, Yehya Al-Adwi, Marie Angele Cucci, Fabrizio Caldera, Francesco Trotta, Giuseppina Barrera, Angela Casini*, Roberta Cavalli, Stefania Pizzimenti

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    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.

    Original languageEnglish
    Article number104800
    Number of pages10
    JournalToxicology in Vitro
    Volume65
    DOIs
    Publication statusPublished - Jun-2020

    Keywords

    • Glutathione-responsive nanosponges
    • beta-Cyclodextrin
    • Doxorubicin
    • HepG2 cells
    • Rat precision-cut liver slices
    • Hepatotoxicity
    • IN-VITRO
    • CANCER-CELLS
    • NANOPARTICLES
    • METABOLISM
    • SLICES
    • TOOL
    • DIFFUSION
    • MODEL
    • VIVO
    • PH

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