Nanotheranostics 2021; 5(2):197-212. doi:10.7150/ntno.53888

Research Paper

Cyclodextrin nanosponge for the GSH-mediated delivery of Resveratrol in human cancer cells

Marco Palminteri1#, Nilesh Kumar Dhakar2#, Alessandra Ferraresi1#, Fabrizio Caldera2, Chiara Vidoni1, Francesco Trotta2✉, Ciro Isidoro1✉

1. Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Novara, Italy.
2. Department of Chemistry, University of Turin, via P. Giuria 7, 10125, Turin, Italy.
#Co-first authors with equal contributions to this work.

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Palminteri M, Dhakar NK, Ferraresi A, Caldera F, Vidoni C, Trotta F, Isidoro C. Cyclodextrin nanosponge for the GSH-mediated delivery of Resveratrol in human cancer cells. Nanotheranostics 2021; 5(2):197-212. doi:10.7150/ntno.53888. Available from

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Smart drug delivery systems are required for the site-specific drug targeting to enhance the therapeutic efficiency of a drug. Resveratrol (RV) is a polyphenolic compound with anti-cancer activity. However, its poor aqueous solubility and non-selectivity are the major challenges for its employment in cancer therapy. In this work, we present the synthesis of RV-loaded glutathione responsive cyclodextrin nanosponges (RV-GSH-NSs) to improve the therapeutic efficiency and selective delivery of RV. The drug loading and encapsulation efficiency were 16.12% and 80.64%, respectively. The in vitro release profile confirmed that RV release was enhanced in response to external glutathione (GSH). Nude NSs were not toxic per se to human fibroblasts when administered for up to 72 h at the highest dose. Cell internalization studies confirmed that RV-GSH-NSs were preferentially up-taken by tumor cells compared to non-tumorigenic cells. Accordingly, RV showed selective toxicity to cancer cells compared to normal cells. GSH depletion by buthionine sulfoximine, a potent inhibitor of its synthesis, reflected in a significant decrease of the NSs accumulation, and consequently resulted in a drastic reduction of RV-mediated toxic effects in cancer cells. These findings demonstrate that GSH- responsive NSs represent an effective delivery system for targeting cancer cells by harnessing the differential tumor characteristics in terms of redox status in parallel with the limitation of side effects toward normal cells.

Keywords: Resveratrol, glutathione, breast cancer, ovarian cancer, β-cyclodextrin nanosponge