Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
Department of Chemistry, University of Turin, via P. Giuria 7, 10125, Turin, Italy.
Nanotheranostics. 2021 Jan 21;5(2):197-212. doi: 10.7150/ntno.53888. eCollection 2021.
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 release profile confirmed that RV release was enhanced in response to external glutathione (GSH). Nude NSs were not toxic 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.
智能药物输送系统是实现药物靶向定位的必要条件，可提高药物的治疗效果。白藜芦醇（RV）是一种具有抗癌活性的多酚化合物。然而，其较差的水溶性和非选择性是将其应用于癌症治疗的主要挑战。在这项工作中，我们制备了载白藜芦醇的谷胱甘肽响应性环糊精纳米海绵（RV-GSH-NSs），以提高 RV 的治疗效果和选择性递送。药物载药量和包封效率分别为 16.12%和 80.64%。释放曲线证实，RV 的释放可以通过外部谷胱甘肽（GSH）增强。在最高剂量下，纳米海绵在长达 72 小时的时间内对人成纤维细胞没有毒性。细胞内化研究证实，RV-GSH-NSs 比非致瘤细胞更优先被肿瘤细胞摄取。因此，RV 对癌细胞的选择性毒性高于正常细胞。谷胱甘肽合成的强效抑制剂丁硫氨酸亚砜胺（BSO）耗尽 GSH，导致 NSs 积累显著减少，从而使 RV 介导的癌细胞毒性作用急剧降低。这些发现表明，GSH 响应性 NSs 代表了一种有效的靶向癌细胞的递送系统，通过利用肿瘤细胞在氧化还原状态方面的差异特征，同时限制对正常细胞的副作用。
