Posted by Oxaliplatin (Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer (CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), which can promote tumor metastasis. Moreover, high glutathione (GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa (IV) prodrug with anti-inflammatory properties (desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles (designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein, and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.
After the nanoparticles were taken up by tumor cells, it releases Oxa and DN under the action of GSH, which induced DNA damage and down-regulation of COX-2 and PGE2 and then synergistically induced cell apoptosis and inhibited metastasis. More importantly, depletion of GSH by IAn-modified cyclodextrin pseudo-polyrotaxane could enhance Oxa sensitivity and improve therapeutic efficacy. Both in vitro and in vivo experiments showed that our system had strong anti-tumor ability and good biological safety. This study not only overcomes the inflammatory defect induced by Oxa chemotherapy and plays the dual anti-tumor effect of Oxa and COX-2 inhibitor, but also overcomes the limitation of easy detoxification of Oxa, which has potential application value in the clinical treatment of platinum-sensitive colorectal cancer.
Wenjia Wang, Xingyue He, Xiaojie Wang, Tiantian Zhao, Osamu Muraoka, Genzoh Tanabe, Weijia Xie, Tianjiao Zhou, Lei Xing, Qingri Jin, Hulin Jiang: Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin (IV) prodrug delivery and enhanced colorectal cancer therapy, Chinese Chemical Letters, 2023, 108656. https://doi.org/10.1016/j.cclet.2023.108656.