Abstract
Triptolide (TP), derived from the herb Tripterygium wilfordii, has a highly potent antitumor effect, but its poor water solubility and high toxicity hinder its clinical use. Here, a novel triptolide prodrug (TP-PEG-SS) was synthesized by conjugating TP and stachydrine (SS) with polyethylene glycol (PEG), which endowed TP with high water solubility, the capability to target tumor mitochondria, significant antitumor efficacy and low toxicity. Subsequently, TP-PEG-SS was self-assembled with ginsenoside Rg3 and lecithin to form nanovesicles (NVs). The NVs exhibited double-targeted performance for actively targeting tumor mitochondria via electrostatic interaction and entering M2 macrophage via glucose transporter GLUT-1, thereby greatly inhibiting the tumor cell growth by triggering apoptosis of tumor and polarization of M1 macrophage. In Pan02 tumor-bearing mice, the NVs were selectively accumulated in the tumor regions and improved the immunosuppressive tumor microenvironment, thereby exerting a more potent synergistic antitumor effect of both Rg3 and TP, as well as less systemic toxicity than free TP. Consequently, the NVs is a promising antitumor nanovesicle with double-targeted capability, which may enhance the clinical applicability of TP.