An oxidation-reduction-triggered thiamine disulfide-based prodrug of 10-hydroxycamptothecin for selective tumor cell locking and therapeutic delivery

Chemotherapy, a primary method of cancer treatment, has been limited in clinical application due to its lack of specificity and tumor multidrug resistance, resulting in numerous undesired side effects. Herein, a small molecule conjugate, TDK-HCPT, was designed and synthesized, which could target tumor cells and prolong the retention of chemotherapy agents within tumor cells. Moreover, a similarly designed control system, TDK-Nap, has been developed as well to enable cancer cell imaging. Two design elements are incorporated into TDK-HCPT: the thiamine disulfide (TDS) and the thioketal subunit (tk). TDS can be reduced in the high glutathione (GSH) conditions within cancer cell to form thiazolium salt, and the resulting enhanced positive charge and lipophobicity make the system difficult to be pumped out of tumor cells, thereby effectively “locking” the chemotherapy drug HCPT inside the tumor cells. Additionally, the tk subunit serves as a ROS trigger, within the tumor cells, the “locked” HCPT were then released and activated by the high ROS conditions, optimizing its targeted potential. This allows TDK-HCPT to serve as a redox-liable molecular platform that targets cancer cells selectively which decreases cancer cell migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a cancer cell “lock in” has been shown to prevent tumorigenesis in an animal model.