Chae Gyu Lee1,Tae-Hyuk Kwon1
Ulsan National Institute of Science and Technology1
Chae Gyu Lee1,Tae-Hyuk Kwon1
Ulsan National Institute of Science and Technology1
Under the reductive conditions in cancer cells, cysteine-containing oxidoreductases, such as thioredoxin (Trx), glutaredoxin (Grx), and protein disulfide isomerase (PDI), accelerate thiol-disulfide exchange reactions through a reversible reaction (CysS–SCys↔Cys–SH), rendering upstream and downstream signaling pathways to maintain redox homeostasis in metabolism-activated cancer cells. In addition, it is difficult to differentiate between tumorous and healthy tissues as the intracellular GSH concentrations of both cell types are approximately 2–10 mM. Therefore, disulfide-bond-based nanocarriers have potential to exhibit cytotoxicity due to the unmanageable drug release in normal cells. This study investigates the spatiotemporally-controlled irreversible degradation of Ir-based photosensitizer (TIr3)- encapsulating nanogels (IrNG) through the hyperoxidation of resulting intracellular thiols using reactive oxygen species (ROS).<sup>1,2</sup> By mimicking the reversible redox reaction of Trx and Grx, we developed IrNG that maintains the self-assembled nanostructure through hydrophobic interactions and reversible crosslinking between its disulfide bonds and thiols in the absence of light. When a highly cytotoxic TIr3 was stably encapsulated within IrNG, it exhibited significantly enhanced biocompatibility under normal cellular conditions. However, upon photoirradiation, TIr3 generated high levels of ROS, irreversibly oxidizing the thiols to induce electrostatic repulsion between the polymer molecules, resulting in the TIr3 release and induction of cancer cell apoptosis. Therefore, we could obtain substantially increased changes in cell viability and <i>in vivo </i>tumor growth regarding the presence and absence of photoirradiation, confirming the manual control of cytotoxic drug release.<br/><sup>1</sup> C. G. Lee et al., “Dual-Modulated Release of a Cytotoxic Photosensitizer Using Photogenerated Reactive Oxygen Species and Glutathione” <i>Angew. Chem. Int. Ed. </i><b>2022, </b><i>61, </i>e202210623<br/><sup>2 </sup>C. G. Lee et al., “Controlling Morphologies of Redox-Responsive Polymeric Nanocarriers for a Smart Drug Delivery System” <i>Chem. Eur. J. </i><b>2023</b>, e202300594