Multiple Stimuli-Responsive Micelles for Photo/ROS/pH-Triggered Chemo/Photo/Ferroptosis Therapy of Colorectal Cancer

Combined phototherapy with other therapeutic strategies can improve the therapeutic outcomes of tumors and reduce the side effects. However, shaping multiple modalities for combination therapy remains challenging. Herein, multiple stimuli-responsive drug-loaded micelles are presented, which are self-assembled from cypate-conjugated pH-sensitive poly(ethylene glycol)–poly(2-(diisopropylamino) ethyl methacrylate)–poly(2-aminoethyl methacrylate hydrochloride) and redox-responsive poly(glycidyl methacrylate)–poly(propylene sulfide) copolymer and loaded with chemo agents doxorubicin (DOX) and sorafenib (SRF, also a ferroptosis inducer) for enhanced tumor therapy. The DOX and SRF chemo drugs were encapsulated into the hydrophobic core of PPS and PDPA to enable multiple stimuli-responsive controlled drug delivery. In vivo and in vitro experiments are carried out to investigate the potential application for controlled drug release and systemic chemo-phototherapy. This study highlights the rational design of cypate-based drug-loaded micelles, offering multiple stimuli-responsive drug releases and synergistic photo-, ferro-, and chemotherapy in colorectal cancer.