Self-Supplied Reactive Oxygen Species-Responsive Mitoxantrone Polyprodrug for Chemosensitization-Enhanced Chemotherapy under Moderate Hyperthermia

Currently, the secondary development and modification of clinical drugs has become one of the research priorities. Researchers have developed a variety of TME-responsive nanomedicine carriers to solve certain clinical problems. Unfortunately, endogenous stimuli such as reactive oxygen species (ROS), as an important prerequisite for effective therapeutic efficacy, are not enough to achieve the expected drug release process, therefore, it is difficult to achieve a continuous and efficient treatment process. Herein, a self-supply ROS-responsive cascade polyprodrug (PMTO) is designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO is degraded by endogenous ROS of the TME, another part of the polyprodrug backbone becomes cinnamaldehyde (CA), which can further enhance intracellular ROS, thereby achieving a sustained drug release process. Meanwhile, due to the disruption of the intracellular redox environment, the efficacy of chemotherapy drugs is enhanced. Finally, the anticancer treatment efficacy is further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrates remarkable antitumor efficacy, effectively addressing the limitations associated with MTO. A self-supply ROS-responsive cascade polyprodrug (PMTO) is ingeniously designed to reduce systemic toxicity during in vivo transportation of chemotherapy drug mitoxantrone (MTO). Upon degradation by endogenous ROS of tumor microenvironment (TME), PMTO releases cinnamaldehyde (CA), which enhances intracellular ROS levels, leading to a sustained drug release process. Furthermore, the mild hyperthermia effect contributes to the enhanced efficacy of anticancer treatment. image