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) was designed. The encapsulation of the chemotherapy drug mitoxantrone (MTO) in a polymer backbone could effectively reduce systemic toxicity when transported in vivo. After PMTO was degraded by endogenous ROS of the TME, another part of the polyprodrug backbone became 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 was further enhanced due to the mild hyperthermia effect of PMTO. In conclusion, the designed PMTO demonstrated remarkable antitumor efficacy, effectively addressing the limitations associated with MTO. This article is protected by copyright. All rights reserved