Smart Unimolecular Micelle-Based Polyprodrug with Dual-Redox Stimuli Response for Tumor Microenvironment: Enhanced in Vivo Delivery Efficiency and Tumor Penetration

Low delivery efficiency and limited tumor penetration of nanoparticle-based drug delivery systems (DDSs), the two most concerned issues in tumor therapy, have been considered as the "Achilles' heel" for tumor treatment. In this study, we have designed a highly sensitive dual-redox-responsive prodrug-based starlike polymer β-CD-b-P(CPT_GSH-co-CPT_ROS-co-OEGMA) (CP_GR) for synergistic chemotherapy. The high glutathione (GSH) concentration and high reactive oxygen species (ROS) levels are in a dynamic equilibrium in the tumor microenvironment (TME) and could trigger the disintegration of CP_GR micelles, which can promote the release of anticancer drug camptothecin (CPT) completely and intelligently. In order to verify the synergistic antitumor mechanism, two corresponding single-responsive β-CD-b-P(CPT_GSH-co-OEGMA) (CP_G) and β-CD-b-P(CPT_ROS-co-OEGMA) (CP_R) were altogether prepared as contrast. Both in vitro and in vivo studies confirmed the enhanced anticancer activity of CP_GR micelles in comparison of single responsive micelles. This work contributes to the orchestrated design of dual-redox-responsive DDSs for synergetic antitumor chemotherapy, which provides a good approach for the development of dual-redox-responsive nanomedicine.