Redox Polyion Complex Micelle-Based Injectable Hydrogel as Local Reactive Oxygen Species Scavenging Therapeutics

The overproduction of reactive oxygen species (ROS) induces oxidative stress on functional biomolecules, leading to numerous human diseases, including inflammation, aging, diabetes, neurodegenerative disease, myocardial infarction, and cancer. The regulation of local ROS level and redox equilibrium plays a critical role in preventing and curing biological disorders. Various endogenous redox enzymes are balanced to maintain physiological hemostasis in vivo, but this balance is lost when ROS is excessively produced, leading to strong oxidative stress and diseases. Not only natural vitamins C and E but also many antioxidants are synthesized to eliminate excessively produced ROS. However, most antioxidants have been largely ineffective in clinical settings, due to their low stability and nonspecific and short activity in physiological conditions. One of the other important problems of these low-molecular-weight antioxidants is that they cause the dysfunction of normal cells by destroying normal redox reactions such as an electron transport chain after their nonspecific cellular internalization. In order to suppress these types of adverse side effects, we have been developing polymer antioxidants, which prevent their internalization in healthy cells to protect important normal redox reactions. Antioxidant polymers composed of an amphiphilic block copolymer self-assemble in water to become redox nanoparticles (RNPs). To date, we have proven that RNPs exert a high therapeutic efficacy on diseases strongly dependent on various oxidative stresses, including ulcerative colitis, Alzheimer;s disease, ischemia reperfusion injuries such as brain, heart, kidney, and intestinal ischemia reperfusion, and cancer. More recently, we started to develop new antioxidant nanomedicines for local diseases related to oxidative stress. For these objectives, we designed novel redox poly ion complex micelles (PIC) that form irreversible temperature-responsive hydrogels at body temperature for local therapies. Since PIC-based hydrogel possesses a nitroxide radical as a catalytic ROS scavenger covalently conjugated in the polymer backbone, it exhibits therapeutic function by regulating the local redox equilibrium. After conversion to a hydrogel, it continuously eliminates ROS locally and suppresses rapid diffusion at injected sites. In this chapter, we describe the design, preparation, and characterization of developed redox injectable hydrogel and its medical applications for arthritis, periodontal disease, local anesthesia, as well as its application as an anti-adhesive gel and its sustained release of bioactive molecules in other medical therapies.