Prevent Drug Leakage via the Boronic Acid Glucose-Insensitive Micelle for Alzheimer’s Disease Combination Treatment

Boronic acid (BA) materials have been widely applied to glucose and oxidative stress-sensitive drug delivery for the treatment of cancer, diabetes, and Alzheimer's disease (AD). There are completely various BA-sensitive delivery conditions in different diseases. BA materials in the treatment of diabetes show better performance at a high-glucose environment than normal. In contrast, the concentration of glucose in the brain is much lower than that in the blood of AD patients. Hence, the typical glucose and oxidative stress dual-sensitive BA materials inevitably encounter drug leakage in circulation in AD. Attempts to decrease the glucose-sensitive capacity of BA materials are extremely essential for AD drug delivery. In this study, the epoxy group (electron-donating group) was introduced to increase the pK_a values of BA materials by increasing the electron cloud density, and thus, the glucose-insensitive micelle (GIM) was obtained. The treatment effect and the synergism mechanism of the drug-loaded GIM micelle were studied on senescence-accelerated mouse prone 8 mice. This work provided excellent antioxidant drugs (vitamin E succinate, melatonin, and quercetin) and a glucose metabolism drug (insulin) loaded in GIM micelle for AD treatment. The discovery of the combination mechanism is enormously valuable for AD clinical research.