A Near-Infrared Responsive Drug Sequential Release System for Better Eradicating Amyloid Aggregates

Polyphenol compounds, such as curcumin, rutin, rifampicin, can inhibit Aβ aggregation and decrease reactive oxygen species (ROS), and have received much attention in recent years for Alzheimer's disease (AD) treatment. However, the excess metal ions in amyloid plaque can chelate to polyphenol compounds. It significantly declines the efficacy of polyphenol compounds when used in the clinic. In this report, a near-infrared (NIR)-caged upconversion responsive system UCNP@SiO₂ @Cur/CQ is designed and synthesized to control drug sequential release by regulating NIR laser. When the system is irradiated at low intensity of the NIR laser, the caged metal chelator, clioquinol (CQ), is first released for removing free metal ions, which affects the efficacy of curcumin. Subsequently, the strongly caged curcumin is released with increasing the intensity of NIR light. In this way, the treatment efficacy of curcumin is improved. This NIR-caged drug release system can not only remove Cu²⁺ but also clean superfluous ROS. Therefore, developing controllable sequential drug releasing may provide clinical benefits of combination treatment of AD. To the best of our knowledge, this work reports for the first time that a sequentially controlled system can overcome the interference of metal ions on polyphenol compounds for AD treatment.