Rational Design of a Theranostic Agent Triggered by Endogenous Nitric Oxide in a Cellular Model of Alzheimer’s Disease

Oxidative damage caused by upregulated nitric oxide (NO) plays an important role in the pathogenesis of Alzheimer's disease (AD). Currently, stimulus-triggered theranostic agents have received much attention due to benefits on disease imaging and targeted therapeutic effects. However, the development of a theranostic agent triggered by NO for AD remains unexplored. Herein, through the mechanism analysis of the reaction between a fluorophore of 9,14-diphenyl-9,14-dihydrodibenzo[a,c]phenazine (DPAC) and NO, which we occasionally found and thereafter structure optimization of DPAC, a theranostic agent DPAC-(peg)₄-memantine was fabricated. In an AD cellular model, DPAC-(peg)₄-memantine exhibits NO sensing ability for AD imaging. Meanwhile, DPAC-(peg)₄-memantine shows improved therapeutic by targeted drug release triggered by NO and sustained therapeutic effects owing to the synergetic antioxidative abilities via the anti-AD drug and NO scavenging. This work provides an unprecedented avenue for the studies on not only AD but also other diseases with NO upregulation.