Real-time monitoring and accurate diagnosis of drug-induced hepatotoxicity in vivo by ratio-fluorescent and photoacoustic imagings of peroxynitrite

Because of the low tissue penetration depth and poor photostability of organic cyanine dye, and the interference of environment, it is a great challenge to monitor the degree of drug-induced hepatotoxicity by in vivo detection of peroxynitrite (ONOO-). Herein, we report a heptamethine cyanine dye (P-cy7)-coordinated upconversion nanoparticles (UCNPs), namely UCY7, as a fluorescent nanoprobe for evaluating drug-induced hepatotoxicity. Based on the luminescence resonance energy transfer (LRET) between UCNPs and the cyanine dye (P-cy7), the irradiation is changed from visible light of 660 nm to near infrared (NIR) light of 980 nm, therefore, the issues of poor photostability and severe photobleaching of cyanine dye can be effectively solved. After injecting via the tail vein, the nanoprobes are rapidly concentrated in liver. Since the level of ONOO- is up-regulated during the drug-induced liver injury, the LRET between UCNPs and P-cy7 is disrupted to release the upconversion luminescence at 656 nm, while the upconversion luminescence at 800 nm remains constant, achieving ratio-fluorescent imaging (RFLI) of ONOO- in liver to calibrate the influence of environment. In addition, the reduction of the absorption of nanoprobes in the presence of ONOO- gives highly sensitive photoacoustic imaging (PAI). Based on the RFLI and PAI of the liver, the real-time monitoring and accurate diagnosis of different degree of hepatotoxicity by using the model of acetaminophen (APAP) induction have been achieved successfully, providing a new idea for the clinical evaluation of drug-induced hepatotoxicity.