Construction Of Activatable Optical Probes Based On Quinolinium Receptor And Their Applications In Detection And Imaging

Optical imaging technology,especially near-infrared（NIR）fluorescence imaging technology and optoacoustic imaging technology,can realize visualized,non-invasive and real-time dynamic monitoring of the physiological and pathological processes of various living organisms,thus enabling researchers and clinicians to gain in-depth understanding of the the development mechanism of various diseases.The activatable fluorescence/optoacoustic probes can change the fluorescence/optoacoustic signals according to the activity of specific biomarkers to achieve the purpose of dual-mode“turn-on”detection and imaging.In this paper,quinolinium receptors are used as the basic framework to construct H₂O₂-activatable nanosystem,NO-activatable nanoprobe and nitroreductase-activatable nanoprobe with aggregation-induced emission（AIE）characteristics.The applications of these nanoprobes in the detection and imaging of specific diseases are evaluated through near-infrared fluorescence imaging technology and optoacoustic imaging technology.The main contents are as follows:1.A H₂O₂-activatable quinolinium-based multifunctional nanosystem QBS-FIS&Thd@MM has been constructed,which can actively target inflammatory diseases,realize activatable dual-mode imaging,and realize on-demand therapy against inflammatory diseases through modulating inflammatory pathways.Inflammatory diseases cover a vast array of disorders,including a number of widespread and devastating diseases that are notoriously difficult to treat.Precisely modulating inflammatory signaling pathways has recently become a promising approach for treating inflammatory diseases.A chromophore-drug dyad（QBS-FIS）is synthesized by linking a quinolinium near-infrared chromophore and an Nrf2 activator fisetin through boronate bond which serves as the fluorescence quencher and ROS-responsive linker.QBS-FIS molecules form nanoparticles in water and are coated with macrophage cell membrane to ensure active targeting towards inflammation sites.To further improve therapeutic efficacy,a NF-?B inhibitor thalidomide（Thd）is co-encapsulated to afford the QBS-FIS&Thd@MM nanosystem.Upon administration into mice,the nanosystem migrates to inflammatory foci,and the pathological H₂O₂ in inflammation site could cleave the boronate bonds in nanosystem,thereby activating a chromophore for imaging liver and kidney inflammatory diseases and releasing the active drugs for treating acute liver inflammation.The released drugs exhibit high therapeutic efficacy against inflammatory disease by activating Nrf2 pathway,inhibiting NF-κB pathway and moderately suppressing the NLRP3 inflammasome formation.While the activated chromophore generates strong fluorescence and optoacoustic signals for disease diagnosis and recovery evaluation.The 3D multispectral optoacoustic tomography imaging has been applied to precisely locate the inflammatory foci in a spatiotemporal manner.2.A NO-activatable quinolinium-based nanoprobe QY-N has been constructed,which can diagnose herbal-medicine-induced liver injury by detecting hepatic NO with NIR-II fluorescence and multispectral optoacoustic tomography（MSOT）imaging.Herbal medicines are widely used for health promotion and therapy for chronic conditions,inappropriate use of them may cause adverse effects like liver injury,and accurate evaluation for their hepatotoxicity is of great significance for public health.The nanoprobe QY-N includes a bismethoxyphenyl-amine-containing dihydroxanthene serving as electron donor,a quinolinium as electron acceptor,and a butylamine as recognition group and fluorescence quencher.The nanoprobe QY-N reacts with NO,thereby generating the activated probe QY-NO which exhibits a red-shifted absorption band（700-850 nm）for optoacoustic imaging and generates strong emission（910-1110 nm）for NIR-II fluorescence imaging.QY-NO is AIE active,which ensures strong emission in aggregated state.QY-N has been utilized in the triptolide-indued liver injury mouse model,and experimental results demonstrate the QY-N can be activated by hepatic NO and thus be used in detecting herbal-medicine-induced liver injury.The temporal and spatial information provided by three-dimensional MSOT images well delineates the site and size of liver injury.Moreover,QY-N has also been employed to monitor rehabilitation of liver injury during treatment process.3.A nitroreductase-activatable quinolinium-based nanoprobe NP-Q-NO₂ has been constructed,which can image breast cancer metastases via NIR-I/NIR-II fluorescence imaging and multispectral optoacoustic tomography（MSOT）imaging.Breast cancer has become the most common type of cancer and over 90%of the breast cancer mortalities are caused by metastasis.Hence,accurate and early detection for the metastasis of breast cancer is important for planing optimized treatment and increasing survival rate.With dihydroxanthene moiety serving as the electron donor,quinolinium as the electron acceptor and nitrobenzyloxydiphenylamino as the recognition element,the probe can specifically respond to nitroreductase and transform into an activated D-π-A structure with a NIR emission band extending beyond 900 nm.The activated nanoprobe exhibits NIR emission enhanced by AIE effect and produces strong optoacoustic signal.The nanoprobe can detect and image sequential metastases from the orthotopic breast tumors to lymph nodes and then to lung in two breast cancer mouse models.Moreover,the nanoprobe can monitor and evaluate the treatment efficacy during chemotherapeutic course via NIR fluorescence and MSOT imaging.3D MSOT images enable us to locate and map the tumor metastases to lymph nodes and lung in a spatiotemporal manner.