Design,Synthesis And The Application Of Novel NIR-Ⅱ Targeted Probes With AIE Property In Orthotopic Hepatic Tumors Theranostics

Conventional fluorescent dyes suffer from the disadvantage of aggregationinduced quenching(ACQ)effect,which limits their practical performance.Fluorescent compounds with aggregation-induced emission(AIE)properties(AIEgens)open up new avenues for the development of novel and efficient optical therapeutic probes due to their unique optical properties,flexible designability,and potential versatility.Previous studies have shown that near-infrared window(NIR,650-1700nm)imaging has the advantages of less photon scattering,low absorption,and low autofluorescence interference,in particular,the second near-infrared window(NIR-Ⅱ:900-1700 nm)with less scattering,minimal absorption and negligible autofluorescence properties,provides real-time stability,high resolution,high sensitivity and high signal-to-noise ratio deeper tissue imaging information.These characteristics make NIR absorption and emission targeted probes the best candidates for the combination of optical imaging and phototherapy.On the other hand,the investitive tumor-targeting property of optical theranostic probes enabled them to maximize accumulation and illumination of tumors and maximize phototoxic damage with minimal side effects on normal tissues.However,probes with targeted AIE NIR-Ⅱ emission were barely reported,and the design strategies and methods of targeting AIE NIR-Ⅱ emission probes at the molecular level were more rarely reported.Based on the above research background,we investigated the optical properties and biological functions of AIEgens with NIR absorption and emission,and determined to develop novel types of AIE NIR-Ⅱ targeted optical theranostic probes to solve the bottleneck of penetration depth and tumor targeting in deep tumors,realizing the efficient diagnosis and treatment.It provides new design strategies and methods for the development of efficient targeted optical diagnosis and treatment probes.The main research contents of this paper were summarized as follows:The first part of research work was mainly based on donor-acceptor-donor(D-AD)structure to design and synthesize of a novel AIE NIR-Ⅱ-emitting phototherapeutic agent PTZ-TQ,and through method of polymer modification to improve its water dispersibility,biological stability,tumor targeting and so on.Based on small molecule PTZ-TQ,taking DSPE-PEG3400-NH2 as the encapsulation matrix,PTZ-TQ-AIE dots was synthesized by nanoprecipitation method,which had good nanometer size and excellent surface charge effect.Compared with indocyanine green(ICG),PTZ-TQ-AIE dots were high stable,exhibiting bright and sharp NIR-Ⅱ emission at 1250 nm and extending to 1600 nm.Furthermore,PTZ-TQ-AIE dots can efficiently generate reactive oxygen species(ROS)for photodynamic therapy.In vitro and in vivo studies on orthotopic liver tumors showed that PTZ-TQ-AIE dots had good tumor penetration and EPR targeting effect.PTZ-TQ-AIE dots could be used for image-guided early-stage surgery of tumors and for "downstaging" intention to reduce the tumor size.According to the tumor size,a personalized treatment strategy was given to achieve the therapeutic effect of almost complete inhibition of the orthotopic tumor without recurrence and fewer side effects.Due to the problems of in vivo metabolism of nanoparticles,small organic molecules have the advantages of easy modification,easy metabolism and so on.Therefore,on the basis of the first part of research work,in order to develop the AIE NIR-Ⅱ emission probes with targeting at the molecular level,the second part of research work was mainly based on the D-A-D configuration to design and synthesize the organic molecular AIE NIR-Ⅱ-emitting probes with tumor mitochondria targeted in the molecular level,and the targeted design strategy was explored in detail,and the rapid and accurate diagnosis of in the orthotopic tumor was realized.Physically,based on triphenylamine,a series of probes were designed(MT-p,MT-1p,MT-2p,MT-1,MT-2,MT-3)and synthesized by regulating the number of triphenylamine and amino groups in the outside of molecular structure,and their structure-propertyapplication relationships are systematically studied.Unlike MT-p,MT-1p and MT-2p exhibited strong AIE emission properties at high concentrations and low cytotoxicity.MT-1p and MT-2p were used as generalizable functional groups to synthesize MT-1 and MT-2,and only the diamino cationized MT-2 showed mitochondria targeting.Furthermore,MT-2 uniquely lighted up tumor cells while normal cells were barely lighted,demonstrating the ability to discriminate cancer cells compared to diamino cationized but destructive structure MT-3.MT-2 had excellent AIE NIR-Ⅱ-emitting properties,low cytotoxicity and high mitochondria-targeted properties and other characteristics.It can be used for rapid and precise diagnosis of the early-stage orthotopic hepatic tumors in zebrafish and mouse.Meanwhile,as a generalizable functional group,MT-2p showed potential application value in the development of preclinical and clinical tumor mitochondria-targeted AIE optical theranostic probes.Finally,this research paper is summarized,It was mainly to develop two new types of AIE NIR-Ⅱ emission probes with targeted,enriching the types of probes,and explore the targeting strategies of probes,providing new ideas for the development of targeted probes.And gives an outlook on the future development of AIE NIR-Ⅱ targeted optical diagnostic probes with AIE properties in the field of biomedical research.