Synthesis Of Novel Near-infrared Tpe-trimethincyanines Probes With Aggregation-induced Emission Feature And Their Applications In Tumor Imaging In Vivo

Non-invasive optical molecular imaging technology has been widely used in drug research,cancer diagnosis,gene therapy and other fields because of its advantages such as high sensitivity,low cost,and easy operation.The development of fluorescent molecular probes has also become a prerequisite for the study of optical molecular imaging.Unfortunately,due to the presence of aggregation-induced quenching(ACQ),common fluorescent reagents include rhodamine,cyanine dyes,has been limited in biological applications.Recently,aggregation-induced emission(AIE)phenomenon conceptually termed by Tang’s group,has extensively application prospects in the field of bioimaging due to the effective avoidance of fluorescence quenching.Herein,based on the tetraphenylethene(TPE)molecules with AIE effect,a novel type of controlled one-pot reaction was developed to obtain a class of near-infrared TPE-trimethincyanines or TPE-vinyl dyes.The physicochemical properties of the two types of compounds were fully studied.In addition,based on TPE-trimethincyanines dyes,fluorescence-activated liposomal probe was prepared.Compared with the biological imaging results of self-assembled AIE molecule,it was found that TPE-LPs can realize imaging of tumor in vivo.The paper’s content is outlined as: 1.We used TPE-CHO and heterocyclic quaternary ammonium salt as reaction materials,controlled the reaction conditions and obtained TPE-vinyl dyes(I)and TPE-trimethincyanines(II)by one-step synthesis.The products included TPE-VQ,TPE-VS,TPE-COOH,TPE-BIVS,and TPE-BICOOH.The reaction selectively generates two compounds by controlling nucleophilic addition or conjugate addition.The reaction conditions are mild and controllable,with few by-products and easy to separate and purify.The spectroscopic properties of these compounds have also been studied,indicating that TPE-vinyl dyes have low fluorescence efficiency to further use inappositely.TPE-trimethincyanines retain the excellent properties of cyanine dyes,have the AIE effect,and improve the fluorescence quenching of cyanine.The novel method for synthesizing AIE compounds can facilitate the introduction of cyanine fluorescent molecules into TPE molecules,which overcomes the shortcomings of previous synthesis methods.What’s more,it provides a new idea for the preparation of such AIE molecules.2.Based on TPE-BICOOH,we design and synthesize liposome TPE-LPs encapsulated with TPE-trimethincyanines.Electron microscopy,particle size,and potential of the liposomes were analyzed,and it was found that the TPE-LPs had spherical bilayers with uniform size compared to the single-particles of the self-assembled dye TPE-BICOOH.The preparation of giant vesicles showed that the hydrophobic TPE-BICOOH dye was located in the phospholipid bilayer of the liposome,and the spectral results showed that the TPE-LPs had weak auto-fluorescence,and the fluorescence after membrane rupture was enhanced almost 20 times.The fluorescence-activated AIE probes are simple to design and synthesize.The liposomes have good biocompatibility and can be used for cell and living tumor detection imaging.3.The novel TPE dyes and TPE-LPs were used for fluorescent bioimaging.The results showed that TPE-BICOOH and TPE-LPs were less toxic than other probes,which had biocompatibility and excellent potential in cell imaging.When used female athymic nude mice model created by subcutaneous inoculation with 4T1 cancer cells,TPE-LPs accumulate in situ at the tumor site due to the EPR effect,exerted its AIE effect from fluorescence "off" to "activation".The tumor signal-to-noise ratio could be achieved 3.8 with a longer tumor retention time.This was also the first time fluorescence-activated AIE probes had been used in bioimaging in vivo,showing good prospects for application.