Quinoxalinone Based Aggregation Induced Emission Molecules for Biomedical Imaging

Author:Shi Lei Lei

Supervisor:zhu xin yuan


Degree Year:2018





In many conventional systems,luminophores experience some effects of emission quenching,partially or completely when they are in aggregate states.The phenomenon was named as aggregation-caused quenching(ACQ).As a result,to avoid this ACQ effect,the fluorescent molecules should be used in dilute solutions.However,the concentration of luminophores is quite low in dilute solutions,which would be resulted in decreased fluorescent intensity.Generally,majority of luminophores were not allowed to be used for biodetection and bioimaging at some certain conditions due to ACQ effects.In 2001,Tang and coworkers found a strange phenomenon,which is opposite to ACQ effects.They found that hexaphenylsilole(HPS)is non-emissive when they are dissolved in a good organic solvent(Tetrahydrofuran,THF),however,fluorescence emission is turned on when the fraction of water reaches to ~80 vol %,as a result of heavy aggregation of the HPS molecules in the aqueous medium.Eventually,this phenomenon is named as “Aggregation Induced Emission”(AIE).In contrast to conventional fluorescent dyes with fluorescence of ACQ feature,AIE fluorophores exhibit bright fluorescence in the aggregated state but very weak fluorescence in a good solvent,making them an ideal “turn-on” fluorescent probes for bioanalysis.Recently,AIE probes with red to near-infrared(NIR)emission are of great interest compared to those of AIE luminogens with short emission wavelengths,since they can minimize photodamage to living cells,eliminate the strong autofluorescence of biological tissues,and increase the penetrating depth.Despite the great advances have been made by AIE luminogens that partially address the issues existed in conventional dyes,there HSA been a move towards the development of new AIE fluorescent probe with all ideal characteristics for bioimaging.For instance,most of currently existing AIE probes exhibit small Stokes shifts and lack in specific organelle-targeting capacity and biomarker responsiveness,which limited their use in tracking biological processes and pathological pathways over long time spans.To overcome these challenges,herein,we constructed two series of novel quinoxalinone derived AIE molecules with large Stokes shift for ferroptosis identification,Parkinson disease diagnosis and vesicular transportation monitoring and non-invasive long-term imaging.1.Reaction Based Color-Convertible Fluorescent Probe for Ferroptosis IdentificationFerroptosis is an iron-mediated,caspase-independent pathway of cell death that accompanies with the accumulations of reactive oxygen species(ROS)and oxygenases,as well as involves in many other pathophysiological procedures.However,specific and rapid monitoring of ferroptosis in living cells or tissues HSA not been achieved so far.Herein,a quinoxalinone-based fluorescent probe(termed as Quinos-4,or QS-4)with a reactive aromatic thioether moiety was designed for ferroptosis identification.Upon exposing to the high levels of ROS and hemeoxygenase-1(HO-1)which are considered as the biochemical characteristics of ferroptosis,QS-4 could be oxidized into a sulfoxide derivative(QSO-4)and its original aggregation-induced enhanced red fluorescence emission could be converted to green fluorescent emission sharply.Based on this unique reaction-induced color conversion,this molecular probe can be employed for identifying the occurrence of ferroptosis both in vitro and in vivo.2.Color-Convertible Fluorescent Nanoreactor for Parkinson Disease DiagnosingMolecular fluorescent probes for Parkinson disease diagnosis typically target a single biomarker in this complex biological system.However,this fluorescence-based single biomarker detection is often insufficient for diagnostic purpose.It is well known that iron accumulation in substantia nigra pars compacta(SNpc)HSA been identified to be a significant pathophysiological characteristic of Parkinson’s disease(PD),which can up-regulate the reactive oxygen species(ROS)level,eventually induce the death of dopaminergic(DA)neurons.Herein,based on the biochemical characteristics of Parkinson disease,an HIV-1 trans-activating transcriptor(TAT)modified hyperbranched polyphosphate(HPHEEP-OH)based color-convertible fluorescent nanoreactor,which contains a functional iron ligand and a fluorescent probe(Q1),was created.Upon meeting highs level of iron and ROS in Parkinson disease model,the fluorescent probe inside the nanoreactor could be oxidized into its sulfoxide derivative under the catalyzation of iron and its functional ligand,then the original red fluorescence could be converted to green fluorescent emission sharply.This unique reaction-based color conversion of fluorescent nanoreactor can be employed for detecting dual biomarkers and identifying the occurrence of Parkinson disease both in vitro and in vivo.3.Endoplasmic Reticulum Targeted Fluorescent Nanodot for Vesicular Transport MonitoringWe report a highly stable aggregation-induced emission(AIE)fluorescent nanodot assembled by an amphiphilic quinoxalinone derivative-peptide conjugate,namely Quino-1-Fmoc-RACR(also termed as Q1-PEP),which exhibits large Stokes shifts and an endoplasmic reticulum(ER)-targeting capacity for bioimaging.It is found that the resulting nanodot can easily enter the ER with high fluorescent emission.As ER is mainly involved in the transport of synthesized proteins in vesicles to the Golgi or lysosomes,Q1-PEP nanodot with ER-targeting capacity could be used to monitor the vesicular transport inside the cells.Compare to the conventional fluorescent dyes with small Stokes shifts,our self-assembled fluorescent nanodot shows superior resistance to photobleaching and aggregation-induced fluorescence quenching,as well as the elimination of the spectra overlap with autofluorescence of biosubstrate owning to their AIE-active and red fluorescence emission characteristics.All these optical properties make the new fluorescent nanodot suitable for non-invasive and long-term imaging both in vitro and in vivo.