Construction And Application Of Microenvironment-Responsive Fluorescent Theranostic Agent

Accurate detection of biological microenvironment parameters is conducive to monitoring related physiological and pathological activities.The unique microenvironment of tumor are considered as a pivotal influence factor for the construction of highly effective photosensitizers.This thesis focuses on the construction of microenvironment-responsive fluorescent probes and photosensitizers and their application of detection,diagnosis and treatment.Proton is the serious disturbance to PET chemosensors in biological microenvironment.Photoinduced electron transfer(PET)probes N5,N4,NMO for Zn2+detection,and compound NDM with different highest occupied molecular orbital energy(EHOMO)of fluorophores were designed and synthesized.By analyzing the Zn2+ concentration and pH influence on fluorescence intensity,we have found that NDM doesn’t recognize Zn2+or protons and NMO respond to both zinc ions and protons,while N4 and N5 are not influenced by protons but respond to zinc ions through PET mechanism.With calculation of the PET process by Gaussian 2009,the method to overcome proton interference in the range of pH less than pKa is deduced to be:the EHOMO of the fluorophore should be tuned to be lower than that of free recognition receptor and protonated recognition receptor,and higher than coordinated recognition receptor.Lysosomal polarity affects lysosomal functions.Unfortunately,lysosomal polarity values is still unclear.NOH synthesized upon ICT fluorophore is nitrogen-heterocyclic compound.π-π*and n-π*transition of excited NOH produce dual fluorescence peaks.Ratiometric fluorescence(I474/I552)of NOH has a Boltzmann function response to polarity in a broad range(△f=0.125～0.32).Besides,polarity-response NOH targets at lysosomes.Through analyzing of NOH ratiometric fluorescence imaging,lysosomal polarity value of MCF-7 cells in different cell conditions can be respectively calculated.PSs that are excited by light in near-infrared(NIR)region(650-900 nm)can realize cancer therapy in the deeper tissues.Photosensitizers(PSs)with tumor-targeting ability not only improve the tumor accumulation efficiency,but also efficiently decrease the toxic side effects to healthy tissues.Cyanine photosensitizer IDMQ was a smart J-aggregate switching system responding to different negative charged microenvironment.IDMQ J-aggregates were carried to tumor site via enhanced permeability retention(EPR)effect.Intracellular RNA providing another negatively charged microenvironment to reconstruct IDMQ J-aggregates pushes the optimal wavelength for PDT from 630(free state IDMQ)to 700 nm with deeper light penetration and improves Φ(1O2),greatly improving in vivo efficacy of photodynamic therapy.