Naphthalimide Dyes For Fluorescence Recognition And Inhibition Of Cancer

As an extremely aggressive disease,cancer cells grow and divide uncontrollably.Cancer faces a wide range of people with high mortality rates.Therefore,research on the early diagnosis and treatment of cancer has been receiving much attention.Fluorescent probes have the unique advantages of high sensitivity,strong specificity and fast response.They have shown application potential in many fields and have received widespread attention.This thesis mainly studies the design,synthesis,spectral testing,cell imaging,tumor suppression in vivo,and application of in vivo imaging of naphthalimide fluorescent dyes.Using nitroreductase(NTR)as the target,a kind of dye NP-Mito-NTR with naphthylidene as the fluorescent precursor was synthesized.In the cellular environment,the triphenylphosphine structure of the dye NP-Mito-NTR can be localized on the mitochondria in the cytoplasm.The nitro group on the naphthalene ring can be specifically reduced to an amino group with the help of nitroreductase and coenzyme NADH,the ICT effect is restored,the maximum emission wavelength is red-shifted from 425 nm to 544 nm,and the fluorescence intensity is enhanced by 25 times.Since nitroreductase is overexpressed in a hypoxic environment in cancer cell/tissue,cancer can be identified by detecting nitroreductase.Using the Dvl protein in the Wnt signaling pathway as a target,a kind of dye SLN was designed and synthesized with naphthalimide as the fluorescent precursor and Wnt pathway inhibitor sulindac as recognition group.Molecular docking simulations show that SLN can bind to the Dvl protein in a fully unfolded conformation;SLN is similar to the original drug-sulindac and forms hydrogen bonds with arginine(R322)in the PDZ domain of the Dvl protein.The fluorophore emits a fluorescent signal when it binds to the Dvl protein in the Wnt pathway for tumor identification.SLN can quickly enter cancer cells/tissues within 5 min with a staining depth of 80 μm,which can be further used for fluorescent surgical navigation.At the same time,the binding of SLN to Dvl protein can inhibit the expression of its downstream protein β-catenin.The expression of β-catenin in the administration group decreased to about 1/2 of the control group,which inhibited tumor proliferation.In the experiment of inhibiting tumor proliferation in vivo,the average tumor volume of the sulindac group was 29%of the control group,the average volume of SLN group was 43%of the control group,and the average tumor weight of the sulindac group was 42%of the control group.The average tumor weight of SLN group was 60%of the control group.The results show that SLN is similar to the original drug sulindac and can inhibit tumor proliferation at a certain concentration.SLN has dual functions of cancer recognition and inhibition.Using COX-2 protein as a recognition target,a kind of dye IBLN was designed and synthesized with naphthalimide as the fluorescent precursor and COX-2 protein inhibitor ibuprofen as the recognition group.When IBLN binds to the COX-2 protein,it emits a fluorescent signal to achieve tumor recognition with a signal-to-noise ratio of 4.6.The results of in vivo inhibition of tumor proliferation experiments showed that no tumor formation occurred in the individual administration group by chemoprevention.The average tumor weight of the ibuprofen group was 20%of the control group,and the average tumor weight of the IBLN group was only 4%.IBLN has dual functions of cancer recognition and inhibition.