Synthesis And Imaging Study Of Novel Tumor-Targeting Contrast Agents

The early diagnosis of tumor means a lot to the control and cure of cancer.Among numerous imaging diagnostic technologies,Magnetic Resonance Imaging(MRI),characterized by nonradioactive and high spatial resolution,has been widely used in the detection of diseases.Due to its low sensitivity,contrast agents(CAs)need to be used to improve tissue contrast by changing the relaxation of neighboring tissue to change MRI signal intensity.CAs are usually classified into two groups:T1 CAs which change longitudinal relaxation time(T1),such as paramagnetic ions(Gd3+,Mn2+and their corresponding complexes);T2 CAs which change transversal relaxation time(T2),such as superparamagnetic nanoparticles(Fe3O4,?-Fe2O3).First,we designed a tumor-targeting contrast agent based on the oil-soluble Fe3O4 nanoparticles synthesized by the organic high-temperature decomposition method.Then 3,4-dihydroxyhydro cinnamic acid(DHCA)was anchored on the surface of Fe3O4,improving its hydrophilicity.Next-SO2NH2 group was introduced,which specifically recognizes the Carbonic Anhydrase IX(CAIX)overexpressed in tumor cells.In vitro and in vivo MRI imaging both showed a better imaging effect of Fe3O4-SO2NH2.And the Prussian Blue stain of tumor tissue slices also confirmed the tumor-targeting property of Fe3O4-SO2NH2.Based on the previous study,we linked PEG with tertiarty amine onto Fe3O4,obtaning two kinds of Fe3O4 CAs:Fe3O4-PEG-N(CH3)2 and Fe3O4-mPEG.The?-potential of Fe3O4-PEG-N(CH3)2 was positive at pH=5,while Fe3O4-mPEG remained neutral during pH=5-8.Both of their r2 were 270-280 mM-1s-1.T2-weighted MRI in HepG2 cells demonstrated Fe3O4-PEG-N(CH3)2 had a better ability of entering cells,and it could be used a long-circulating tumor-targeting CA.In the third part,a dendrimer based tumor-hypoxia bioreductive MRI CA was designed and synthesized.Based on a polyglycerol dendrimer CA,N,N-dimethyl amine was oxidized by H2O2,forming an ion pair-like structure N+-O-,which not only prolonged the circulation time but also could be reduced by tumor hypoxia to positively charged tertiary amine,resulting in more endocytosis and binding to the macromolecules,keeping it in tumor for a longer time.In vivo MRI in nude mice showed that O--N+(CH3)2-G3-DTPA-Gd could markedly identify tumor from normal tissue and clearly distinguish tumor boundary,with a higher signal brightness and a longer retention time compared with N(CH3)2-G3-DTPA-Gd and Magnevist.So,this novel tumor-hypoxia bioreductive MRI CA can be a promising probes in tumor diagnosis.