Design,Synthesis And Biological Evaluation Of A Tumor Hypoxia-responsive Probe Integrating Imaging And Therapy

Hypoxia plays an important role in tumor resistance to radiotherapy and chemotherapy,immune escape and promoting invasion and metastasis,which leads to poor prognosis of tumor treatment.In another way,tumor cells under hypoxia express high level of several reductases,such as nitroreductase,azo reductase,quinone reductase,etc.,which also provide a potential target for tumor imaging and treatment.Hypoxic-sensitive fluorescence probes are designed and developed for the high expression of specific reductases in hypoxic tumor cells,which have been used for real-time tumor hypoxic imaging.Especially,near-infrared hypoxic fluorescence probes possess potent tissue penetrating ability and are successfully used in mouse tumor hypoxic imaging.The integrated probe for diagnosis and treatment can achieve tumor real-time diagnosis as well as tumor therapy at the same time.In additon,the therapeutic effect can be monitored and the dosage regimen can be adjusted during the treatment process to achieve the best therapeutic effect with minimal side effects.In recent years,researchers have focused on integrated probes for diagnosis and treatment due to its obvious superiorities.To develop integrated probe for diagnosis and treatment targeting hypoxia,a novel near-infrared probe azo-PDT was designed and synthesized through connecting Si-rhodamine near-infrared fluorophore w-11(based on SiR720)and photodynamic(PDT)porphyrin derivative Pyro with azo linker using FRET strategy.The azo-PDT demonstrated good selectivity and time response to hypoxia at molecular level.Confocal imaging experiments showed that azo-PDT could selectively image Hepg-2 and BEL-7402 hepatocellular carcinoma cells under hypoxia,and the BEL-7402 cells were more sensitive to the probe.Cell survival experiments showed that azo-PDT could potently inhibit tumor cells proliferation under hypoxia(inhibitory rate 81.0%at 2.5?M),while only showed weakly inhibit effect under normoxia(inhibitory rate:33.7%at 2.5?M)after near-infrared irradiation.These results revealed that azo-PDT achieved the integration of hypoxia targeting diagnosis and treatment at the cellular level.The in vivo imaging and therapy experiments are under way.In summary,a novel infrared azo-PDT probe which was designed according to FRET has demonstrated real-time tumor cell imaging and inhibition on tumor cells proliferation under hypoxia,it can be used as a dual functional tool for detecting hypoxia and treatment of tumors.