Research Of IR-783 For Cervical Cancer-specific Imaging And Mechanism

The World Health Organization data show that cervical cancer will result in more than270,000 female deaths each year,and it has become the second largest disease compared with breast cancer in development country. In China, because of the population base is too large cervical cancer incidence rate accounts for about 29% of the world. Therefore, the prevention and treatment of cervical cancer is quite grim.Early symptoms and physical signs of cervical cancer are not special, signs and symptoms will appear in an advanced stage. So, its early diagnosis and severity prediction in time will have important significance in reducing mortality and the levels of disease. The major detection method in early stage of cervical cancer is cytology screening, but due to lack of specific tumor markers, parts of patients have been found in middle-late phase and missed treatable stage. How to control its occurrence and development effectively, and do early detection or diagnosis has become an urgent task.Functional imaging evaluation affects the diagnosis and treatment of cervical cancer,so it has been developing rapidly in recently. Molecular Imaging technology is a new technology which integrated traditional imaging and molecular biology. It mainly through traditional imaging methods, which refers to analytical approach to molecular or cell, recording the distribution of cellular and molecular in space and time during the biogenesis events happened. It can reach multiple goals including diagnosing,angiography, intraoperative imaging guidance, therapeutic monitoring and prognosis evaluation. Near-infrared fluorescence imaging is a new imaging technique which can be used in clinical diagnosis and treatment process, real-time visual monitoring of tumor tissue, detection of lymph node metastasis and surgical image guidance.Near-infrared fluorescent probe as a key part of the technology was focused by researchers. According to previous findings, IR-783 and NHI-148 dye had a broadspectrum ability to target tumor cell, it can be used as a potential carrier transporting to enhance the specificity of the radioactive pharmaceutical. This thesis studies the following contents :1. Specificity of near-infrared fluorescent small molecule IR-783 in cervical cancer cellsWe used near-infrared fluorescent dye IR-783 treated normal cervical epithelial cells and cervical cancer cells to observe the effect of cell proliferation and selective absorption capacity. The results show that dye IR-783 is safe and effective, and it can specially recognize cervical cancer cells. We determined the situation of cervical cancer cell organelle in which dye IR-783 was positioned. In the aim of evaluating the potential use of near-infrared fluorescence dye IR-783 in cytological, blood samples were spiked with cervical cancer cells and then stained by dye IR-783 to detect cancer cells. And we also detected cervical tumor tissues and normal tissues in clinical specimens after stained by dye IR-783. Results show that IR-783 dye was selectively accumulated in mitochondria and lysosomes with good stability and long-term nature.Dye IR-783 can distinguish He La cells and monocytes respectively which has specific recognition. In clinical specimens, dye IR-783 can distinguish normal tissue and tumor tissue.2. Near-infrared fluorescence imaging dye IR-783 for cervical cancer in vivo imaging In order to explore the uptake and accumulation ability of dye IR-783 in animal tumor tissue and normal tissue, we have established a tumor-bearing mouse model, when a tumor-bearing nude mouse tagged with near-infrared dye model established, we used histological section to study the uptake and accumulation ability of dye IR-783. The results showed a strong fluorescence signal on tumor site in vivo that can clearly distinguish normal tissue and tumor tissue. Unbound dye was metabolized by liver,then through into intestine and may be excreted in the faeces. Histological sections showed that the tumor tissue reacted positively in range of 700-1000 nm.3. Mechanism of Near-infrared fluorescent dye molecular IR-783 in cervical tumor-specific uptakeWe used HeLa cells and SiHa cells verify the dye IR-783 intakes of different subtypesfor OATPs in cervical cancer cells. The results showed a significant difference on OATP1, OATP1B3 and OATP1B1 which compared to H8. Near-infrared fluorescence imaging results were negative after treatment of cervical cancer cells with sodium sulfonate bromine phthalate. Therefore BSP is accompanied with inhibition of dye IR-783 uptake. When we used to treat cells in different subtypes OATPs inhibitors,inhibitor of OATP1B3 showed marked inhibition of dye IR-783.In summary, the near-infrared fluorescent small molecule IR-783 is safe, specificity,stability and effectiveness in diagnosis and treatment of cervical tumors. Based on specific imaging Near-infrared fluorescent small molecule IR-783 can be realized cervical cancer screening, safe non-invasive diagnosis, treatment monitoring,prognosis prediction results, and it will improve the form of detection, diagnosis and treatment.