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目的:开发一种具有“找寻、治疗、可视”功能的生物造影剂。方法:采用化学合成的方法得到近红外标记的维甲酸类造影剂,并进行骨肉瘤细胞的体外结合试验;皮下接种裸鼠,构建骨肉瘤的异种移植模型,持续10d对裸鼠进行体内光学成像,观察药物在体内的重新分布,并最终用免疫组织化学法对成像结果进行验证。结果:体外细胞结合试验证明,合成的维甲酸造影剂可以很好的与人的骨肉瘤细胞相结合,进而内化。近红外光学成像表明,该造影剂可用于骨肉瘤的早期和晚期诊断。全身成像显示了在肿瘤和肝脏的高信号强度。正电子发射断层显像(PET)显示肿瘤部位具有较高水平的18F-FDG代谢。剂量增加反应和毒性试验表明,高剂量的维甲酸造影剂必然与其全身毒性息息相关。免疫组化染色显示,发光组织中肿瘤细胞呈阳性。结论:合成的近红外标记的维甲酸造影剂可以用于检测人类骨肿瘤的异种移植,实现个体化分子诊疗的同时减少全身毒性。
OBJECTIVE: To develop a bio-contrast agent with the function of finding, treating and visualizing. Methods: NIR-labeled retinoic acid contrast agent was obtained by chemical synthesis and in vitro binding assay of osteosarcoma cells. Nude mice were inoculated subcutaneously to establish a xenograft model of osteosarcoma. The in vivo optical imaging , Observing the drug redistribution in the body, and finally using immunohistochemistry to verify the imaging results. Results: In vitro cell-binding experiments demonstrated that the synthesized retinoic acid contrast agent can be well combined with human osteosarcoma cells and then internalized. Near infrared optical imaging shows that the contrast agent can be used for early and advanced diagnosis of osteosarcoma. Whole-body imaging shows high signal intensity in tumors and liver. Positron emission tomography (PET) showed a higher level of 18F-FDG metabolism at the tumor site. Increased dose response and toxicity tests show that high doses of retinoic acid contrast agents are bound to be closely related to their systemic toxicity. Immunohistochemical staining showed that the tumor cells in the luminescent tissue were positive. CONCLUSIONS: The synthetic near-IR labeled retinoic acid contrast agent can be used to detect xenografts in human bone tumors to achieve personalized molecular diagnostics while reducing systemic toxicity.