靶向超声造影动态监测局部晚期宫颈癌序贯性治疗

The response of tumor to radiotherapy and chemotherapy is the mainstay for the formulation of sequential therapy for locally advanced cervical cancer. At present，the evaluation of curative effect based on morphological indices cannot accurately reflect the active function state and invasion potential of tumor as well as provide reliable information to guide the therapeutic schedule in dose and drug selection. The development of the ultrasonic molecular imaging is a novel technique to evaluate the tumor response according to the imaging of targeted microbubbles combined with its specific receptors, and the curative effect of the target region is judged. This study intends to apply targeted contrast-enhanced ultrasonic technology, using BR55 targeting vascular endothelial growth factor receptor 2 as targeted contrast agent and Hela subcutaneous xenograft tumor of cervical cancer in mice as model, to dynamically estimate the microcirculation perfusion of tumor after treated with radiotherapy, chemotherapy and concurrent radiochemotherapy respectively. By quantitatively analyze the ultrasonic imaging characteristics compared with microvessel density、 expression of vascular endothelial growth factor receptor 2 、cellular microstructure on the tumor region during treatment, this study will achieve to build up the accurate correlation among imaging characteristics，pathological features and therapeutic effectiveness. Then，the cisplatin resistance and radiation resistance animal models will be established and treated with Multiple treatment schemes. According to the differences of sonographic characteristics between the groups with different treatments, the significance of targeted contrast-enhanced ultrasound for guiding the subsequent treatment can be reveal, including chemical drug selection, radiotherapy dose adjustment et al. The ultimate aim of this study is to optimize the sequential therapy of cervical carcinoma with targeted contrast-enhanced ultrasound which enables the visualization of vascular endothelial growth factor receptor 2 in order to improve the 5-year survival rate of patients.

肿瘤对放化疗的反应性是制定局部晚期宫颈癌序惯性治疗方案的主要依据，目前基于形态学指标的疗效评估无法准确监测肿瘤的活性状态及进展情况，难以为放化疗剂量及药物选择提供可靠信息。超声分子影像的发展为实现肿瘤活性状态的可视化打开了新思路。本研究拟以裸鼠宫颈癌Hela细胞皮下移植瘤为模型，①分别给予放疗、化疗、同步放化疗三种治疗，采用VEGFR2靶向造影剂BR55进行超声造影实时监测，量化分析肿瘤微循环灌注的动态变化，对照微血管密度、血管内皮生长因子受体2表达量及细胞微观结构等病理改变，建立超声造影、病理特征与治疗反应性的准确关联；②建立耐药及耐放射模型，探讨多种治疗方案组合，结合超声造影声像图变化，揭示其指导化疗药物选择、放疗剂量调整等后续方案的意义，实现通过靶向超声造影动态可视化监测优化宫颈癌序贯治疗方案，提高患者5年生存率的目标。

肿瘤对放化疗的反应性是制定局部晚期宫颈癌序贯性治疗方案的主要依据，但目前尚缺乏准确监测肿瘤的活性状态及进展情况的疗效监测方法，难以为放化疗剂量及药物选择提供可靠信息。本研究①筛选出合适的VEGFR2靶向多肽S1，构建了VEGFR2靶向S1微泡用于超声造影，②以裸鼠宫颈癌Hela细胞皮下移植瘤为模型，对不同种瘤时间的荷瘤裸鼠进行靶向超声造影，计算标准化强度差异（NID），量化分析肿瘤微循环灌注的动态变化，对照微血管密度、VEGFR2表达量等病理改变，验证S1-微泡靶向超声造影可对宫颈癌早期肿瘤生长进行监测；③建立耐药细胞株及耐药动物模型，对耐药动物与非耐药动物模型化疗过程性靶向超声造影监测，根据靶向超声造影对不同组动物模型肿瘤分子活性状态的定量分析，对照微血管密度、VEGFR2表达量病理改变的组间差异，建立超声造影、病理特征与治疗反应性的相关关联，实时动态识别治疗无反应或反应性降低的病例，揭示其指导化疗药物选择、放疗剂量调整等后续方案的意义，实现通过靶向超声造影动态可视化监测优化宫颈癌序贯治疗方案。