反义miRNA寡核苷酸拮抗血管生成通路改变乏氧微环境增敏肺腺癌脑转移放疗效果的MR评价

It is still a great puzzle for the early diagnosis and the improvement of treatment effect for brain metastasis from lung adenocarcinoma. Therefore, to explore the radiosensitivity of brain metastases by changing the hypoxia microenvironment resulted from inhibiting angiogenesis have important significance. When researching the regulation of antisense VEGF in brain metastases, we found that which can inhibit angiogenesis, down-regulate VEGF expression and enhance radiotherapy sensitization in vitro and in vivo. There was close relationship between MR perfusion, ADC values ,MRS and metastatic tumor size, angiogenesis, growth curve, hypoxia level and VEGF expression. Therefore in future, we use antisense miR-27a oligonucleotide to silence the angiogenesis and to change hypoxia microenvironment as well as enhance radiosensitization of brain metastases, the aim is to prevent metastatic tumor cell "implantation" process and eradicating the metastatic tumor growth of "soil", and to explore the possibility of evaluating biological behavior by MR perfusion, the blood oxygen saturation, rCBV, hypoxia index; To set up the effective, noninvasive, living imaging methods for evaluating radiosensitization of brain metastases from lung adenocarcinoma due to changing the hypoxia microenvironment and inhibit angiogenesis by antisense miRNA oligonucleotide.

肺癌脑转移特异性早期诊断及提高治疗效果一直是临床面临的难题，探讨阻断血管生成信号通路，改善乏氧微环境增敏全脑放疗的综合性治疗方案具有重要现实意义。我们在进行脑转移瘤离体和活体实验时，发现血管内皮生长因子（VEGF）反义核酸有阻断血管生成、下调其表达和增敏放疗效果的作用。利用MR灌注、DWI测定肿瘤组织的ADC值、磁共振波谱分析与转移瘤大小、微血管形成、生长曲线、乏氧程度、VEGF表达存在密切相关性。为此本研究在原基础上进一步利用miR-27a的反义寡核苷酸特异性沉默其基因表达，拮抗转移瘤血管生成，阻止转移瘤细胞"着床"过程，铲除转移瘤滋生的"土壤"，切断转移瘤细胞内信号传导的同时，调节肿瘤细胞外乏氧微环境，增敏放疗效果。探索活体MR灌注、血氧饱和度、相对脑血容量、乏氧指数定量判定转移瘤生物学行为，建立有效、无创、活体检测反义miRNA拮抗微血管生成，增敏放疗对脑转移瘤治疗效果的影像学依据。

肺癌脑转移特异性早期诊断及提高治疗效果一直是临床面临的难题，阻断血管生成信号通路、改善乏氧微环境从而改善其诊治效果的影像学探索研究具有重要现实意义。本项目执行期间，建立了脑转移瘤、颌面部VX2肿瘤模型从而筛选了合适的动物模型，并进行了常规和功能磁共振成像（DCE-MRI）的病理-影像对照研究。结果显示建立的模型稳定、可靠，运用DCE-MRI可提高脑转移瘤的检出率且DCE-MRI的功能参数最大强化率和强化率斜率可以评价肿瘤缺氧。进一步在立体定向颅内接种的肿瘤上发现，纳米铁标记的肿瘤细胞可以用高分辨MRI观察、评估其生物学活性。因此，项目组分别探索性合成、优化了T1W、T2W及多模态成像的纳米铁等探针，并携带不同的靶向分子进行了治疗检测和影像学评估，从而发现不同纳米探针可干预肿瘤的生物学进程并可用影像学进行定量和定性评估。为实现肿瘤的诊治一体化后续临床探索提供了实验依据。本项目基本按原计划顺利完成，发表标准本项目资助的SCI论文18篇，中文核心期刊论文1篇，获得省部级科技进步二等奖2项，三等奖1项，毕业博士生4名，培养博士后1名，主办国内学术会议4次，参加国际学术会议4次。