程序响应酸性微环境MRI/荧光纳米对比剂的构建及其用于胶质瘤分级诊断研究

Diagnosis grading of glioma is of great significance for patients, which is the basis to develop accurate individualized treatment. Previous studies have found a positive correlation between the acidity and the severity of glioma tumors. Our early studies have proved the potential of the sensitive probe in revealing the pathology information of tumor. The aim of this project is to develop non-invasive imaging diagnostic grading method of glioma based on developing acid-triggered MRI/Fluorescent nano probe and studying the relationship between acidic strength and malignant degree of glioma. The contrast effect of the nano probe is controlled by the environment acidity, the stronger acidity, the faster the trigger initiation imaging, the greater the change of the signal. The glioma grading diagnosis model can be established by the change of the signal of the probe, In particular, first of all, the NRP target acid-response activated MRI/ Fluorescent nano probe was prepared by self-assembly preparation from the acid-sensitive amphiphilic polymer, the target polymer, the acid sensitive fluorescent probe and iron oxide nanoparticles. The acid-trigger response imaging profile of the probe was evaluated by the construction of different levels of in situ glioma model system. The quantitative relation between the probe response imaging and malignant degree of glioma was also studied. And a digital model of glioma grading was established based on imaging related parameters. The successful implementation of this project can provide a new method for the non-invasive grade of glioma imaging.

胶质瘤的分级诊断对于患者意义重大，是制定个体化精准治疗的关键基础，当前通过影像手段无创分级诊断仍然是临床难点。最新研究表明胶质瘤酸性强弱与其恶性程度正相关，酸性越强，恶性程度越高。我们发现：前期构建的响应性对比剂，可特异性提示肿瘤分子病理信息。据此假设推测：设计酸响应启动，且具有酸性越强触发，启动成像越快，信号变化越大的MRI/荧光对比剂，并基于此发展胶质瘤影像学无创分级诊断方法具有较大可行性。具体而言，首先基于酸敏感两亲聚合物、含tLyP-1多肽靶向聚合物、酸敏感荧光探针及纳米氧化铁,通过自组装的方式制备得到靶向跨膜蛋白受体、酸响应触发启动MRI/荧光纳米对比剂，并以构建不同级别原位胶质瘤模型系统评价探针酸触发程序响应增强成像效果，研究探针响应成像与胶质瘤恶性程度的定量关系；并建立基于成像相关参数的胶质瘤分级数字模型。本研究的顺利实施可为胶质瘤的影像学无创分级诊断提供新思路。

神经胶质瘤是颅内最常见的原发恶性肿瘤，起源于神经胶质细胞。当前早期诊断主要通过病理活检，操作复杂且风险较大，而通过影像手段无创早期定性诊断仍然是面临巨大挑战。通过影像学手段无创早期并分级诊断胶质瘤，获取准确的分子、生理及病理等方面的信息，从而制定科学的个体化治疗方案，是建立个体化精准治疗的关键基础，对于患者意义重大。针对当前研究中造影剂无法反映病理信息的问题，本课题拟利用胶质瘤微环境与胶质瘤恶性程度的关系，通过构建的还原/酸性响应启动MRI探针发展胶质瘤影像学无创早期定性诊断方法。通过课题研究发现，本课题所设计的纳米探针具有酸性/还原性越强，触发启动成像越快，信号变化越大的特点，因此可通过探针的程序信号变化建立的胶质瘤早期定性诊断及分级方法。本项目研究发现，通过肿瘤微环境响应聚合物修饰IONPs，制备还原敏感IONPs对比剂，可实现响应触发的粒径改变及MRI成像效果的放大及启动切换，可定量检测肿瘤组织还原性强弱，并由此判断胶质瘤性质及用于早期诊断，具有较好的科学价值，为此类对比剂的开发提供了新的思路和理论基础。