磁共振/荧光石墨烯量子点用于可视化的肺癌联合疗法

As a malignant tumor with the highest morbidity and mortality in China, lung cancer has been given rising attentions along with environmental deterioration. Development of comprehensive and reliable technique for early diagnosis and therapy are the key to cure lung cancer. In this project, fluorescent graphene quantum dots (GQD) are introduced as vehicles to load redox biological drug and photosensitizer for accurate diagnosis and efficient treatment of lung cancer. The concentration of the designed probe is increased in lung cancer cells through EPR, active targeting and photothermal effect. Meanwhile, the fluorescent and MR signal will turn on in targeted cells. Signal noise will be decreased by the above two designations, thus, the accuracy of lung cancer diagnosis is increased. Moreover, reactive oxygen species resulted from the reaction between redox active drug and cellular reducing metabolites lead cancer cells more impressionable to photodynamic therapy from photosensitizer. The therapy efficiency enhances by the combination of photothermal therapy, photodynamic therapy and biological redox therapy. The designed multi-model probe combines diagnosis and therapy in a singlet vehicle, which could monitor the tumor progression and then improve the treatment in time. Hence, the project will provide a new way to imaging guided and combined lung cancer therapy.

肺癌是我国发病率和死亡率第一的恶性肿瘤，发展精确的诊断方式和微创、高效的治疗方法是攻克肺癌的关键。本项目拟以石墨烯量子点(GQD)负载诱导氧化应激的药物和光敏剂，对肺癌进行精确诊断和高效治疗。通过EPR效应、主动靶向和光热力学效应提高探针在靶细胞中的浓度，并利用探针在靶细胞中由“off”到“on”的磁共振和荧光信号，降低背景噪音，提高检测准确度。通过靶细胞中富集的药物，以氧化应激提高光动力学治疗效率，使光热力学疗法、光动力学疗法和生物氧化疗法彼此相互促进，用多种手段提高疗效。这种双模态探针集检测和治疗功能为一体，可实时监测治疗过程中肿瘤的发展情况以便及时调整治疗方案，为肺癌的可视化治疗提供一种新方法。

肺癌是我国发病率和死亡率第一的恶性肿瘤，发展精确的诊断方式和微创、高效的治疗方法是攻克肺癌的关键。本项目拟以生物兼容性较好的石墨烯量子点(GQD)为载体，探索在成像指导下的肺癌高效疗法。首先，从弛豫的机理出发，设计了一种在临床应用最为广泛的1.5T下具有最佳弛豫的T1造影剂：通过PEG将Gd-DOTA连接到石墨烯量子点上，在不同温度和磁场强度下的实验探索，证明弛豫率与柔性PEG链的链长有关，通过调控PEG链来控制Gd的翻转，最终，筛选出一种在1.5 T磁场下具有最高弛豫率的造影剂GQD-PEG12-Gd。其弛豫率为临床用磁共振造影剂的16倍，以浓度仅为临床使用浓度1/20尾静脉注射后，GQD-PEG12-Gd进入模型老鼠的肿瘤部位，在1.5T MRI下能观察到造影剂从肿瘤逐渐边缘进入中心的过程，证明了这种造影剂在1.5T下良好的成像效果。进一步，将光敏剂Lu-texaphyrin和抗癌药Gd-texaphyrin通过π-π作用负载到GQD上。通过EPR效应、主动靶向和光热力学效应提高探针在癌细胞中的浓度，并利用探针在靶细胞中由“off”到“on”的磁共振和荧光信号，降低背景噪音，提高检测准确度。尾静脉注射进肺癌荷瘤小鼠体内1.5小时之后，复合纳米粒子可大量富集至肿瘤部位。由于癌细胞内纳米粒子的近红外荧光和顺磁弛豫效应，我们能通过近红外荧光成像和磁共振成像定位肿瘤部位。之后，以功率仅为300mW/cm2 的765 nm激光照射所确定部位，对肿瘤进行近红外光诱导下的多种方式联合治疗。由于我们将造影剂和治疗药物一同运送到了肿瘤组织中，在每次给药之后，皆能通过近红外荧光或磁共振成像观察肿瘤的发展进程。若还在增生，就对肿瘤组织进行近红外照射以诱导联合治疗。结果证明，经过3次治疗之后，给药联合疗法组裸鼠的肿瘤体积明显减小，而空白组和单一疗法组裸鼠的肿瘤体积都在增大，在活体层面证明了联合疗法的高效性。这种可视化的联合疗法对非治疗区域无明显细胞和组织毒性，为个高效的性化治疗提供了一种全新的思路。