基于活性氧触发超分子自组装的体内肿瘤检测方法的研究

The invasion, the heterogeneity, and the microenvironment of tumor result in a harsh task for tumor diagnosis. Thus, the establishment of an accurate detection method is crucial for effective tumor theranostics. Comparing to normal cells, tumor cells are adaptive to higher oxidative stress status. Based on this unique phenomenon, our proposed research is to realize the visualization for tumor detection in vivo. Starting with peptide-quinazolinedione small molecules, the over produced reactive oxygen species (ROS) elicits the planarization of quinazolinedione derivative and make the molecules specifically accumulated inside tumor cells and fluoresce. Comparing to recent tumor detection methods which focus on the characteristic of individual tumors, our method aims at one of the common features of tumors, namely over-produced ROS. The combination of ROS as the inducer and the supramolecular self-assembly process will provide a new mechanism for tumor detection. The apparent advantage of this method is to overcome the intra-tumoral heterogeneity and target multiple tumor types. Based on the reversibility of the supramolecular self-assembly, this platform attains the advantage of biodegradability and biocompatibility in a swift manner. Therefore, the success of our research will come up with a novel and effective tumor diagnosis.

肿瘤细胞的转移性和异质性，以及肿瘤内环境的复杂多变，给肿瘤检测造成了极大困难。建立准确的肿瘤检测方法对其有效诊疗意义重大。与普通细胞相比，肿瘤细胞具有处于高氧化压力状态的特点。基于肿瘤细胞的这一特点，本研究设计一系列多肽-喹唑啉酮衍生物，利用肿瘤细胞过生产的活性氧，触发喹唑啉酮分子平面化的构型变化，使该类小分子特异性地在肿瘤细胞内实现具有荧光特性的超分子自组装，并通过荧光成像实现对肿瘤的可视化检测。相比于现有肿瘤检测方法强调各器官肿瘤的特性的思路，本研究提出利用肿瘤的共性，即过生产的代谢产物活性氧作为诱导因子，结合超分子自组装过程用于检测肿瘤的机理。其最大的优势在于：可克服肿瘤细胞异质性，同时检测不同类型的肿瘤。此外，基于超分子自组装的可逆性，用于检测的纳米材料具备了快速解聚，降低毒性的优点。该研究的实施，将能提供一种新型且安全有效的肿瘤检测方法。

肿瘤细胞的转移性和异质性，以及肿瘤内环境的复杂多变，给有效肿瘤诊断治疗造成了极大困难。根据肿瘤细胞普遍过生产活性氧这一特点，我们在本研究中拟提出设计一系列多肽-喹唑啉酮衍生物，利用肿瘤细胞过生产的活性氧，触发喹唑啉酮分子平面化的构型变化，使该类小分子选择性地在肿瘤细胞内实现具有荧光特性的超分子自组装，为肿瘤等多种疾病的可视化诊断和有效治疗提供平台。研究表明，喹唑啉酮的苯硼酸衍生物是良好的活性氧触发超分子组装的开关，连接特定短肽序列后能准确相应活性氧过生产的多种癌细胞以及细菌感染的炎症微环境，提供可视化的诊断依据。继而通过超分辨成像以及理论计算，我们进一步研究超分子组装体的内部结构以及在生物环境下的动态变化过程。最后，联用活体内的超分子组装和生物正交反应，我们实现了生物正交前药在活体内时空可控的激活，达到化疗药物减毒增效的目的，展示了活体内超分子组装活性纳米材料在多种疾病诊断治疗中的独特优势。