基于生物分子器件发展肿瘤标志物智能化检测新方法的基础研究

Cancers present a very high mortality rate and seriously influence the social development. Their early symptoms are not obvious. Once symptoms appear it is already at moderate or advanced stage and difficult to be cured. It is hard to defence the cancers if one only accounts on therapy. Early warning and early therapy is considered as a longterm strategy to greatly enhance the cure ratio. Various techniques have been developed for cancer cell detection. However, it is hard to diagnose tumor at the early stage with these approaches, which usually need large amount of cancer cells to be detected, resulting in the loss of the optimum time for therapy. Furthermore, most of these modalities are highly cost in experimental process or instrumentation. Therefore, it is highly desirable to develop new approach and technology with high sensitivity & selectivity and low cost to rapidly and simply detect tumor at an early stage. To address these specific requirements, in this project, electrochemical and fluorescent methods are mainly used for developing biosensors since they can decrease the cost and time required for analysis with simple instrumentation. We will concentrate our investigations on the early-diagnosis and early-warning of liver tumor by selecting liver tumor markers as target molecules. Taking advantage of bio-nanomaterials, intelligent logic system and molecular devices with magnification function, we try to develop new approaches and novel biosensing systems for highly sensitivite and selectivite detection of tumor markers based on molecular recognition technology. It is believed that new intelligent analytical platform of tumor marker will be developed, which has great potential application in the early-warning and early-diagnosis of serious diseases.

恶性肿瘤的致死率非常高，严重影响着社会发展。其初期症状并不明显，一旦症状出现己到中晚期，很难治愈。因此，仅依靠治疗全球无法赢取与癌症的抗争，早发现早治疗才是大幅提高成功治疗可能性的长期战略。而目前的检测方法很难做出早期诊断，通常需要在肿瘤生长到含有相当数量的癌细胞时才能检出，此时已失去了最佳治疗时机。不仅如此，其检测所需时间较长，费用也很高，因此对开发快速简便、费用低廉的、高灵敏度、高选择性的肿瘤早期诊断新方法的需求十分迫切。在此背景下，本项目立足于解决肿瘤早期诊断这一关键问题，以肝癌标志物为主要检测目标，基于分子识别技术，创新性地将具有信号放大功能的分子器件与生物纳米技术相结合，并融合新兴的智能化逻辑分析理念，从全新的角度出发，发展对肿瘤标志物高灵敏度、高特异性的多元检测新方法。以电化学方法、光谱法为主要检测手段，建立生物分析智能检测平台，以满足我国重大疾病早发现早治疗的实际需求。

由于具有非常高的致死率，恶性肿瘤严重威胁着人类身体健康及社会发展。而其初期症状并不明显，难以发现。一旦出现症状通常己到中晚期，很难治愈。目前，国际公认早发现早治疗是提高成功治疗可能性的长期战略。而目前的检测方法通常需要在肿瘤生长到含有相当数量的癌细胞时才能检出，此时已失去了最佳治疗时机。另外，其检测通常耗时长费用高，因此亟需开发快速简便、费用低廉的、高灵敏度、高选择性的肿瘤早期诊断新方法。.在国家自然科学基金委的支持下，本项目以肿瘤疾病相关的标志物基因DNA、RNA、双氧水、癌细胞等为主要研究对象，利用生物纳米技术通过与分子生物学技术相结合，构建成本低、操作简单的新型生物传感器，发展多种信号放大策略，实现对致病基因及癌细胞的高灵敏度、高特异性检测，对DNA检测灵敏度达到费摩尔级，癌细胞检测限达到10cell/mL。将癌细胞DNA与肝脏特有DNA基因同时检测，提高了诊断准确性。并融合新兴的智能化逻辑分析理念，构建了一系列高等分子逻辑门，包括AND、INH、YES、OR、XOR等基本分子逻辑门及半加、半减、多路选择器及多路解码器的高等分子逻辑门。从全新的角度出发，发展对肿瘤标志物高灵敏度、高特异性的多元检测新方法，建立生物分析智能检测平台。基于multiplexer逻辑门发展了可实现多元检测的智能化分析检测新方法。构建了具有AND逻辑门功能的诊疗一体化多功能新平台，以小鼠为模型实现了对肿瘤的高灵敏度检测、多模态成像及靶向治疗。相关研究为重大肿瘤疾病的早发现、早治疗提供了有益参考。目前已发表SCI论文17篇，其中影响因子大于5的12篇。