基于次氯酸调控的示踪/治疗一体化平台的构建

The concentration change of hypochlorous acid (HOCl) is closely related with many diseases. The disease induced HOCl outbreak does not only serve as a diagnostic basis for major diseases, but can also be used as an initiator to trigger controlled release of related therapeutic drugs, which is expected to achieve the integration of diagnosis and treatment. However, the existing hypochlorite probe remains in the stage of HOCl detection, HOCl as a trigger factor for related disease therapy has not been reported. This project is based on our recently proposed new mechanism of HOCl detection and release. In this project, we hope to combine fluorescence detection groups that have high fluorescence quantum yield and near infrared emission with drug compounds containing carboxyl or amino, or carboxyl/ amino modified nano drugs, to construct various kinds of functional detection/therapy integration platform based on high sensitive response of hypochlorite. When the probe molecules or nanocomposites are located at the low expression region of HOCl, the fluorescence and drug groups are in the "silent" state. When the composite is in the high expression region of HOCl, probes can react with HOCl, and release both the fluorescence and the active drug, to realize the simultaneous diagnosis and treatment of related diseases such as inflammation and cancer. The development of this project will open up new ideas and strategies for the construction of multifunctional tracer/ treatment integrated platform based on reactive oxygen species.

人体中次氯酸浓度的变化与许多疾病密切相关，这种疾病诱导的次氯酸爆发不仅可作为重大疾病的诊断依据，同时可利用病灶处高浓度的次氯酸作为引发剂，诱导相关治疗药物的可控释放，集诊断治疗于一体。但现有的次氯酸探针仅停留在对次氯酸的检测阶段，将次氯酸作为调控因子进行相关疾病的治疗尚未报道。本项目拟利用申请人提出的新的次氯酸检测和释放机理，将具有高荧光量子产率、近红外发射的荧光检测基团与含有羧基或氨基的药物化合物或纳米药物体系结合，构建功能化的基于次氯酸高灵敏响应的检测/治疗一体化平台。当探针分子或纳米复合物处于机体次氯酸低表达区域时，其荧光和药物基团处于“静默”状态，而当该复合物处于次氯酸高表达区域时，探针与次氯酸发生反应，在发出荧光的同时释放出活性药物，实现炎症、恶性肿瘤相关疾病的治疗。本项目的开展，将为构建基于活性氧的新型多功能示踪/治疗一体化平台开辟新的思想和策略。

本项目按计划完成项目内容，取得了突破性的研究成果。通过开发次氯酸等活性氧特异性激活的多功能诊疗平台，在模式动物层面实现了多种疾病模型包括实体肿瘤及其转移灶、药物诱导肝/肾损伤等的在线示踪和活体多模式成像。提出激活型前药策略和激活型纳米粒子聚集策略，构筑了靶向型的诊疗一体化平台，提高了药物分子在肿瘤部位的富集浓度和停留时间，增强了恶性肿瘤的治愈效率，实现了包括原位肝癌、肺癌脊柱转移灶和宫颈癌腹腔转移瘤等恶性肿瘤有的放矢的协同治疗。本项目的实施为抗肿瘤药物的研发提供了有效的构建策略，为激活型诊疗药物的临床应用提供了重要的理论基础和实验数据。.本项目研究结果共发表标注资助的SCI收录论文26篇（包括Angew. Chem. Int. Ed.（2篇）, Adv. Sci., Chem. Sci等化学类顶级期刊），会议论文或邀请报告12篇。获授权专利3项，培养博士生5人，硕士生5人。