pH/乏氧双重响应分子靶向纳米载体可视化多途径联合抗非小细胞肺癌研究

The oncology community has seen a paradigm shift in molecular treatment of non-small cell lung cancer (NSCLC) thanks to the identification of molecular targeted drugs. However, only the NSCLC patients with specific molecular mutation could benefit from molecular targeted drugs, and the majority of the treated NSCLC patients develop acquired resistance. The aim of this project is to construct new nanotheranostics which could not only have the ability of recognition of lung cancer cells which are sensitive to molecular targeted drugs and real-time monitoring the therapeutic effects by optical/ultrasonic imaging to guide the rational use of the molecular targeted drugs, but also have the ability of exerting combined molecular targeted/photodynamic therapeutic effects and improvement of tumor hypoxia microenvironment for overcoming drug resistance and improving efficacy. The project is to design, preparation and characterization of nanocomplexes using mesoporous silica nanoparticles as a drug carrier in which the channels could open in response to pH changes, with optical imaging agent ICG and oxygen carrier/ultrasound contrast agent PFOB molecules entrapped inside, and with erlotinib-modified chitosan cross-linked with azo-bond on the surface. The selective diagnostic ability and molecular targeted/photodynamic combination therapeutic effects and the improvement of tumor hypoxia microenvironment of the nanocomplexes will be studied in the erlotinib-sensitive and erlotinib-resistant cancer cells or tumor-bearing mouse models. The mechanisms of nanocomplexes for selective diagnosis and combination treatment of NSCLC will also be studied. The research ideas and the research contents of this project are both new. The results of this project will provide new strategy for improving medication accuracy and efficacy of molecular targeted drugs. The results of this project will also provide new research ideas and methods for individualized lung cancer treatment. We believe this kind of nanotheranostics possess a vast range of application prospect.

分子靶向药物在非小细胞肺癌治疗中表现出巨大潜力，但其疗效与特定基因突变水平密切相关，且易产生耐药。本项目拟构建新型纳米诊疗系统将分子靶向治疗/光动力治疗/改善肿瘤乏氧微环境以及光学/超声成像合为一体，通过多模态成像识别对药物敏感的突变型肺癌并可实时监测药物疗效变化指导临床用药，以及多途径、多机制协同治疗，克服耐药，提高疗效。本项目利用孔道pH响应开放纳米介孔硅为载体，包载光学成像剂ICG分子和携氧载体超声造影剂PFOB分子，并在表面包覆一层厄洛替尼修饰的偶氮键交联的壳聚糖，形成复合物纳米粒并表征其理化性质；在厄洛替尼敏感和耐药型肺癌细胞及荷瘤鼠模型中研究其pH/乏氧双重响应成像及分子靶向/光动力治疗/改善肿瘤乏氧微环境联合治疗效果和机制。本项目的研究思路和内容新颖，其结果可为提高肿瘤分子靶向药物的用药准确性及有效性提供新策略，同时为肺癌个体化治疗提供新的研究思路和方法，具有重要的应用前景。

分子靶向药物在非小细胞肺癌治疗（NSCLC）中表现出巨大潜力，但其疗效与特定基因突变水平及肿瘤微环境密切相关，且易产生耐药。选用介孔二氧化硅纳米粒（MSN）为药物载体，包载吲哚菁绿（ICG）分子，用氧化锌（ZnO）纳米粒子封闭MSN孔道，并在表面包覆一层二硫键交联的厄洛替尼修饰的壳聚糖（EC），制得双重响应的纳米诊疗剂ECMI。ECMI中的厄洛替尼可选择性识别EGFR基因敏感突变的NSCLC细胞，入胞后，可利用ZnO的pH响应降解和二硫键的还原响应降解特性，特异性释放ICG分子做出荧光成像诊断，并发挥ICG的光动力治疗作用，克服厄洛替尼耐药，提高抗肿瘤效果。在此基础上，选用第三代EGFR-TKI奥希替尼为模型药物，合成重氮键偶联的氟硼二吡咯（BODIPY）修饰的壳聚糖，构建pH/低氧双响应成像/光热治疗纳米诊疗剂CsBANs。CsBANs可对肿瘤低氧微环境进行选择性成像，并能联合BODIPY的光热治疗逆转低氧诱导的奥希替尼耐药。该工作通过响应成像诊断以及多途径、多机制协同治疗肺癌，能精确筛选靶向治疗获益人群，克服分子靶向药物耐药，为提高肿瘤分子靶向药物的用药准确性及有效性提供新策略，同时为肺癌个体化治疗提供新的研究思路和方法，具有重要的科学意义。. 相关研究在国内外重要学术刊物上发表标注受本项目资助的高质量SCI论文22篇（其中IF>10的6篇），中文核心期刊2篇。申请并获专利授权17项。培养博士生1人，硕士生7人。