氯毒素靶向聚合物磷脂纳米载体用于脑胶质瘤诊疗一体化研究

This research project aims to develop a novel nanocarrier system which simultaneous combining nano probe and nano drug in one for the significant demand of tumor early diagnosis and treatment. We developed a chlorotoxin (CTX) targeting polymer lipid nanoparticles which encapsulated anti-tumor drug 17-AAG and near-infrared (NIR) fluorescence dye indocyanine green (ICG) for combining brain glioma diagnosis and treatment. When the vector carrying drug and probe into the body, CTX can be targeted glioma specific chloride channel, which can improve the enrichment probes and drugs in tumor cells. Then use near infrared laser irradiation in the tumor region of nano particle enrichment, ICG in the nanoparticles generate high fever, high fever toxicity of ICG and high concentration of 17-AAG chemotherapy toxicity, mutual inhibition of tumor growth. This system can ultimately realize the specific targeting diagnosis of nanocarrier system and treatment integrated tracer, chemical, thermal combination therapy. We study the vector system from two aspects of cells and in vivo, which include targeting, stability, fluorescence characteristics, pharmacokinetics and anti-tumor mechanism. Such combined strategy will provide reliable experimental basis for the diagnosis and treatment of integration of brain glioma, and provide new ideas and theoretical basis for the development of drug carrier of brain tumor.

本项目面向肿瘤早期诊断与治疗的重大需求，设计了一种氯毒素靶向的集纳米探针和纳米药物于一体的载体系统并将其用于脑胶质瘤的诊断与治疗的实验研究。这种载体同时负载近红外荧光染料吲哚菁绿(ICG)和化疗药物17-烯丙氨基格尔德霉素(17-AAG)。当该载体携载药物和探针进入体内后，氯毒素能够靶向神经胶质瘤特有的氯离子通道，进而提高探针和药物在肿瘤细胞中的富集浓度，在纳米颗粒富集的肿瘤区域加以近红外激光照射，纳米颗粒内的ICG激发产生高热，通过纳米颗粒内ICG的高热毒性和高浓度化疗药物17-AAG的毒性，共同抑制肿瘤的成长。最终实现纳米载药系统的特异靶向示踪、化学-光热联合治疗的诊疗一体化。我们从细胞和活体两个层面研究该载体系统的靶向性、稳定性、荧光特性、深入研究该纳米载体的药代动力学和抗肿瘤作用机制，为脑胶质瘤的诊断治疗一体化提供可靠的实验依据，为临床脑胶质瘤药物载体的研制提供新的思路和理论依据。

针对肿瘤治疗的障碍和瓶颈，开发制备生物相容性优良，具有特异靶向示踪、化学-光热联合治疗的诊疗一体化纳米载体。成功设计和制备了氯毒素、透明质酸等靶向的聚合物纳米颗粒，在聚合物磷脂纳米载药系统高效治疗癌症方面和可视化精准治疗癌症上取得重要进展，构建了双模态成像及光动力治疗肿瘤的诊疗一体化平台；诊疗一体化纳米颗粒用于脑胶质瘤的诊断和治疗效果显著。近红外荧光试剂ICG的荧光可实施监控纳米颗粒的分布，化疗/光热联合抑制肿瘤。结果表明，构建的聚合物纳米颗粒尺寸均一，荧光稳定性良好。利用荧光活体成像系统/光声成像平台，深入研究纳米颗粒的体外/体内行为规律。在此基础上，通过脑胶质瘤荷瘤小鼠模型，乳腺癌荷瘤小鼠模型，研究纳米颗粒对肿瘤的靶向光热化疗治疗效应，通过肿瘤成像和肿瘤尺寸检测对疗效进行实时评估，并探索体外体内抑瘤效应及相关机制，为临床应用提供理论依据。本项目研究共发表SCI论文15篇，发明专利3项，参加国际学术会议3次，培养博士研究生1名，硕士研究生1名。