构建ROS响应的“OFF/ON”可控型F-19 MRI纳米探针用于肿瘤诊断

Early diagnosis is one of the most effective methods for improving cancer cure rates, and F-19 magnetic resonance imaging is an effective tool for cancer early and accurate diagnosis. Tumor microenvironmentally regulated F-19 probes are widely concerned and clinically applied due to their sensitive responsiveness. However, ROS-responsive nanoprobes have not been reported so far. In this project, we will construct a ROS-responsive F-19 MRI nanoprobe with long circulation capacity, good biocompatibility, high sensitivity and binary “OFF/ON” controllability by self-assembly of the amphiphilic block copolymer (PEG-b-PAsp'(CF3)), which is composed of PEG as the hydrophilic section and thiazolidinone protected poly(α-trifluoromethyl aspartate acid) (PAsp'(CF3)) as the hydrophobic section. Taking advantage of the different ROS concentration between normal tissues and tumor tissues in vivo, the reversible conversion of assembly/disassembly of the nanoprobe was realized, and the controllable release of F-19 signal was achieved in order to achieve the purpose of tumor early diagnosis. The imaging performance of the nanoprobe is optimized by adjusting the proportion of each component of the polymer via in vitro and in vivo experiments. This project provides new ideas for the development of highly secure, sensitive, accurate and efficient F-19 MRI nanoprobes for clinical diagnosis.

肿瘤的早期诊断是提高癌症治愈率最有效的手段之一，而F-19磁共振成像是肿瘤早期准确诊断的有效工具。基于肿瘤微环境调控的F-19探针由于其敏感的响应性受到了广泛关注和临床应用，然而具有肿瘤ROS响应性的纳米探针至今仍未见报道。本项目拟通过以PEG为亲水段，含噻唑啉酮保护基的聚α-三氟甲基天冬氨酸（PAsp'(CF3)）为疏水段的两亲性嵌段共聚物（PEG-b-PAsp'(CF3)）自组装，制备具有体内长循环能力、ROS响应性及良好生物相容性的高灵敏度“OFF/ON”可控型F-19 MRI纳米探针。利用体内正常组织与肿瘤组织之间的ROS浓度差别，实现该纳米探针的组装/解组装可逆性转换，同时实现F-19信号的可控性释放，以期达到对肿瘤早期诊断的目的。通过体内外实验调整聚合物各组分比例，对纳米探针的成像性能进行优化，为开发适合临床诊断的安全灵敏、精准高效F-19 MRI纳米探针提供新思路。

癌症已成为人类最为致命的疾病，目前仍无完善的治疗方案。研究表明，肿瘤的“早发现、早治疗”仍然是目前提高癌症治愈率的最有效手段，而多模态成像能充分发挥各种影像学方法的优势，得到同时具有高灵敏度和高空间分辨率的医学影像，有望成为肿瘤早期、快速、精确诊断的有效工具。本项目基于分子影像学和纳米医学交加学科，将荧光染料吲哚菁绿（ICG）键合到以聚乙二醇（PEG）为亲水段，聚酪氨酸（PTyr）为疏水段的两亲性嵌段共聚物上，同时在Tyr残基上标记放射性核素I-125，通过聚合物自组装制备出能够在体内长循环且通过增强渗透滞留（EPR）效应被动靶向肿瘤组织的聚合物胶束PEG-PTyr(I-125)-ICG PMs，作为一种新型的荧光/光声/SPECT多模态成像纳米探针，用于肿瘤诊疗。该纳米探针展现出良好的粒径/光学/放射性标记稳定性、高光热转化效率、优异的生物相容性及令人满意的肿瘤细胞摄取和杀伤效果。通过尾静脉注射，该探针能够高效富集于小鼠肿瘤组织，并在肿瘤部位发射出高灵敏度的荧光信号、高空间分辨率的光声信号及低背景干扰的同位素信号，综合分析上述三种影像信息便可实现对肿瘤的精确诊断和准确定位。在影像学诊断的指导下，对肿瘤组织进行局部激光照射，可快速提升肿瘤部位温度，有效杀伤肿瘤细胞，从而实现对肿瘤的光热治疗。本项目的研究将推动多模态影像技术与纳米技术的进一步融合，为开发更加理想的多模态纳米探针提供重要的理论及实验基础，加快多模态影像技术在临床肿瘤诊疗领域的发展速度，具有较高的学术价值。