叶酸靶向智能型多功能分子探针CT/光声/超声多模态显像及增效放疗研究

Early diagnosis and treatment of malignant tumor has been the hot and difficult field of forefront research in modern medical science. The rapid development of molecular imaging is expected to make this important research breakthrough, and the multi-functional molecular probes are the potential candidates to achieve the integration of tumor targeted molecular imaging and for accurate visualized therapy. Now radiotherapy is one of main therapeutic methods of tumors, but the tumor microenvironment is more hypoxic than normal tissues, which wound increase the neoplasm invasion and distant metastasis, hence hypoxic can be a direct obstacle of radiotherapy resistance. Therefore，this research prepares the folate-targeted intelligent multifunctional molecular probes, which incorporate CAT and Bi2S3 nanoparticles. The folate of probes could specifically bind to the receptors existing on the surface of tumor cells, and then mediated probes with CAT and Bi2S3 actively transport into tumor cells. Under the stimulation of high concentration of hydrogen peroxide (H2O2), the catalase are then active and catalyzed in the tumor environment, O2 is evolved when intracellular H2O2 of tumor microenviroment penetrates into the multifunctional molecular probes. Therefore, the O2 produced in the release process can be helpful for overcoming hypoxia-induced radiotherapy resistance and enhancing the efficiency of tumor radiotherapy. Furthermore, based on good radio-sensitizer ability, favourable high X-ray absorption properties, and near-infrared optical absorption properties of Bi2S3 nanoparticles, the smart probe could achieve multimodal imaging and accurate visualized enhance radiotherapy effects. In a word, the smart probes will lay a foundation for theranostic integration of tumors.

恶性肿瘤的早期诊疗一直是现代医学研究热点与难点，分子影像学的迅猛发展有望使其取得突破性进展，而多功能分子探针是实现肿瘤靶向分子显像及可视化精准治疗的重要基础。目前，放疗是肿瘤的主要治疗方法之一，但乏氧的肿瘤微环境会极大地增加肿瘤侵袭力及远处转移机会，降低放疗效果。本课题研制了一种包裹过氧化氢酶（CAT）与硫化铋（Bi2S3）的叶酸靶向智能型多功能分子探针，该探针偶联的叶酸分子能特异性地与肿瘤细胞表面受体结合，介导载CAT与Bi2S3探针主动转运入细胞内。在肿瘤微环境中高浓度过氧化氢（H2O2）“刺激”下，CAT自发性地对H2O2产生特异性响应，持续性地产氧，实现氧气的“自补充”，克服乏氧引起的放疗耐受，增效放疗作用。同时，结合Bi2S3的放疗增敏、X射线及近红外光吸收特性，实现肿瘤多模态显像与可视化精准增效放疗作用，为肿瘤诊疗的一体化奠定基础。

随着现代医学的快速发展，单一成像模式与诊断功能的显像剂已远远不能满足日益增长的医学可视化、多样化、个性化及精准需求，对分子显像技术有了更高要求。本课题设计并成功制备出包裹过氧化氢酶（CAT）与硫化铋（Bi2S3）的智能响应型多功能分子探针，该探针能介导载CAT与Bi2S3探针主动转运入细胞内，在肿瘤微环境中高浓度过氧化氢（H2O2）“刺激”下，CAT自发性地对H2O2产生特异性响应，持续性地产氧，实现氧气的“自补充”，克服乏氧引起的放疗耐受，增效放疗作用。同时，结合Bi2S3的放疗增敏、X射线及近红外光吸收特性，实现肿瘤多模态显像与可视化精准增效放疗作用，为乳腺癌在体无创性、早期诊疗及疗效评价提供新方法。因制备的分子探针平均粒径小于300nm，可以通过肿瘤血管内皮细胞间隙进入肿瘤组织，是成功进行肿瘤分子成像及治疗的前提条件及保障。Bi2S3纳米颗粒因具有独特X射线及近红外光吸收性能，能实现CT、光声显像，为临床提供更加完整而准确的生物信息，有效避免为进行各种检查摄入多种显像剂加重身体及经济负担。随着Bi2S3纳米颗粒浓度增加，显像效果逐渐增强。同时，释氧及溶氧实验显示该分子探针在H2O2特异性刺激下能自发产氧，随着反应时间延长，氧气量逐渐增加，克服乏氧引起的放疗耐受，大体解剖显示该探针能明显减小荷瘤裸鼠肿瘤体积，HE及免疫组化结果表明该探针增效放疗效果最佳，为肿瘤早期诊断与治疗打下坚实基础，具有广阔应用前景。