富勒烯基磁性纳米诊疗试剂系统的构建及针对荷瘤动物的MRI分析

Magnetic theranostic nanoparticles (MTNs), which the tumor-targeted ligand and anticancer drugs were decorated to the nanostructural magnetic resonance imaging (MRI) contrast agents, have attracted considerable attention for their application in nanotheranostics. So far, it has not been found in the reported literatures that the water soluble derivatives of fullerenes were loaded with the targeted ligand, chemotherapeutic drug and MRI contrast agent to fabricate MTNs for tumor-targeted MRI diagnosis and therapy. In the present program, we firstly carried out the facile synthetic procedure to manufacture the water-soluble multiazafulleroid[60] derivatives by improved one-step nitrene chemistry. Secondly, the active targeting ligand (folic acid), paramagnetic probe (metalloporphyrin) and chemotherapeutics (doxorubicin) were conjugated to the newly synthesized fullerene-based nanoparticles, which the nanocomposites were acted as multifunctional MTNs for tumor-targeted chemotherapeutic drug delivery, photodynamic therapy and MRI contrast agents. Thirdly, In vitro studies of the nanocomposites were carried out, such as drug release, MRI phantom and cell imaging, cytotoxicity assays, and evaluation of photodynamic therapy and chemotherapy in order to research the synergistic enhancement of antitumor effects for the dual modal treatment. Finally, in vivo MRI of nude mice bearing xenografted breast tumor were carried out to investigate that the nanocomposites were accumulated in the tumor via the folic acid-mediated active targeting, and to monitor the therapeutic effect for the dual modality of anti-tumor treatment. These multifunctional fullerene-based MTNs system are very promising for applications in versatile imaging diagnosis and as multi-modal therapy tools in future biomedical engineering and offer new opportunities in theranostic nanomedicine and in nanooncology for cancer diagnosis and therapy.

纳米磁共振成像(MRI)造影剂结合靶向及抗肿瘤药物，组建磁性纳米诊疗试剂可实现肿瘤的MRI诊断及治疗。这是刚刚新兴的纳米诊疗技术研究的新亮点。当前，利用富勒烯水溶性衍生物制备肿瘤靶向且具备MRI诊断及双重治疗功能的磁性纳米诊疗试剂尚未见文献报道。本项目通过氮宾多加成反应发展新型富勒烯多氮杂桥水溶性衍生物，偶联顺磁标记及肿瘤主动靶向配体形成新型磁性纳米载体，以用于MRI造影、负载抗肿瘤药物，构建富勒烯-叶酸-金属锰卟啉-阿霉素四元组合的具有MRI诊断及光动力疗法与化疗双模式治疗肿瘤的三功能化富勒烯基磁性纳米诊疗试剂，并开展体外抗肿瘤实验及荷瘤动物活体MRI的纳米诊疗技术应用研究。这既可拓展与深化富勒烯基纳米生物材料在MRI医学影像技术及纳米肿瘤学领域的应用，也将大大促进纳米诊疗技术发展。最终，为构建富勒烯基磁性纳米诊疗试剂及其应用于MRI诊断与双模式治疗肿瘤的方法学研究建立理论基础。

纳米磁共振成像(MRI)造影剂结合抗肿瘤药物，组建磁性诊疗纳米颗粒可实现恶性肿瘤的早期影像诊断及治疗。这种“合二为一”多功能诊疗纳米颗粒在纳米医学领域是刚刚新兴的诊疗纳米技术研究的新亮点。本项目开展以下研究：（1）利用氮宾反应，发展出一系列碳笼外接短直侧链数目和长短不同及侧链末端亲水性官能团为-OH、-NH2、-COOH的新型富勒烯多氮杂桥水溶性衍生物以及侧链同时含多个亲水基的衍生物C60(NCH2CHOHCH2OH)12，并采用固液反应策略大规模制备出氮杂富勒醇C60(NCH2CH2OH)14；（2）利用氮宾反应，发展了顺磁性金属富勒烯多氮杂桥水溶性衍生物Gd@C82(NCH2CH2OH)14、Gd@C82(NCH2CH2NH2)x、Gd@C82(NCH2COOH)x作MRI造影剂；（3）利用富勒烯多氮杂桥水溶性衍生物，偶联水溶性锰卟啉构建出新型的富勒烯基MRI造影剂作纳米影像探针，偶联抗肿瘤药物、主动靶向分子构建出新型的纳米载药系统，并开展体外性能测试，如：弛豫性能、由基属性及清除自由基能力、细胞毒性等；（4）利用富勒烯基纳米影像探针实现荷瘤动物活体MRI影像诊断。成功完成本项目后取得两方面成果，成果一：成功发展富勒烯水溶化新途径，利用氮宾反应，采用固液反应策略，在实验室条件下0.5 L容器内发生反应即可获得百克量级的富勒烯多氮杂桥水溶性衍生物产品。成果二：利用富勒烯多氮杂桥水溶性衍生物作纳米载体成功构建富勒烯基MRI影像诊断试剂与纳米载药系统。以上成果紧密联系富勒烯类碳纳米材料作为诊断或治疗探针应用于纳米医学领域的基础问题，创新性较强。这既可拓展与深化富勒烯基纳米生物材料在MRI医学影像技术及纳米肿瘤学领域的应用，也将大大促进纳米诊疗技术发展，还可为其在纳米医学领域构建其他类型的多功能影像诊断或纳米载药系统的研发提供关键共性技术。

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