钆离子诱导碳点自组装荧光超纳米颗粒及在胃癌精准诊疗中的应用基础研究

Due to superior optical properties, biosafety and biocompatibility, carbon dots (Cdots) has been applied in optoelectronics, biosensors and biomedicines. Recently, we found that the photoluminescence of Cdots can be significantly enhanced after self-assembled carbon superparticles (CSPs) and some new properties have been also derived. But the assembled mechanism and application of CSPs have not further been explored. In this project, CSPs will be synthesized by self-assemble of Cdots induced by gadolinium ions. then we will use CSPs as nanocarries to load Doxorubicin(Dox) hydrochloride, as a model of chemotherapy drugs, graphene oxides（GO）as a gatekeeper coating outer side of the CSPs-Dox, and then the fluorescent labeled aptamers absorbed on the GO surface as biological target molecules to build the photoresponsive drug delivery system (PDDSs). The effect of PDDSs on the diagnosis and treatment of tumor was determined by the model of gastric carcinoma in mice. Meanwhile, The distribution and metabolism of CSPs and the effects on the genital and genetic systems will be investigated systematically. And the assembly mechanism of the CSPs and the biological effects were systematically studied Via single-molecule force curves by atomic force microscope technologies. Through the implementation of this project, we hope that we can invent a biosafty and intelligent PDDSs probe combined with multi-mode imaging functions, duel-targeting and photoresponsive drug release, explain the mechanism of self-assembled and the biological effect of nanoparticles, and provide a effective tool to therapy cancer.

碳点因其独特的光学特性和生物安全性，在光电子、生物传感和生物医学等方面具有良好的应用前景。前期研究我们发现由碳点自组装的超纳米颗粒(CSPs)具有超强的荧光特性，其组装机制及应用尚待深入探索。本项目拟以钆离子诱导碳点自组装成荧光CSPs，通过静电作用在CSPs表面负载抗肿瘤药物阿霉素制备CSPs药物载体，然后在其表面包被氧化石墨烯并连接生物靶分子荧光标记的适配体，构建近红外光控释药物输送诊疗系统(PDDSs)；建立小鼠原位胃癌模型，考察PDDSs诊疗肿瘤的效果；以斑马鱼为模型评价，纳米探针遗传、发育及生殖等毒性和代谢机制；利用原子力显微镜单分子力谱研究纳米颗粒、纳米探针及细胞之间的相互作用力，探讨纳米颗粒自组装机制和纳米探针的生物效应。通过本项目的实施，阐释CSPs自组装机制和纳米探针的生物效应，构建一种生物安全性治疗胃癌的PDDSs，为攻克胃癌提供新技术和新方法。

碳点因其独特的光学特性和生物安全性，在光电子、生物传感和生物医学等方面具有良好的应用前景。本项目主要围绕着碳点及金属（钆，镧系金属掺杂为主）掺杂碳点的制备和纯化新技术和新方法开发，调控量子点表面官能团和电荷，制备金属担载量也高达20%以上金属掺杂碳点，确保批次之间重现性好，可批量自动化制备转化，发射可见光全波段荧光量子点，并阐述了量子点形成新机制。我们系统考察了以Gd@Cdots和Gd3+诱导碳点自组装超纳米颗粒（CSPs）为主，分别偶联光敏剂Ce6或Ce6/Ver，利用多次能量共振转移作用，实现对药物靶向递送和在肿瘤部位缓慢释放；多模式（荧光和MR）成像成功监控药物在体内的分布、在肿瘤部位的聚集过程、光动力治疗效果及药物体内代谢的过程。利用CCK、MTT和小鼠及斑马鱼为肿瘤模型，从细胞水平、小动物证实了智能纳米探针具有良好生物安全性，系统考察了碳点对细胞和动物体内的脂肪酸代谢影响，发现了低浓度的碳点可引起谷胱甘肽（GSH）的升高，造成细胞内不饱和脂肪酸的氧化抵抗，从而造成细胞增殖，而高浓度的碳点可产生高浓度ROS，导致不饱和脂肪酸的过渡氧化，增加细胞膜的通透性，导致细胞膜的完成性的丧失，最终细胞的铁死亡。另外，在上述研究的基础上我们还开展了以金属掺杂碳点作为荧光和质谱流式的金属标签，实现了同一片组织切片上同时完成荧光成像和质谱流式成像，开发具有中国知识产权的新一类质谱流式同位素金属标签。在此基金项目的支持下，在国际期刊发表研究论文11篇，其中具有重大影响期刊上论文3篇分别为PNAS 1篇、Adv. Maters. 1篇和Adv. Sci.，另有一篇Sci. Adv （返修中），新增发明专利3项，培养硕士研究生4名，博士研究生2名，组建了一支多交叉且具有很好凝聚力、创新力和执行能力的研发团队。

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