808nm光激发的上转换纳米复合材料在核靶向光动力/光热治疗肿瘤的应用研究

The research on the diagnosis and therapy systems based on the luminescent nanocomposites has been the hot focus during the past five years, and great progress has been achieved on the design, functionalization, and improvement of therapy. However, the possible damage induced by the excessive heating derived from the conventional 980 nm irradiation still exists. Furthermore, the therapy within the cell cytoplasm fails to enter the nucleus, which inevitably lowers the therapeutic efficacy. Based on these concerns, this proposal is to construct a kind of Nd3+ doped up-conversion nanocrystals with high emission intensity, the mesoporous silica layer, the photothermal agents, and the photosensitizer agents are subsequently functionalized on the up-conversion nanoparticles, thus obtaining a dual-modal synergistic photothermal and photodynamic therapeutic platform. The nuclear- targeting agent, TAT peptide, is then grafted on the system to deliver the platform to the nucleus, which highly improve the therapeutic efficacy by inhibiting the DNA synthesis. Finally, the anti-cancer efficacy, imaging effect, and bio-safety are evaluated by the in intro and in vivo experiments. The safety, superiority, and therapy enhancement of 808 nm NIR light, nuclear-targeting, and synergistic therapy are also systematically studied, which is to provide the basic research data and theoretical guidance for the clinical application.

基于荧光纳米复合材料的诊疗体系在抗癌领域的应用探索研究是近5年全球热点研究课题之一，目前已经在体系设计、功能整合和提高诊疗效果等方面取得了重要进展，但仍存在常规980 nm近红外光激发产生组织过热损害生物体及诊疗体系停留于细胞质内部无法进一步提高治疗效率等严重缺陷。针对上述问题，本项目拟设计一类Nd3+掺杂的高荧光强度稀土上转换纳米晶，并在纳米晶表面依次功能化介孔二氧化硅层、光热材料和光敏剂，获得单一808 nm近红外光激发的光动力治疗/光热治疗双模式协同治疗体系；然后进行核靶向剂TAT肽修饰，将治疗体系靶向输送到细胞核内破坏遗传信息，进而大幅提高治疗效率；最后以癌细胞和小鼠为研究对象进行治疗效果、成像诊断和生物安全性检测，系统深入地评估808 nm激发光、核靶向及光学协同治疗等在癌症诊疗应用中的安全性、优越性和抗癌增强能力，为体系的临床应用提供基础研究数据及理论指导。

光动力治疗和光热治疗等光学疗法是近年来热点研究课题之一，与传统疗法相比具有副作用低、靶向性好和无耐药等独特优势，拥有十分重要的基础和临床意义。但仍存在一些亟需解决的关键问题，如常规紫外光、可见光和980nm近红外光等激发源产生组织过热损害生物体，以及诊疗体系停留于细胞质内部无法进一步提高治疗效率等。针对上述问题，本项目一方面设计合成了多种Nd3+掺杂的核壳结构上转换纳米粒子，因为纳米晶内部存在能量传递路线“808nm→Nd3+→Yb3+→镧系离子”，从而实现了镧系离子在808nm光激发下的上转换发射。由于生物组织对808nm光几乎没有吸收，因此低功率808nm光照不会产生热效应，克服了传统激发光作用后生物组织产生的过热受损问题，安全性更高。另一方面，利用溶胶-凝胶法、静电吸附法和模板法等将上转换纳米粒子、CuS等光热成分以及Ce6和g-C3N4等有机/无机光敏剂复合，获得了一类集上转换荧光、光热效应和光动力性能于一体的多功能纳米复合材料。808nm光激发下，上述体系的功能组分产生的强氧化性物质和热量可有效杀灭癌细胞。此外，发现调整功能组分的成分、比例、结构和结合方式等参数，可实现多种功能的同时呈现，并可调变获得最优性能。进一步结合化学治疗药物、靶向剂叶酸或磁靶向效果等，实现了808nm光激发的靶向光动力治疗、光热治疗、药物治疗和生物成像联合应用的诊疗体系。研究表明多模式治疗可完全抑制小鼠体内的癌细胞生长，而每种治疗模式单独作用只能稍微抑制癌细胞的生长，一定程度上解决了现有癌细胞治疗模式单一和抗癌效率低的难题。