基于Nd3+敏化纳米晶的上转换生物成像与光热治疗及光学量效研究

Upconverting nanoparticles (UCNPs) constitute a novel type of contrast agent with unique properties for optical bioimaging. Superior to organic dyes and quantum dots, UCNPs enable autofluoresence-free, high resolution, high photostability imaging under near-infrared excitation. The research topic of UCNPs has become popular for biomedical applications. As emerging powerful UCNPs, Nd3+ sensitized UCNPs can minimize the overheating effect due to its excitation has very low absorption by the tissue. However, there are still some problems to be studied and explored. For example, how do the emission spectrum, the energy transfer efficiency from Nd3+ to Yb3+ impact the imaging depth? Furthermore, the study of improve the imaging resolution using shorter wavelength has not been reported yet. The photothermal and photoluminescence properties of UCNPs have a contradictory requirements on the concentration of Nd3+ ion doping. Photothermal therapy using UCNPs also need to be explored for extended application and functional imaging...In this project, we are going to combine solid theoretical analysis and experimental studies. First of all, optical mechanism of Nd3+ sensitized UCNPs improving imaging depth will be investigated and how to further optimize the deep imaging ability will be also demonstrated. This project will design and synthesize multifunctional UCNPs with upconversion luminescence and photothermal effect. High resolution 3D microscopy using UCNPs will be excited under short wavelength excitation. Uponversion luminescence guided photothermal therapy will be performed both in vitro cancer cells and in vivo mice experiments. Based on multiphysical (light-thermal-damage index) computation, the parameter-efficacy mechanism will be investigated for highly efficient mouse tumor photothermal therapy. This proposed project and its expected achievement will greatly improve the applicability of UCNPs and further promote their development in the field of biomedical optics.

上转换纳米颗粒(UCNPs)分辨率高、无背景噪声、无光漂白，应用前景广阔。作为新一代UCNPs，Nd3+敏化UCNPs有效克服了激发光加热样品的弊端，研究价值很大。然而，尚存在很多问题值得深入研究与探索。荧光光谱和能量传递效率会如何影响成像深度并如何优化；短波长激发是否可用于提高分辨率实现高分辨率三维成像；光热效应与上转换发光对Nd3+掺杂浓度要求的矛盾也尚未解决。..本项目结合理论模型和实验研究，揭示Nd3+敏化UCNPs提高组织成像深度的内在规律；解决瓶颈问题构筑上转换成像与光热治疗的多功能纳米晶；用短波长光激发四光子荧光实现高分辨三维成像；并实现离体癌细胞与小鼠肿瘤的高效率癌症光检测与可视化光热治疗。构建“光-热-损伤”模型进行多物理场计算，探明光功率、治疗时间和UCNPs浓度等参数与疗效的量效机制。本研究将极大地提升和推动Nd3+敏化UCNPs的功能优势与应用范围。

稀土掺杂上转换纳米颗粒(UCNPs)分辨率高、无背景噪声、无光漂白，应用前景广阔。作为新一代UCNPs，新型敏化如Nd3+敏化UCNPs有效克服了激发光加热样品的弊端，研究价值很大。然而，尚存在很多问题值得深入研究与探索。比如：荧光光谱和能量传递效率会如何影响成像深度并如何优化；短波长激发是否可用于提高分辨率实现高分辨率成像；光热效应与上转换发光对浓度要求的矛盾也尚未解决。.本项目以数理模型为指导以实验研究为目标，①已经从光学理论角度，通过光学量效计算研究，揭示Nd3+敏化UCNPs提高成像深度的内在规律，并通过计算研究提出了增强Nd3+敏化UCNPs红光的发光强度提高成像深度的结论 (Biomedical Optics Express 6(3): 838-848.)；②本课题已经通过选择合适波长激发Nd3+敏化UCNPs发射四光子，实现廉价连续光激发、无共聚焦小孔的高分辨率的显微光成像，横向分辨率已经达到了161 nm，逼近理论值（Optics Express 24(2): A302-A311.）；并在本课题研究目标的基础上，进行了新型纳米材料的设计，通过超分辨实现了66-nm的空间分辨率（Nature Communications 8(1): 1058.）； ③本课题已经设计合成了敏化增强兼具上转换发光和光热效应的复合纳米晶，并实现癌细胞的靶向治疗，并通过光学成像引导光热控治疗（Optical Materials Express 6(4): 1161-1171.）；④本课题已经通过改变新星敏化离子，优化激发波长同时对显微成像和组织光学成像实现了深度成像，解决了长期存在的“两者对深度的矛盾关系”（Biomedical Optics Express 7(6): 2174-2185.等）；⑤本项目已经从光学理论角度，探明了优化激发光照射模式、光功率及纳米颗粒大小等参数实现有效的光学发光增强，明确上转换成像与光学增强的量效机制（Laser & Photonics Reviews 9(5): 479-487.）。上转换纳米颗粒在本课题执行的几年内也得到了非常快速的发展，后续研究也会在本课题基础上继续深入研究，其中包括优化并探究更好的光学成像分辨率，突破衍射极限，优化并寻找对上转换纳米颗粒的新型的有效的激励方式（多光束激发），优化并扩展其在生物医学领域的应用范围等。