成像、测温和治疗于一体的多功能纳米光热转换体系的构建

Malignant tumor or cancer is one of the main killers to human’s healthy and life, and surgical resection, radiotherapy and chemotherapy are clinically accepted as the mainstreams for human cancer therapy, but all these methods have many disadvantages and causing damage to healthy tissues. Photo-thermal therapy (PTT) with a near infrared (NIR, 650-1350nm) light source can penetrate into deep tissue and possess high spatio-temporal selectivity, in which photo-thermal agents play the determinant role. In the process of therapy, the bio-imaging of the tumor cells for real-time location and monitoring of cellular events; and the achievement of remote detection of the temperature variation in deep-tissue malignancies for better controlled NIR laser irradiation are important. The aim of the present project is to develop a novel photo-thermal agent with bio-imaging, thermometry and high photo-thermal conversion efficiency. The multifunction integrated converters were obtained through coating a layer of conventional photo-thermal agents, such as noble metal nanoparticles (Au, Ag, etc) and copper chalcogenide semiconductors (CuxS), on the surface of rare earth up-conversion nanoparticles (UCNPs) using co-precipitation or other soft methods. Here, rare earth UCNPs should meet two basic requirements: first, they could be excited efficiently by 980 or 808 laser; second, rare earths with thermal coupled energy levels, which endow the UCNPs property of optical heater and thermometer based on the integrated fluorescence intensity ratio (FIR) of transitions of the thermal coupled energy levels. According to our design, the present proposal includes three steps. The factors those affect the sensitivity of optical thermometry and photo-thermal conversion efficiency, including the shape and the size distribution of UCNPs, dopant concentrations, photon energy of the host and the difference between the coupled energy levels, were investigated in detail and obtain the optimal parameters. Base on above mentioned results, the UCNPs were coated a layer of traditional photo-thermal agents and their photo-thermal conversion efficiency and sensitivity of thermometry with different shell thickness and thermal agents were also measured in order to obtain the novel photo-thermal agents with core-shell structures bioimaging, optically heating and thermometry properties. Finally obtained converters were further coated with SiO2 or other surfactant, such as polyacrylic acid (PAA) and polyethylenimine (PEI) to improve biocompatibility.

光热治疗恶性肿瘤较传统的手术切除、化疗和放疗手段副作用更小,收效更快；而光热转换剂在光热治疗中起着决定性作用。本课题拟以合成808nm近红外光激发下具有成像功能的FIR(荧光强度比)上转换纳米晶光学温度传感粒子为基础，并详细研究纳米晶基质声子能量、热耦合能级差等因素对测温灵敏度及光热转换效率的影响；然后通过共沉淀和热分解法在上转换纳米颗粒表面包覆一层贵金属金或银或CuxS等传统纳米光热治疗剂，对壳层厚度、种类等参数优化并进行表面修饰提高其生物相容性，最终构建成像、测温和光热治疗于一体的多功能核壳结构上转换纳米光热转换体系。此光热转换体系不但具有高的光热转换效率，其上转换成像功能还可确定肿瘤的位置、大小及其在体内的分布和在肿瘤组织的富集情况；而且可在光热治疗过程中对肿瘤及周围健康组织温度的变化进行实时监控；并可对治疗效果进行最终的评价。

肿瘤是威胁人类健康的重要杀手之一，光热治疗肿瘤较传统的手术切除、化疗和放疗副作用更小,收效更快；而光热转换剂在光热治疗中起着决定性作用，产热过多会损伤正常细胞，不足则无法达到治疗效果。基于荧光强度比（FIR）技术的上转换发光材料不但可以吸收红外光发射出可见或红外光，具有成像和测温功能，同时上转换发光材料的大部能量用于产生热量，使其有希望成为多功能的光热治疗剂。本课题以合成808nm近红外光激发下具有成像功能的FIR上转换纳米晶光学温度传感颗粒为基础，首先以Yb3+-Er3+为其激活剂，详细研究纳米晶基质声子能量、热耦合能级差、激活剂局部对称性、颗粒尺寸形貌及掺杂离子浓度等因素对温传绝对灵敏度及光热转换效率的影响；在此基础上选择结构和组成简单、声子能量适中、Er3+局部对称性低且与Er3+热耦合能级差接近的基质Y2O3、LuVO4等，通过共沉淀和水热法合成上转换纳米颗粒；并利用Nd3+在808的强吸收，与Yb3+的高能量传递，得到808激发下的纳米晶；并通过改变激活剂为Tm3+, Nd3+等实现NIR-to-NIR的发光纳米晶，然后依次在纳米颗粒表面包覆生物相容性较高的SiO2层、Cu2S/IR780等传统光热治疗剂，对壳层厚度、种类等参数优化，最终构建成像、测温和光热治疗于一体的多功能核壳结构上转换纳米光热转换体系。此体系中Nd3+负责对808近红外光的吸收，发光材料担负成像和热耦合能级测温功能，同时上转换还负担部分光热转换功能，表层包覆的光热剂担负大部分的光热转换功能。获得的复合纳米颗粒测温比红外热像仪更准确，且对细菌和癌细胞杀伤95%以上，因此多功能光热转换体系不但具有高的光热转换效率，其上转换成像功能还可确定肿瘤的位置、大小及其在体内的分布和在肿瘤组织的富集情况；而且可在光热治疗过程中对肿瘤及周围健康组织温度的变化进行实时监控；并可对治疗效果进行最终的评价。