具有双模成像功能的癌细胞敏感的光子纳米材料及其医学应用

Aiming at the problems with easily leading to metastasis of tumor cell and complications due to in vivo the wound after resection of tumor specimen for in vitro pathological analysis of tumor, based on the characteristic that there is a significant difference in electric charges between benign and malignant tumor cells, in this project, we will combine the properties, such as the paramagnetism, photon upconversion of the lanthanide ions (Ln3+), and the Cr3+ fluorescence properties susceptible to microenvironment charge to develop a novel photo-nanomaterial as bioprobes for in vivo noninvasive diagnosis of benign or malignant tumor. The following research contents will be addressed: 1) design and construction of NaGdF4: Er3+,Yb3+, Li+,K+ photo-nanoparticals (MUNs) with double mode imaging function of magnetic resonance imaging (MRI) and upconversion photon imaging (UPI), 2) design and construction of NaGdF4:Er3+,Yb3+, Li+,K+@NaGdF4:Cr3+ (MUNs@Cr) sensitive to the charge properties of tumor cells，3) effects of surface and interface of MUNs@Cr on properties of upconversion photon emission of Er3+ in core and downconversion photon emission of Cr3+ in shell, 3) the influences of the changes in tumor cell charges in cells and mouse model on MRI, UPI and spectral lineshape of MUNs@Cr, 4) high sensitivity and specificity of MUNs@Cr for in vitro and in vivo of mouse model. The two key questions are expected to be answered, i.e. photo upconversion / downupconversion efficiency of MUNs@Cr, and the the relationship between the structure and conformation of targeted antibody coupled with the surface of MUNs@Cr and high sensitivity and specificity of MUNs@Cr for in vitro and in vivo. The the relative research foundation will be provided to realize a novel MUNs@Cr sensitive to microenvironment of benign and malignant tumor cells.

针对良恶性肿瘤体内取样体外诊断方法易引起并发症和扩散等问题，本项目基于良恶性肿瘤细胞间电荷性质存在的差异，将镧系离子顺磁性及其光子上转换性质与Cr3+荧光性质易受环境电荷影响特点相结合，开展构建核磁共振（MRI）和上转换绿光子成像（UPI）及红光功能的NaGdF4 Er3+,Yb3+, Li+, K+上转换纳米粒子（MUNs）和细胞电荷敏感的NaGdF4:Cr3+壳包覆MUNs的MUNs@NaGdF4:Cr3+核壳结构光子纳米材料（MUNs@Cr）、MUNs@Cr表面和界面对Er3+光子上转换和Cr3+光子下转换性质影响、MUNs@Cr高灵敏和高特异性靶向四项内容研究。重点解决MUNs@Cr结构与光子上/下转换效率关系和MUNs@Cr表面抗体结构和构像与癌细胞靶向灵敏度和特异性关系二个关键问题，为实现MRI和UPI成像及对肿瘤细胞电荷敏感的MUNs@Cr纳米材料提供前期研究。

针对良恶性肿瘤体内取样体外诊断易引起并发症和扩散等问题，本项目开展了具有MRI和上转换光子成像（UPI）癌细胞特异性敏感多功能的壳（SS）包覆上转换纳米粒子（MUNs）核壳结构MUNs@SS构建、表面和界面的光学性质、MUNs@SS高灵敏和特异靶向性内容研究。扩展了具有癌细胞敏感的多模态成像引导的肿瘤光动力和热动力治疗的新材料研究。揭示了MUNs@SS与上/下转换效率关系及其面传感分子与癌细胞靶向灵敏度和特异性关系的二个关键科学问题。获得了如下重要研究结果：.1. 首次获得了MUNs结构从相向相过渡期间的（+）双相共存结构，突破了2 mol%Er3+掺杂浓度极限，将Er3+掺杂浓度先后提高到40 mol%和100 mol%，抑制了浓度猝灭，提高上转换发光强度。.2. 通过癌细胞敏感的MRI和UPI成像引导诊断和治疗一体化的光子纳米材料MUNs@Cr3+、MUNs-Ce6@CaP:Mn/DOX、Cd@SiO2、MnFe2O4生物探针构建与表征分析研究，获得了MRI和UPI对癌细胞敏感的癌细诊断和治疗一体化的多功能光子纳米材料以及肿瘤治疗结果。.3. 获得了MUNs表面包覆SS功能壳层是解决光子能量效率和供受体能量效率以及MRI和UPI多模态成像功能的重要途径的研究结果。.4. 获得了MUNs@SS多功能生物探针纳米材料“刚性”表面与“软性”抗体之间强相互作用是制约表面耦联抗体生物特异识别能力下降的重要机制之一。.5、应用对癌细胞微环境具有特异识别功能的聚合物分子替代普遍应用抗体作为生物靶向分子是解决“硬”表面与“软”抗体分子相互作用导致抗体分子生物特异性下降关键科学问题的一种有效技术途径。. 发表SCI论文17篇，申请专利4项。培养博士4人，硕士2人。本项目研究结果为癌细胞特异性传感的多模态成像引导癌症治疗的光子纳米平台的发展提供了材料、物理及医应用研究基础。