面向肿瘤诊断和治疗上转换光学一体化探针的构建与应用

Accurately localizing and effectively treating tumors, have become the basic scientific questions facing cancer research. The upconversion luminescent (UCL) imaging based on rare earth nanocrystals, could integrate the high sensitivity of optical imaging with the advantages of UCL, such as great penetration depth and no auto-fluorescence. However, the currently used sensitizer Yb3+ has only one excited state, which result in narrow absorption band located at ca. 980 nm, coinciding with the strong absorption of water. Therefore, continuous laser irradiation at 980 nm to trigger the UCL process would lead to a risk of local temperature rise, and substantial overheating may even induce tissue damages. On the other hand, photodynamic therapy as a new technology to treat tumor not only has several advantages, such as minimal trauma, low toxicity, high selectivity and security, but also can prevent metastasis. However, the photosensitizers in clinical treatments are excited by visible light, which has limited penetration depth, resulting in ineffective therapeutic effects to internal tumors. This proposal intends to address these challenges, by introducing Nd3+ as a new near-infrared absorbers and sensitizers in the conventional Yb3+-doped upconversion luminescent nanocrystals to extend the excitation from 980 nm to 808 nm. In the mean time, by attaching the photosensitizer and tumor specific antibody to the nanoparticles, we also propose to develop the theranostic agent for both contrast: upconversion luminescent imaging and photodynamic therapy, and explore the in vivo application methods for the above probe.

肿瘤的精准定位及有效治疗是肿瘤研究面临的基本问题。基于稀土纳米晶体的上转换光学成像，将光学成像灵敏度高、成像时间短等优点，与上转换发光组织穿透深度大、无自发荧光干扰等优势相结合，可提高肿瘤检测精度。目前广泛研究的Yb3+敏化体系，采用的980 nm激发光与水分子的近红外吸收重叠，长时间照射，可导致照射区域组织温度过高，甚至灼伤。光动力疗法作为肿瘤治疗的新技术，具有创伤小、毒性低、选择性好、安全性高等优点，并可避免癌细胞转移。但是，临床用卟啉类光敏剂所需的激活光组织穿透深度浅，限制了光动力疗法适应症范围。本项目针对上述问题，拟在Yb3+敏化体系中引入新的敏化离子，减小上转化发光激发光与水分子吸收的重叠，有效降低激发光的组织热损伤；另一方面，通过纳米颗粒表面修饰光敏剂构建受上转换发光调控的纳米光敏药物，并与抗体耦联实现肿瘤特异性的上转换光学成像与治疗一体化功能，并发展上述探针的体内应用方法。

癌症是导致死亡的主要疾病之一，然而目前仍然缺乏针对肿瘤早期诊断、转移预警、疗效预测及有效治疗的临床方法。本项目是以上转换发光（UCL）稀土纳米颗粒为核心构建诊疗一体肿瘤分子影像探针为目标，开展上转换发光稀土纳米颗粒化学组成、掺杂结构与上转换发光效率的关系，实现生物组织吸收弱、发光效率高的稀土上转换发光纳米晶体的制备，进而将上转换发光纳米颗粒与抗肿瘤光敏药物等耦联，构建肿瘤微环境激活高灵敏诊疗一体分子影像探针，为肿瘤的精准定位与治疗提供新的思路；并针对肿瘤侵袭、转移、耐药等预后因素与微环境密切相关的特点，构建了响应型肿瘤微环境智能探针，发展了肿瘤微环境实时、无创的影像检测方法，为肿瘤预后评估提供依据；针对肿瘤微环境高还原性特点，构建了谷胱甘肽诱导聚集的多模态纳米探针，为发展高灵敏肿瘤多模态分子影像提供了新思路；利用偶氮氯膦III与稀土离子络合的特异性显色反应，发展特异性好、灵敏度高、操作简便的稀土纳米探针的组织化学分析方法，为定量化分析稀土纳米颗粒在组织中分布提供依据。项目执行期间，已在J. Am. Chem. Soc.、Adm. Mater.、ACS Nano、Small等国际著名期刊发表相关成果论文10篇，授权专利2项、培养博士毕业生4人。