基于Cerenkov发光能量转移的金量子点探针的构建及活体多模态成像应用

Design of the smart optical molecular probe is one of the hot spots for molecular imaging. However, the use of existing optical probes requires the excitation from external illumination sources, and this is challenging for in vivo imaging because of the strong auto fluorescence background arising from ubiquitously ex-pressed endogenous chromophores as well as the light-absorption and -scattering properties of biological tissue. In this context, design of the free auto fluorescent and high sensitive NIR probes is significant issues faced by optical molecular probe. The energy transfer systems based on the Cerenkov luminescence of radionuclide could serve as an internal source for illumination of fluorescent materials, and can effectively avoid the biological tissue autofluorescence. But so far, the literatures concerning Cerenkov luminous energy transfer system were relatively few, and most of them are simply the radionuclide mixed with energy acceptor. The disadvantage of previous probes is poor stability and low energy transfer efficiency. This proposal is aimed at the development of activatable probes by Cerenkov luminescence energy transfer between dihydrolipoic acid grafted polyethylene glycol stabilized near infrared gold quantum dots (AuQDs) and radionuclide 188Re. The Cerenkov luminescence of 188Re could serve as an internal source for illumination of AuQDs via energy transfer. In this design, dihydrolipoic acid grafted polyethylene glycol not only acts as a stabilizer, but also serves as a linker controlling the distance between AuQDs and 188Re for fabrication of the free auto fluorescent and high sensitive NIR probes. Moreover, radionuclide 188Re is also expected for SPECT/CT imaging and radiotherapy of tumor in vivo. In the project, the U87-MG human glioblastoma xenograft is selected as the research object. Moreover, the tumor vasculature targeted cyclic [RGDfK] peptides serve as the targeted recognition molecules. It is expected that the nanoprobes not only efficiently achieved the optical imaging of high target to background signal ratio, but also attained the SPECT/CT imaging and precisely radiotherapy of the U87-MG human glioblastoma xenograft. The prospective findings in this project will have a meaningful theoretical reference value for real-time optical-image-guided brain tumor resection during surgery of human glioblastoma. It is predicted that the research results of this proposal will be potentially helpful for designing multimodality molecular imaging probes as well as early tumor diagnosis and therapy. The project provides new ideas and new methods for high sensitive optical molecular imaging detection and study surgery therapy of tumor.

智能化高灵敏光学探针的设计是分子影像探针研究的热点之一，但目前大多数光学探针都需要额外的激发光源，无法避免生物组织自荧光，成像灵敏度较低。因此，设计一种无生物背景荧光且高灵敏的光学探针是非常有意义的。由具有Cerenkov发光的放射性核素与荧光探针而设计的能量共振转移体系无需额外激发光源，可有效避免生物组织自荧光。但目前，有关Cerenkov发光能量转移体系的报道较少，并且都只是简单的将放射性核素与能量受体混合，探针的稳定性较差且能量转移效率较低。本项目旨在以双巯基聚乙二醇稳定的近红外荧光金量子点为能量受体，以放射性核素188Re为能量供体，构建一种高Cerenkov发光能量转移效率且稳定的光学分子探针，以期实现活体肿瘤的高灵敏光学成像，此探针还有望用于活体肿瘤的SPECT/CT成像及肿瘤放射治疗。本项目将为研究肿瘤的高灵敏光学分子影像检测和手术治疗提供新思路与新方法。

生物成像分析是现代影像分析技术与化学、医学以及生物医学工程等学科发展和融合形成的新的研究领域，是生命分析化学的重要研究方向。生物成像分析可原位、实时、非侵入性可视化分析生物信号分子的在体活动规律，对其生物学行为在活体层面进行定性和定量研究，为理解肿瘤等重大疾病的相关生命过程与精准诊疗提供新技术。为克服单一成像模式的不足，融合多种成像技术的多模态成像技术已成为生物成像分析发展的重要趋势。多模态成像分析技术在体内同时导入具有多种成像功能的探针，然后通过不同成像技术的检测，获取病灶部位的详细结构与功能信息，它融合了不同成像技术的优势，能够无创、在体、实时、精细、特异性地显示肿瘤等重大疾病的相关生命过程，提供更加全面和精确的信息，为疾病的早期精准诊断与高效治疗提供保证。目前，发展具有特异性识别、生物安全性好、体内代谢情况统一且满足多种成像技术等性能的多功能探针是活体多模态成像分析的关键。.本项目中，申请人主要以构建基于放射性核素的核医学多模态成像探针，发展活体肿瘤的近红外光学、SPECT/CT以及核磁共振等多模态成像分析方法，实现活体肿瘤的多模态精准成像及放射联合治疗。共发表SCI论文7篇，其中包括2篇Analytical Chemistry，2篇Advanced Materials，1篇Advanced Functional Materials。.（1）发展了基于放射性核素与近红外荧光染料标记的蛋白质仿生氧化钆多模态成像探针，实现了活体淋巴转移的SPECT、近红外荧光成像与磁共振成像等多模态成像分析。相关成果详见：Anal. Chem., 2018, 2018, 90, 4529-4534.（通讯作者）。.（2）发展了基于放射性核素与近红外荧光染料标记的蛋白质仿生硫化铜多模态成像探针，实现了活体肿瘤的近红外荧光、SPECT、光声多模态成像分析与活体肿瘤的光热消融治疗。相关工作详见：Adv. Mater., 2016, 28, 5923-5930.（共同第一作者）。.（3）发展了基于放射性核素的配位效应而构建集SPECT/CT、光声成像与放射光热联合治疗等一体化的多模态诊疗探针，实现了活体肿瘤的成像分析与高效治疗。相关工作详见：Adv. Funct. Mater., 2016, 26, 5335-5344.（第一作者）。