1. 针对胶质瘤高灵敏检测的问题，提出了核素多内源激发荧光分子成像新方法。创新性地利用临床放射药物18F-FDG衰变产生的低能契伦科夫光子及同步产生的高能β粒子和γ光子，从生物体内部激发铕离子掺杂的氧化钆纳米颗粒，实现能量转移，产生峰值为620 nm的荧光，显著提高了荧光信号强度和成像信背比。与现有的契伦科夫光学成像相比，荧光信号强度提升了369倍，信背比提高了4倍。在此基础上，通过胶质瘤小鼠模型验证了该方法的有效性，实现了胶质瘤的高精准检测，并进一步将该方法拓展到乳腺癌小鼠模型，检出了PET影像遗漏的微小病灶，并成功引导了肿瘤切除。
Glioma is of severe malignancy and poses a serious threat to human life and health. Patients with glioblastomas, the most malignant gliomas, had a median overall survival of only 14.6 months. The most recommended treatment by the guidelines on the diagnosis and treatment of glioma is surgical resection, in which maximal safe resection is required. However, maximal safe resection of the gliomas is seldom achieved with the existing imaging methods because of the infiltration into the eloquent areas and the difficulty in distinguishing the tumor tissue from the normal tissue in the resection margin even in the non-eloquent area. Optical molecular imaging is expected to provide the accurate detection and resection of gliomas with novel technological support.
Fluorescence molecular imaging is a type of optical molecular imaging that has received extensive attention in recent years. It can facilitate the visualization and investigation of complex biochemical phenomena by labeling tumor-specific biomarkers. The conventional FMI uses the emission light of 700-900 nm. It has shown broad application prospects in basic research and clinical applications, including detection of tumors, evaluation of drug efficacy, and fluorescence image-guided surgery. However, the light with a wavelength of 700 – 900 nm was greatly affected by surrounding tissues as it passes through. The obligatory scattering and absorption effects of tissue lead to obvious background noise to the images, resulting in a low signal-to-background ratio. Besides, it even leads to the ill-posedness of fluorescence molecular tomography (FMT), which strictly limited the accuracy of light source reconstruction.
In view of the above challenging problems, a novel triple-excited fluorescence imaging (TEFI) method and a second near-infrared window (NIR-II) fluorescence imaging method was first established, which realized the improvement of signal intensity, signal-to-background ratio, and localization accuracy of lesions. Based on the imaging methods, an optical molecular imaging system was constructed and verified by a variety of animal experiments. With all the efforts made, the clinical application of the imaging method was finally achieved. Patients with gliomas were involved in the clinical trials of NIR-II fluorescence imaging and image-guided surgery. During the surgery, the tumor margins of gliomas were clearly distinguished by the NIR-II fluorescence imaging. The tumor was then resected under the guidance of NIR-II fluorescence images, with a complete resection rate significantly increased to 100% from 50% of the conventional surgical method. Survival of patients was prolonged and the quality of life of patients was improved.
The main research contents of the dissertation are as follows:
To achieve an improved detection sensitivity of gliomas, a novel Triple-excited fluorescence imaging (TEFI) method was developed by combining radio-pharmaceuticals and metal oxide nanoparticles. The 18F-fludeoxyglucose (18F-FDG) was applied as the excitation source. Cerenkov light, β particles, and γ ray that were generated along with the decay of 18F-FDG were used to interact with the Eu3+ doped Gadolinium Oxide (Gd2O3: Eu) to achieve a red-shifted fluorescence with an emission peak of 620 nm. Compared with Cerenkov luminescence imaging, the fluorescence signal intensity of the novel TEFI method reached 369 times higher than that of CLI. Based on the establishment of the TEFI method, in vivo TEFI imaging of gliomas in a subcutaneous model of small animals verified the effectiveness of the method in detecting gliomas in living animals. The method was further expanded to the guidance of breast tumor resection using small animal models. Using the TEFI method, small tumor lesions of breast tumor that were omitted by pre-operative PET imaging was detected. And the TEFI method was applied successfully in the resection of the tumor.
To achieve the localization of gliomas with high precision, an FMT method of NIR-II fluorescence was then raised based on a tissue-specific transmission model of NIR-II fluorescence and oblique projection matching pursuit algorithm. The absorption and scattering coefficients of NIR-II fluorescence in various tissues of the head were analyzed, based on which a tissue-specific transmission model of NIR-II light in the head was constructed. Therefore, the transmission process of NIR-II photons in complex head tissues was accurately described. Besides, the matching pursuit method was further modified by intraducing the oblique projection operator. Compared with the traditional orthogonal matching pursuit method, a pre-selected data support set was introduced according to the intensity of the fluorescence signal, and the non-orthogonal components were retained in the correlation calculation during the iterative process. Both operations aimed to improve the localization accuracy and shape recovery ability. In simulation experiments, the localization error of the tumor was reduced by 36% and the shape recovery coefficient was improved by 55%.
Based on the development of the imaging methods, a randomized controlled clinical trial on NIR-II fluorescence image-guided surgery of gliomas was carried out to further verify the clinical use. A NIR-II fluorescence imaging system was specially designed for gliomas to facilitate the clinical trial. Clinically approved indocyanine green (ICG) was injected as an imaging probe. With the approval of the ethics committee of Beijing Tiantan Hospital, Capital Medical University, 33 patients were involved in the trial.The NIR-II fluorescence can assist in the accurate identification of tumor resection margin and the detection of small residual tumor lesions that were omitted by the existing methods. The use of the NIR-II fluorescence imaging significantly improved the complete resection rate of the tumor and prolonged the survival time of patients. Compared with patients assigned to surgery under white light, the complete resection rate of the tumor was significantly increased by 50%, and the median progression-free survival and median overall survival were significantly prolonged by 2 months and 3.5 months, respectively. At the same time, the damage to the eloquent areas was minimized and paralysis after surgery can be avoided.
In summary, this dissertation raised the triple-excitation fluorescence imaging method and an FMT method of NIR-II fluorescence based on a tissue-specific transmission model of NIR-II fluorescence and oblique projection matching pursuit algorithm. Based on that, a clinical imaging system used for NIR-II fluorescence image-guided surgery of gliomas was constructed. With all the efforts made, a clinical trial of NIR-II fluorescence imaging and image-guided precise surgery of gliomas was then performed, which brought patients clinical benefits.
|Keyword||激发荧光分子成像 断层成像 手术导航 契伦科夫光学成像 近红外二区荧光成像|
|史小静. 新型荧光分子成像用于胶质瘤手术导航的研究[D]. 中国科学院自动化研究所. 中国科学院自动化研究所,2022.|
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