双示踪剂PET动态成像方法及其应用研究

发布时间：2018-03-07 16:02

本文选题：正电子发射断层成像(PET)　切入点：多示踪剂动态成像　出处：《华中科技大学》2014年博士论文　论文类型：学位论文

【摘要】：正电子发射断层成像(Positron Emission Tomography, PET)是当前超高灵敏度和特异性的活体分子成像方法之一,己成为肿瘤研究和临床诊断与治疗的重要工具。采用对各生理或药理特征变化敏感的不同示踪剂进行PET成像,可刻画肿瘤病理各方面特征,包括代谢、新生血管生成、细胞增殖、血流和乏氧等。鉴于恶性肿瘤的复杂性和不均一性,这些信息互相补充,可以促进对肿瘤的深入理解,从而提高肿瘤早期诊断、分期、治疗、疗效监测及预后评估的准确性。相比于多示踪剂分开进行多次扫描的方式,多示踪剂单次PET扫描成像可以实现该目标,同时极大减少费用、节省时间和减少辐射剂量,并避免由于多次扫描之间的时间间隔而导致不能得到各示踪剂在同一生理条件下反映的信息。本论文在单次动态PET数据采集中实现18F-氟脱氧葡萄糖(18F-Fluorodeoxyglucose,18F-FDG)和18F-精-甘-天冬氨酸肽(Arg-Gly-Asp, RGD)双示踪剂活体成像同时监测肿瘤的葡萄糖代谢和新生血管生成,评估了双示踪剂信号分离方法的准确性并应用于肿瘤疗效监控。主要研究内容和成果如下： 1)优化基于RGD分子探针F-18标记过程并探讨18F-RGD体外及活体分布特性。通过F-18标记含聚乙二醇(Polyethylene glycol, PEG)修饰和不含PEG修饰的二聚体RGD肽合成αvβ3整合素成像探针,然后进行离体生物结合分析、离体血清稳定性和在体代谢稳定性分析、在体静态和动态成像定量以及生物分布实验比较三种示踪剂,选择性能最佳的示踪剂用于双示踪剂成像,该示踪剂被命名为18F-Alfatide Ⅱ。 2)仿真18F-Alfatide Ⅱ/18F-FDG双示踪剂成像时间活度曲线(Time activity curve, TAC),比较不同示踪剂注射时间间隔的信号分离结果,以及两种信号分离方法的准确性。根据已知的示踪剂动力学参数和动力学模型仿真单示踪剂TACs,给TACs添加与实际动物实验相近水平的噪声,并将两种示踪剂含噪声的TACs组合成10min,20min,30min和40min示踪剂注射时间间隔的双示踪剂TACs。采用并行房室模型拟合法(Parallel compartment fitting)直接获取两示踪剂的动力学参数,或房室模型外推法(Compartment extrapolation)分离双示踪剂TAC并计算动力学参数。并行房室模型拟合法分离结果表明18F-Alfatide Ⅱ的动力学参数K1及18F-FDG的所有动力学参数几乎不受时间间隔的影响,可以被准确地计算。18F-Alfatide Ⅱ k2也较好地得到恢复,但各组准确性相差不大,其k3、k4、分布容积及结合能(Binding potential, Bp)仅在40min间隔时有较好的分离准确性。两种信号分离方法对40mmin示踪剂注射间隔数据的信号分离准确性相近。 3)进行18F-Alfatide Ⅱ/18F-FDG双示踪剂单次PET动态扫描小动物成像,研究两种分离方法对小动物成像实验数据TAC信号的分离并进行验证。通过尾静脉导管先给己接种肿瘤的小鼠注射18F-Alfatide Ⅱ,同时进行PET动态数据采集,40分钟后再通过导管给小鼠注射18F-FDG,并持续动态数据采集至90分钟。房室模型外推法首先应用于信号分离：采用三房室可逆模型拟合18F-Alfatide Ⅱ的TAC并外推至90分钟,再用双示踪剂TAC减去拟合的90分钟18F-Alfatide Ⅱ的TAC以恢复18F-FDG的TAC。为评估信号分离的可靠性,分别进行了18F-Alfatide Ⅱ和18F-FDG单示踪剂动态PET成像,比较双示踪剂和单示踪剂动态成像的TAC、肿瘤摄取以及动力学参数。结果表明两组参数有极好的显著线性相关性,从而证明该方法可以有效地恢复18F-Alfatide Ⅱ和18F-FDG信号,用于同时观察肿瘤新生血管生成和葡萄糖代谢。并行房室模型拟合法也应用于同组数据进行信号分离,结果与房室模型外推法相一致。 4)利用18F-Alfatide Ⅱ/18F-FDG双示踪剂成像方法进行肿瘤治疗监测与评估。分别给接种有人脑胶质瘤U87MG和人恶性乳腺瘤MDA-MB-435的小鼠注射多柔比星(Doxorubicin)和白蛋白结合型紫杉醇(Abraxane)进行治疗,在治疗前后进行双示踪剂动态成像,分析肿瘤摄取、18F-Alfatide Ⅱ的结合能以及18F-FDG摄取速率等动力学参数的变化。结果表明动力学定量参数比肿瘤体积变化和静态肿瘤摄取更早,更灵敏地反映了肿瘤对药物治疗的响应,且双示踪剂成像提供了比单示踪剂成像更丰富的肿瘤状态信息。
[Abstract]:Positron emission tomography (Positron Emission Tomography, PET) is one of the in vivo molecular imaging method of the ultra high sensitivity and specificity, has become an important tool for cancer research and clinical diagnosis and treatment. Using different tracers sensitive to various physiological or pharmacological characteristics of PET imaging, and can depict the pathological characteristics, including metabolism, angiogenesis, cell proliferation, blood flow and hypoxia. In view of the complexity and heterogeneity of malignant tumor, the information complement each other, can promote the understanding of the tumor, so as to improve the early diagnosis, tumor staging, treatment, evaluation of curative effect and prognosis of the monitoring accuracy. Compared to the multi tracer separate times scan mode, multi tracer single PET imaging can achieve the goal, and greatly reduce the cost, save time and reduce the radiation dose, and to avoid the To repeatedly scan the time interval between each tracer resulted in the same physiological conditions reflect the information. This paper realizes 18F- fluorodeoxyglucose in a single dynamic data collection of PET (18F-Fluorodeoxyglucose, 18F-FDG) and 18F- RGD peptide (Arg-Gly-Asp, RGD) double tracer in vivo imaging and monitoring glucose metabolism and angiogenesis, evaluated the accuracy of the double tracer signal separation method and application in tumor curative effect monitoring. The main research contents and results are as follows:
1) optimization of RGD molecular probe F-18 labeled 18F-RGD in vitro and in vivo and explore the process based on distribution characteristics. By F-18 markers (Polyethylene glycol, PEG containing polyethylene glycol) modified and PEG containing two mer RGD peptide synthesis of alpha v beta 3 integrin imaging probe, then the in vitro biological analysis, serum stability in vitro in vivo metabolic stability and analysis, in the static and dynamic imaging and biodistribution of quantitative comparison of three kinds of choice the best performance of the tracer, tracer is used to double tracer imaging, the tracer was named 18F-Alfatide II.
2) simulation of 18F-Alfatide II /18F-FDG double tracer imaging time activity curve (Time activity, curve, TAC), the separation of different signal tracer injection time interval, and the accuracy of two methods for signal separation. According to tracer kinetic parameters known and dynamic model simulation of single tracer TACs, add a similar level of noise and the actual experimental animal for TACs, and two kinds of tracers with noisy TACs combined into 10min, 20min, 30min and 40min tracer injection time interval double tracer TACs. using parallel fitting compartmental model (Parallel compartment fitting) direct access to two kinetic parameters of the tracer, or compartment model (Compartment extrapolation) separated double extrapolation method to calculate the kinetic parameters and TAC tracer parallel. Compartmental model fitting results show that separation kinetics of K1 and 18F-FDG 18F-Alfatide II The influence of all kinetic parameters is almost not influenced by the time interval, can be accurately calculated.18F-Alfatide II K2 better recovery, but each accuracy difference, K3, K4, volume of distribution and binding energy (Binding potential, Bp) with good separation accuracy only in the interval of 40min. Two kinds of signal separation method of signal separation accuracy of 40mmin tracer injection interval data are similar.
3) 18F-Alfatide II /18F-FDG dual tracer single dynamic scanning PET small animal imaging, and separation of two kinds of separation methods for small animal imaging experimental data of TAC signal is verified by tail vein catheter for mice injected with 18F-Alfatide II has been inoculated tumor, and PET dynamic data acquisition, 40 minutes after catheter to the mice injected with 18F-FDG, and the dynamic data acquisition to 90 minutes. The compartment model was first applied to the extrapolation of signal separation by TAC extrapolation and three compartment model fitting reversible 18F-Alfatide II to 90 minutes, and then the double tracer TAC minus the fitting 90 minutes of 18F-Alfatide TAC to restore 18F-FDG TAC. for reliability evaluation of signal separation. Were 18F-Alfatide II and 18F-FDG single tracer dynamic PET imaging, double and single tracer tracer dynamic imaging of TAC, tumor uptake And the kinetic parameters. The results showed that significant linear correlation between two groups of parameters are excellent, it is proved that this method can effectively restore the 18F-Alfatide II and 18F-FDG signal for simultaneous observation of tumor angiogenesis and glucose metabolism. The parallel model is used for fitting the AV signal separation in the same set of data. The results are consistent with the model extrapolation.
4) by using 18F-Alfatide /18F-FDG double tracer imaging methods for tumor therapy. Monitoring and evaluation respectively to mice inoculated with human glioma U87MG and human malignant breast tumor MDA-MB-435 doxorubicin (Doxorubicin) and albumin bound paclitaxel (Abraxane) treatment, double tracer dynamic imaging before and after treatment, tumor. Intake, combined with 18F-Alfatide II and 18F-FDG can uptake kinetic parameters. The results show that the quantitative kinetic parameters than the changes of tumor volume and tumor uptake static earlier and more sensitive to reflect the tumor response to drug treatment, and the double tracer imaging provides more information than single tumor tracer imaging.

【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R730.44

【共引文献】