本文選題：正電子發(fā)射斷層成像(PET)　切入點(diǎn)：多示蹤劑動(dòng)態(tài)成像　出處：《華中科技大學(xué)》2014年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：正電子發(fā)射斷層成像(Positron Emission Tomography, PET)是當(dāng)前超高靈敏度和特異性的活體分子成像方法之一,己成為腫瘤研究和臨床診斷與治療的重要工具。采用對(duì)各生理或藥理特征變化敏感的不同示蹤劑進(jìn)行PET成像,可刻畫(huà)腫瘤病理各方面特征,包括代謝、新生血管生成、細(xì)胞增殖、血流和乏氧等。鑒于惡性腫瘤的復(fù)雜性和不均一性,這些信息互相補(bǔ)充,可以促進(jìn)對(duì)腫瘤的深入理解,從而提高腫瘤早期診斷、分期、治療、療效監(jiān)測(cè)及預(yù)后評(píng)估的準(zhǔn)確性。相比于多示蹤劑分開(kāi)進(jìn)行多次掃描的方式,多示蹤劑單次PET掃描成像可以實(shí)現(xiàn)該目標(biāo),同時(shí)極大減少費(fèi)用、節(jié)省時(shí)間和減少輻射劑量,并避免由于多次掃描之間的時(shí)間間隔而導(dǎo)致不能得到各示蹤劑在同一生理?xiàng)l件下反映的信息。本論文在單次動(dòng)態(tài)PET數(shù)據(jù)采集中實(shí)現(xiàn)18F-氟脫氧葡萄糖(18F-Fluorodeoxyglucose,18F-FDG)和18F-精-甘-天冬氨酸肽(Arg-Gly-Asp, RGD)雙示蹤劑活體成像同時(shí)監(jiān)測(cè)腫瘤的葡萄糖代謝和新生血管生成,評(píng)估了雙示蹤劑信號(hào)分離方法的準(zhǔn)確性并應(yīng)用于腫瘤療效監(jiān)控。主要研究?jī)?nèi)容和成果如下： 1)優(yōu)化基于RGD分子探針F-18標(biāo)記過(guò)程并探討18F-RGD體外及活體分布特性。通過(guò)F-18標(biāo)記含聚乙二醇(Polyethylene glycol, PEG)修飾和不含PEG修飾的二聚體RGD肽合成αvβ3整合素成像探針,然后進(jìn)行離體生物結(jié)合分析、離體血清穩(wěn)定性和在體代謝穩(wěn)定性分析、在體靜態(tài)和動(dòng)態(tài)成像定量以及生物分布實(shí)驗(yàn)比較三種示蹤劑,選擇性能最佳的示蹤劑用于雙示蹤劑成像,該示蹤劑被命名為18F-Alfatide Ⅱ。 2)仿真18F-Alfatide Ⅱ/18F-FDG雙示蹤劑成像時(shí)間活度曲線(xiàn)(Time activity curve, TAC),比較不同示蹤劑注射時(shí)間間隔的信號(hào)分離結(jié)果,以及兩種信號(hào)分離方法的準(zhǔn)確性。根據(jù)已知的示蹤劑動(dòng)力學(xué)參數(shù)和動(dòng)力學(xué)模型仿真單示蹤劑TACs,給TACs添加與實(shí)際動(dòng)物實(shí)驗(yàn)相近水平的噪聲,并將兩種示蹤劑含噪聲的TACs組合成10min,20min,30min和40min示蹤劑注射時(shí)間間隔的雙示蹤劑TACs。采用并行房室模型擬合法(Parallel compartment fitting)直接獲取兩示蹤劑的動(dòng)力學(xué)參數(shù),或房室模型外推法(Compartment extrapolation)分離雙示蹤劑TAC并計(jì)算動(dòng)力學(xué)參數(shù)。并行房室模型擬合法分離結(jié)果表明18F-Alfatide Ⅱ的動(dòng)力學(xué)參數(shù)K1及18F-FDG的所有動(dòng)力學(xué)參數(shù)幾乎不受時(shí)間間隔的影響,可以被準(zhǔn)確地計(jì)算。18F-Alfatide Ⅱ k2也較好地得到恢復(fù),但各組準(zhǔn)確性相差不大,其k3、k4、分布容積及結(jié)合能(Binding potential, Bp)僅在40min間隔時(shí)有較好的分離準(zhǔn)確性。兩種信號(hào)分離方法對(duì)40mmin示蹤劑注射間隔數(shù)據(jù)的信號(hào)分離準(zhǔn)確性相近。 3)進(jìn)行18F-Alfatide Ⅱ/18F-FDG雙示蹤劑單次PET動(dòng)態(tài)掃描小動(dòng)物成像,研究?jī)煞N分離方法對(duì)小動(dòng)物成像實(shí)驗(yàn)數(shù)據(jù)TAC信號(hào)的分離并進(jìn)行驗(yàn)證。通過(guò)尾靜脈導(dǎo)管先給己接種腫瘤的小鼠注射18F-Alfatide Ⅱ,同時(shí)進(jìn)行PET動(dòng)態(tài)數(shù)據(jù)采集,40分鐘后再通過(guò)導(dǎo)管給小鼠注射18F-FDG,并持續(xù)動(dòng)態(tài)數(shù)據(jù)采集至90分鐘。房室模型外推法首先應(yīng)用于信號(hào)分離：采用三房室可逆模型擬合18F-Alfatide Ⅱ的TAC并外推至90分鐘,再用雙示蹤劑TAC減去擬合的90分鐘18F-Alfatide Ⅱ的TAC以恢復(fù)18F-FDG的TAC。為評(píng)估信號(hào)分離的可靠性,分別進(jìn)行了18F-Alfatide Ⅱ和18F-FDG單示蹤劑動(dòng)態(tài)PET成像,比較雙示蹤劑和單示蹤劑動(dòng)態(tài)成像的TAC、腫瘤攝取以及動(dòng)力學(xué)參數(shù)。結(jié)果表明兩組參數(shù)有極好的顯著線(xiàn)性相關(guān)性,從而證明該方法可以有效地恢復(fù)18F-Alfatide Ⅱ和18F-FDG信號(hào),用于同時(shí)觀(guān)察腫瘤新生血管生成和葡萄糖代謝。并行房室模型擬合法也應(yīng)用于同組數(shù)據(jù)進(jìn)行信號(hào)分離,結(jié)果與房室模型外推法相一致。 4)利用18F-Alfatide Ⅱ/18F-FDG雙示蹤劑成像方法進(jìn)行腫瘤治療監(jiān)測(cè)與評(píng)估。分別給接種有人腦膠質(zhì)瘤U87MG和人惡性乳腺瘤MDA-MB-435的小鼠注射多柔比星(Doxorubicin)和白蛋白結(jié)合型紫杉醇(Abraxane)進(jìn)行治療,在治療前后進(jìn)行雙示蹤劑動(dòng)態(tài)成像,分析腫瘤攝取、18F-Alfatide Ⅱ的結(jié)合能以及18F-FDG攝取速率等動(dòng)力學(xué)參數(shù)的變化。結(jié)果表明動(dòng)力學(xué)定量參數(shù)比腫瘤體積變化和靜態(tài)腫瘤攝取更早,更靈敏地反映了腫瘤對(duì)藥物治療的響應(yīng),且雙示蹤劑成像提供了比單示蹤劑成像更豐富的腫瘤狀態(tài)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.

【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R730.44

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