【摘要】：目的近年來(lái),放射性藥物的發(fā)展十分迅速,尤其是正電子發(fā)射成像(PET)診斷藥物和放射免疫治療藥物。雙功能金屬螯合劑作為連接放射性金屬核素與功能性配體的紐帶,在放射藥物的研究中發(fā)揮著重要的作用。64Cu和68Ga是科研和臨床中兩種常用的金屬核素,目前已有多種雙功能金屬螯合劑可用于對(duì)二者的標(biāo)記。然而這些螯合劑通常需要較為苛刻的標(biāo)記條件,且對(duì)放射性金屬的選擇性低,放射比活度低等,嚴(yán)重限制了新型放射性藥物的研究。功能性配體是研究放射藥物的另一個(gè)重要的因素。受制于傳統(tǒng)單價(jià)的/單靶向和單模態(tài)的分子探針的固有屬性,很難應(yīng)對(duì)腫瘤等疾病的復(fù)雜性和多樣性。近年來(lái),多價(jià)的和多模態(tài)的新型分子探針由于它們較高的受體親和力和相互補(bǔ)充的成像能力等優(yōu)點(diǎn)而備受關(guān)注。然而它們的制備過程常常涉及到繁雜的保護(hù)和脫保護(hù)、多次HPLC純化和較低的產(chǎn)率等問題,嚴(yán)重的制約了這些分子探針的應(yīng)用和發(fā)展。針對(duì)這些問題,有必要設(shè)計(jì)并合成出一些具備標(biāo)記條件溫和,所得標(biāo)記物穩(wěn)定性高、放射比活度高等性質(zhì)的雙功能金屬螯合劑,并以之為平臺(tái)應(yīng)用于放射性藥物的研究中,這也是本研究的主要目的之一。本研究另一個(gè)主要的期望是設(shè)計(jì)并合成出一個(gè)基于雙功能金屬螯合劑結(jié)構(gòu)的通用平臺(tái)來(lái)簡(jiǎn)化多價(jià)的和多模態(tài)的分子探針的合成過程,從而促進(jìn)這一領(lǐng)域的發(fā)展。方法設(shè)計(jì)并合成三種基于NE3TA結(jié)構(gòu)的雙功能螯合劑,并將其與多肽LLP2A偶聯(lián)并分別進(jìn)行64Cu和6SGa標(biāo)記,測(cè)試其放射比活度、血漿穩(wěn)定性等性質(zhì)。利用LC-MS研究p-NO2-PhPr-NE3TA對(duì)Cu2+螯合的選擇性。測(cè)試被64Cu和68Ga標(biāo)記的分子探針在B16F10細(xì)胞中的攝取及流出情況。建立荷B16F10腫瘤小鼠模型,并將被64Cu和6SGa標(biāo)記的分子探針應(yīng)用于該模型的腫瘤靶向PET/CT顯像。接著設(shè)計(jì)并合成具有兩個(gè)不同偶聯(lián)功能基團(tuán)的雙功能金屬螯合劑NOTA2tBu-N3,然后利用該平臺(tái)將靶向uPAR的多肽AE105及靶向整合素αvβ3受體的c(RGDyk)偶聯(lián),從而制備具有不同長(zhǎng)度PEG連接基團(tuán)的多肽異源二聚體分子探針。將各異源二聚體分子探針進(jìn)行64Cu標(biāo)記后,通過細(xì)胞實(shí)驗(yàn),篩選出一個(gè)性質(zhì)較好的多肽異源二聚體分子探針,并應(yīng)用于荷U87MG腫瘤小鼠的PET/CT成像。其結(jié)果與它相應(yīng)的單聚體分子探針64Cu-AE105及64Cu-RGD的成像結(jié)果進(jìn)行比較。另外,利用NOTA2tBu-N3為平臺(tái),通過點(diǎn)擊化學(xué)或者固相合成的方法制備其他類型的分子探針,比如多肽同源二聚體和PET/光學(xué)多模態(tài)分子探針等。結(jié)果即使在十倍量Fe(Ⅲ)存在的情況下,p-NO2-PhPr-NE3TA依然能優(yōu)先與Cu(Ⅱ)進(jìn)行螯合,顯示出對(duì)Cu(Ⅱ)較高的選擇性。其多肽偶聯(lián)物NE3TA-LLP2A可在室溫下被64Cu標(biāo)記,并具備良好的血漿穩(wěn)定性,同時(shí)其放射性比活度值達(dá)3～4mCi/nmol,遠(yuǎn)高于NOTA-LLP2A的～1 mCi/nmol。雖然所合成的另外兩個(gè)雙功能金屬螯合劑與64Cu的標(biāo)記結(jié)果不理想,但p-SCN-PhPr-NE2P1A表現(xiàn)出優(yōu)秀的68Ga標(biāo)記屬性。其偶聯(lián)物NE2P1A-LLP2A可在室溫、中性的pH下在15 min內(nèi)完成6SGa標(biāo)記,且具備較好的血漿穩(wěn)定性；而在相同的條件下NOTA-LLP2A的68Ga標(biāo)記率低。64Cu-NE3TA-LLP2A和68Ga-NE2P1A-LLP2A在荷B16F10小鼠的生物分布結(jié)果類似,均在腫瘤部位有較高的攝取,且腫瘤/肌肉比值高。64Cu-NE3TA-LLP2A的腫瘤/肌肉比值在2h,4h和24 h分別達(dá)到5.81±0.99、10.50±2.02和25.19±7.78。68Ga-NE2P1A-LLP2A的腫瘤/肌肉的比值在1 h,2 h和4h分別達(dá)到6.66±1.87、10.62±2.98和10.25±1.45。將二者用于同一腫瘤模型的PET/CT成像中時(shí),在注射64Cu-NE3TA-LLP2A后的2h,4h和注射68Ga-NE2P1A-LLP2A后的1 h,2 h均能明顯分辨出腫瘤。同時(shí)注射了阻斷劑量的LLP2A的阻斷組小鼠的生物分布及PET/CT成像均充分體現(xiàn)了B16F10腫瘤對(duì)LLP2A攝取的特異性。利用NOTA2tBu-N3平臺(tái),方便地合成出四個(gè)多肽異源二聚體分子探針AE105-PEGn-NOTA-PEG4-RGD(n=0,4,8,12,分別簡(jiǎn)寫為T1, T2, T3, T4),一個(gè)多肽同源二聚體分子探針(AE105-NOTA-PEG4-AE105)及兩個(gè)PET/光學(xué)雙模態(tài)分子探針(AE 105-NOTA-nonclick-Cy3和AE105-NOTA-click-Cy5)。所有分子探針均能與64Cu在放射比活度～1 mCi/nmol下進(jìn)行標(biāo)記,且標(biāo)記后在人血漿中穩(wěn)定性較好。細(xì)胞實(shí)驗(yàn)表明,隨著PEG鏈的增長(zhǎng),各分子探針在U87MG細(xì)胞中的攝取率有逐漸增加的趨勢(shì),順序?yàn)門4T3T2≥T1,而與U87MG細(xì)胞結(jié)合的穩(wěn)定程度順序?yàn)門3T2≥T1T4。在荷U87MG裸鼠模型的生物分布試驗(yàn)中,64Cu-T3在腫瘤組織中攝取比較高,其腫瘤/肌肉比值在1 h,4 h,24 h分別為4.37±1.46,12.69±3.08,和15.47±3.32。PET/CT成像實(shí)驗(yàn)結(jié)果顯示,64Cu-T3在腫瘤中的攝取率顯著高于64Cu-RGD和64Cu-AE105。64Cu-T3的腫瘤/肌肉比值顯著高于64Cu-AE105,與64Cu-RGD接近。結(jié)論及創(chuàng)新點(diǎn)設(shè)計(jì)并合成了多個(gè)新穎的雙功能螯合劑,其中成功p-SCN-PhPr-NE3TA表現(xiàn)出對(duì)Cu(Ⅱ)較高的選擇性,且與64Cu標(biāo)記的條件溫和,放射比活度高。所合成的p-SCN-PhPr-NE2P1A是一個(gè)很好的68Ga螯合劑,可以應(yīng)用于溫度和酸敏感的生物分子的68Ga標(biāo)記。64Cu-NE3TA-LLP2A和68Ga-NE2P1A-LLP2A均對(duì)B16F10腫瘤具有出色的靶向性,在黑色素瘤的診斷中具有很好應(yīng)用前景。我們也成功的合成了一個(gè)基于雙功能螯合劑結(jié)構(gòu)的合成平臺(tái),可極大的簡(jiǎn)化多肽異源二聚體等分子探針制備過程。與其它平臺(tái)比較,我們所合成的這個(gè)平臺(tái)具有多重優(yōu)勢(shì),包括簡(jiǎn)單的合成(無(wú)需大量的保護(hù)和脫保護(hù)及反應(yīng)條件優(yōu)化過程)、簡(jiǎn)單的純化過程(需要更少的或只需一次色譜分離),更高的產(chǎn)率。更重要的是,這個(gè)平臺(tái)還可以用于制備多肽同源二聚體、PET/光學(xué)雙模態(tài)等分子探針,用途廣泛。多肽異源二聚體分子探針64Cu-T3展示了比其單聚體分子探針更高的腫瘤攝取率以及更好的體內(nèi)腫瘤成像效果�？偠灾�,這個(gè)平臺(tái)提供了一條通用和可靠的方法用于制備多模式的分子探針,并且可以作為一個(gè)模塊化的平臺(tái)用于多模式分子探針的結(jié)構(gòu)優(yōu)化或者日常的臨床前/臨床研究。
[Abstract]:Objective in recent years, the development of radiopharmaceuticals is very rapid, especially positron emission imaging (PET) for the diagnosis of drugs and radioimmunotherapies. Double functional metal chelating agents as a link between radionuclides and functional ligands, the important role of.64Cu and 68Ga in the study of radiopharmaceuticals is scientific and clinical. There are two common metallic nuclides. There are a variety of double functional metal chelating agents that can be used to mark the two. However, these chelating agents usually require more stringent labeling conditions, low selectivity to radioactive metals and low radiological activity, which seriously restrict the study of new radiative drugs. Functional ligands are the study of radiation drugs. Another important factor in objects is the inherent properties of the traditional monovalent / single target and single modal molecular probes, which are difficult to cope with the complexity and diversity of cancer and other diseases. In recent years, multivalent and multimodal molecular probes have been closely related to their higher receptor affinity and complementary imaging capabilities. However, their preparation processes often involve complex protection and deprotection, multiple HPLC purification and low yield, which seriously restrict the application and development of these molecular probes. It is necessary to design and synthesize some mild labeling conditions, high stability and high radioactivity. One of the main expectations of this study is to design and synthesize a common platform based on the structure of a bifunctional metal chelating agent to simplify the synthesis of multivalent and multimodal molecular probes. In order to promote the development of this field, three kinds of double functional chelating agents based on NE3TA structure were designed and synthesized, and they were coupled to the peptide LLP2A and were labeled with 64Cu and 6SGa respectively. The properties of their radioactivity and plasma stability were tested. LC-MS was used to study the selectivity of p-NO2-PhPr-NE3TA for Cu2+ chelation. The test was tested by 64Cu and 68Ga standard. The uptake and outflow of molecular probes in B16F10 cells were recorded. A B16F10 tumor bearing mouse model was established and the molecular probes labeled by 64Cu and 6SGa were applied to the tumor targeting PET/CT imaging of the model. Then, a dual functional metal chelating agent, NOTA2tBu-N3, with two different coupling functional groups, was designed and synthesized, and then the platform was used to make use of the platform. The polypeptide AE105 of the target uPAR and the C (RGDyk) of the target integrin alpha v beta 3 receptor were coupled to prepare a polypeptide heterogenous two polymer molecular probe with different length PEG connecting groups. After 64Cu labeling of the heterogenous two polymer molecular probes, a polypeptide heterologous two polymer molecular probe with good properties was screened and should be screened. PET/CT imaging for U87MG tumor bearing mice. The results were compared with the imaging results of its homopolymer molecular probe 64Cu-AE105 and 64Cu-RGD. In addition, using NOTA2tBu-N3 as a platform, other types of molecular probes were prepared by clicking on chemical or solid phase synthesis, such as polypeptide homopolymer two and PET/ optical multimodality Molecular probe, and so on. Even in the presence of ten times Fe (III), p-NO2-PhPr-NE3TA still preferred to chelate with Cu (II) and showed a high selectivity to Cu (II). Its polypeptide coupling NE3TA-LLP2A could be labeled at room temperature by 64Cu, and had good plasma stability, and its radioactivity value was 3 to 4mCi/nmol, Far higher than NOTA-LLP2A to 1 mCi/nmol., although the other two other bifunctional metal chelating agents synthesized were not ideal with 64Cu, p-SCN-PhPr-NE2P1A showed excellent 68Ga marker properties. The coupling agent NE2P1A-LLP2A could complete 6SGa marking at room temperature, neutral pH in 15 min, and had better plasma stability; Under the same conditions, the 68Ga marker rate of NOTA-LLP2A was low,.64Cu-NE3TA-LLP2A and 68Ga-NE2P1A-LLP2A were similar in the biological distribution of B16F10 mice, all of which were higher in the tumor site, and the tumor / muscle ratio of high.64Cu-NE3TA-LLP2A / muscle ratio in 2H, 4H and 24 h was 5.81 + 0.99,10.50 + 2.02 and 25.19 + 7.78.68Ga. The tumor / muscle ratio of -NE2P1A-LLP2A was 1 h, 2 h and 4H reached 6.66 + 1.87,10.62 + 2.98 and 10.25 + 1.45. for the same PET/CT imaging in the same tumor model. The tumor was clearly identified by the 2H, 4h, and 1 h after the injection of 68Ga-NE2P1A-LLP2A 64Cu-NE3TA-LLP2A, and 2. The biological distribution and PET/CT imaging of the block mice fully reflect the specificity of the B16F10 tumor to LLP2A uptake. Using the NOTA2tBu-N3 platform, four polypeptide heterogenous two polymer probes AE105-PEGn-NOTA-PEG4-RGD (n=0,4,8,12, respectively, T1, T2, T3, T4), a polypeptide homologous two polymer molecular probe (AE105-NOT) A-PEG4-AE105) and two PET/ optical dual mode molecular probes (AE 105-NOTA-nonclick-Cy3 and AE105-NOTA-click-Cy5). All molecular probes can be labeled with 64Cu at the radiological specific activity to 1 mCi/nmol, and the stability is better in human plasma. Cell experiments show that with the increase of PEG chain, the molecular probes are in U87MG cells. The uptake rate has a gradual increase in the order of T4T3T2 > T1, and the stability of the binding with U87MG cells is T3T2 > T1T4. in the biodistribution test of the nude mice bearing U87MG. The uptake of 64Cu-T3 in the tumor tissues is higher, and the ratio of the tumor / muscle is 1 h, 4 h, and 24 h is 4.37 + 1.46,12.69 + 3.08, and 15.47 + 3.32.PET/CT. The results of the experiment showed that the uptake rate of 64Cu-T3 in tumor was significantly higher than that of 64Cu-RGD and 64Cu-AE105.64Cu-T3. The ratio of tumor / muscle was significantly higher than that of 64Cu-AE105 and was close to 64Cu-RGD. Conclusion and innovation point design and synthesis of several novel double functional chelating agents, of which the successful p-SCN-PhPr-NE3TA showed high selectivity to Cu (II), and The conditions of the 64Cu markers are mild and the radioactivity is high. The synthesized p-SCN-PhPr-NE2P1A is a good 68Ga chelating agent, which can be applied to the 68Ga markers of temperature and acid sensitive biomolecules.64Cu-NE3TA-LLP2A and 68Ga-NE2P1A-LLP2A, both of which have excellent targeting of the B16F10 tumor, and have a good prospect in the diagnosis of melanoma. We have also successfully synthesized a biosynthesis platform based on the structure of a dual functional chelating agent, which can greatly simplify the preparation of molecular probes such as polypeptides, heterogenous two polymers. Compared with other platforms, the platform has multiple advantages, including simple synthesis (without a large amount of protection and deprotection and optimization of reaction conditions. A simple purification process (requiring less or only one chromatographic separation), higher yield, and more importantly, the platform can also be used to prepare polypeptide homooligomers, PET/ optical dual mode and other molecular probes, widely used. The polypeptide heteropolymer molecular probe 64Cu-T3 exhibits a higher tumor uptake than its monopolymer molecular probe. In summary, this platform provides a general and reliable method for preparing multimodal molecular probes, and can be used as a modular platform for structural optimization of multi mode molecular probes or daily pre bed / clinical studies.
【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】：2016
【分類號(hào)】：R981

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