靶向磁共振成像造影剂的合成及其在癌症早期诊断中的应用
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摘要
核磁共振成像(MRI)是一种非侵害性的诊断方法,用于临床医学上评估人体解剖结构和组织或器官的功能。最近,MRI的一些新应用,如在基因表达成像上,在体内药物传递的实时评价等方面引起了研究者的极大兴趣。MRI技术有其独特的优点如分辨率高、无放射性辐射、长效成像等。但是,当用来监测微小组织的病灶、分子活动或者细胞活动时灵敏度并不高。通过采用顺磁性小分子造影剂Gd-DTPA或者Gd-DOTA等可以帮助提高成像的灵敏度和对比度。这是因为小分子造影剂可以缩短水质子的纵向弛豫时间(T1),使T1加权成像的图像亮度提高。Gd-DTPA和Gd-DOTA等几种小分子MRI造影剂已经得到了美国食品和药品管理局的批准,并且被广泛应用在临床肿瘤的诊断中。然而,这些小分子造影剂存在严重的问题,例如血液半衰期短、弛豫率低、对器官或组织缺少靶向特异性等,因此无法对早期肿瘤进行诊断,这就限制了它们的应用。为了使用MRI造影剂对肿瘤进行早期诊断,研究人员一直努力开发大分子造影剂,如通过将DTPA或其他小分子配体与高分子载体链接可制备大分子造影剂。高分子如聚乙二醇、右旋糖酐、聚赖氨酸、聚谷氨酸、聚酰胺、α，β-聚[(2-氨乙基)-L-天冬酰胺]、可生物降解聚合物、树状聚合物以及大分子胶束等已被用作造影剂的大分子载体。与小分子造影剂相比,大分子MRI造影剂显示出前所未有的优点,如对比度的增强、敏感度的提高、诊断成像时间的延长等。另外,通过将靶向基团如叶酸、抗体或小分子肽链接到造影剂上,还可以制备对肿瘤组织有特异性的靶向造影剂,特别适用于肿瘤早期诊断。
本论文制备了两种靶向MRI造影剂用于肿瘤的早期诊断：一是以树状大分子PAMAM为核心的FA-PEG-PAMAM-Gd肺癌靶向MRI大分子造影剂；另一种是具有肝癌靶向功能的Pep-PEG-g-PAA-(DTTA-Gd)聚合物胶束MRI造影剂。
在第一种造影剂的制备过程中没有使用小分子配体。因为考虑到小分子配体的使用将增加制造成本,从而影响其批量应用。FA-PEG-PAMAM-Gd大分子MRI造影剂是以含32个端羧基的PAMAM-COOH为核,用聚乙二醇-叶酸(聚乙二醇的分子量分别为1000,2000和4000 Da)修饰端羧基,然后再与钆离子络合形成的大分子螯合物。大分子配体FA-PEG-PAMAM-COOH的结构通过核磁共振、红外以及质谱进行表征；FA-PEG-PAMAM-Gd造影剂中钆含量通过ICP-AES测定。大分子造影剂的粒径通过透射电镜表征大约在70 nm左右,这意味着它们对肿瘤具有被动靶向性。与小分子商用造影剂相比,FA-PEG-PAMAM-Gd表现出较低的毒性和高弛豫率。因该造影剂以叶酸为靶向基团,为此我们评价了其对A549实体肿瘤的靶向性。另外,也评价了该造影剂的毒性以及对小鼠体内各器官,如心脏、肝脏、肾脏的MRI增强效果。使用Siemens Tim Tri MRI扫描仪跟踪其代谢过程。结果表明FA-PEG-PAMAM-Gd造影剂的最低检测浓度比小分子造影剂低15倍左右,弛豫率比小分子造影剂高10倍左右FA-PEG4k-PAMAM-Gd的MRI影像显示出长效肿瘤信号增强效果,可以很好的显现5毫米左右的A549实体肿瘤。FA-PEG4k-PAMAM-Gd树状大分子MRI造影剂对KB细胞和A549细胞高度富集,将来可用于分子靶向造影。
然而,MRI造影剂的最大风险在于从配体中游离出的钆离子。游离的钆离子将引起肾源性系统纤维化或者急性金属中毒。临床上对造影剂的安全性要求较高。聚合物胶束MRI造影剂可在体内分散成共聚物分子,这些共聚物分子经过一段时间可以经肾脏等途径完全排出体外,所以此类造影剂的毒性较低,安全性较好。研究还发现,聚合物胶束MRI造影剂在靶向肿瘤的特定时间内表现出优先的动力学性能,而且在血液中的稳定性很好。
基于聚合物胶束MRI造影剂的优点,本论文合成了第二种造影剂,其合成步骤简述如下：MAL-PEG-NH2 (PEG分子量为2000 Da,MAL是6-(马来酰亚胺基)己酸琥珀酰亚胺酯的英文缩写)和叠氮丙胺分别连续开环聚天冬酰亚胺(PSI)得到MAL-PEG-g-PAA-N3接枝共聚物。然后再利用DTTA的炔基衍生物DTTA-der与MAL-PEG-g-PAA-N3发生Click反应得到共聚物MAL-PEG-g-PAA-DTTA,脱除DTTA-der上羧基的叔丁酯保护基团就得到大分子配体MAL-PEG-g-PAA-DTTA-COOH。该配体再与靶向基团-小分子肽(Pep)进行反应得到含有靶向基团的大分子配体Pep-PEG-g-PAA-DTTA-COOH。目标产物Pep-PEG-g-PAA-(DTTA-Gd)聚合物胶束是通过Pep-PEG-g-PAA-DTTA-COOH和钆离子络合反应得到。然后通过荧光光谱验证其胶束的形成；通过测量粒径大小验证其粒径的纳米尺度；透射电镜试验结果表明该螯合物呈壳核状球形胶束结构,粒径在50-80 nm之间,分布窄,意味着它们将具有肿瘤被动靶向性。随着PEG接枝量的增加,Pep-PEG-g-PAA-(DTTA-Gd)纳米胶束粒径呈增大趋势。与小分子造影剂Gd-DTPA相比,Pep-PEG-g-PAA-(DTTA-Gd)纳米胶束MRI造影剂的毒性小,生物相容性好,在低浓度时仍然表现出较好的T1加权成像增强效果。靶向性试验表明Pep-PEG-g-PAA-(DTTA-Gd)造影剂对肝癌实体肿瘤具有良好的靶向性,可以清晰呈现直径5mm左右的实体肿瘤。这样的试验结果表明了Pep-PEG-g-PAA-(DTTA-Gd)作为靶向MRI造影剂的可行性。
Magnetic resonance imaging (MRI) is currently one of the most useful noninvasive techniques in clinic for assessing anatomy and function of tissues and organs. The novel applications such as imaging of gene expression and real-time evaluation for drug delivery in vivo are actively studied. This technique is characterized by its excellent temporal and spatial resolution, its non-exposure to radiation and long effective imaging windows. However, MRI is less sensitive than nuclear medicine when used to monitor small tissue lesions, molecular activity, or cellular activities. With the appilication of paramagnetic contrast agents such as chelated Gd-diethylenetriaminepentaacetate (Gd-DTPA) or Gd-tetraazacyclododecanetetraacetic acid (Gd-DOTA), the imaging contrast and sensitivity can be increased by shortening the T1-relaxation time of water protons, and thus the tumor image appears brighter in the T1-weighted image. Several kinds of low molecular MRI contrast agents based on Gd-DTPA and Gd-DOTA have been approved by American Food and Drug Administration and widely used in clinical diagnosis of tumors. However, these low molecular weight contrast agents have serious drawbacks which limit their application for MRI contrast agents, such as short half-life in blood, low relaxivity rate, and lack of specificity to target organs and tissues for early diagnosis of tumor. To overcome the above disadvantages and achieve the early diagnosis of tumors, macromolecular MRI contrast agents have been developed by the conjugation of DTPA or other chelating units and polymer carriers. Polymers such as poly (ethylene glycol) (PEG), dextran, poly (L-lysine), poly (glutamic acid), poly [N-(2-hydroxypropyl) methacrylamide],α,β-poly [N-(2-aminoethyl) aspartamide], disulfide-based biodegradable synthetic polymers, dendrimer and polymeric micelles have been investigated as the carriers of gadolinium complexes. Macromolecular MRI contrast agents showed increased contrast, sensitivity, diagnostic imaging time, and specificity to tumor tissues for early dignosis after conjugated with targeting moieties such as folate, antibody or peptide.
In this study, we prepared two kinds of MRI contrast agents. One is FA-PEG-PAMAM-Gd nanoparticles as potential lung cancer-targeted macromolecular MRI contrast agent. Another one is polymer-gadolinium complex nanomicelle of Pep-PEG-g-PAA-(DTTA-Gd) as MRI contrast agent for early diagnosis of liver cancer.
FA-PEG-PAMAM-Gd MRI contrast agent was prepared without using low molecular ligands for the reason of increased cost in clinical applications. In particular, poly (amidoamine) (PAMAM) dendrimer with 32 carboxylic groups was modified with folate-conjugated poly (ethyleneglycol) amine (FA-PEG-NH2, Mw:1 k,2 k and 4 kDa). FA-PEG-PAMAM-Gd macromolecular MRI contrast agents were prepared by the complex reaction between the carboxylic groups in PAMAM and GdCl3. The structure of FA-PEG-PAMAM-COOH was confirmed by nuclear magnetic resonance (1H NMR), Fourier transform infrared (FT IR) spectra and electrospray ionization mass spectra (ESI-MS). The mass percentage content of Gd (Ⅲ) in FA-PEG-PAMAM-Gd was measured by inductively coupled plasma-atomic emission spectrometer (ICP-AES). The sizes of these nanoparticles were about 70 nm measured by transmission electron microscopy (TEM), suggesting their passive targeting potential to tumor tissue. In comparison with small molecular available in clinc, Gadopentetate dimeglumine, FA-PEG-PAMAM-Gd showed comparable cytotoxicity and higher relaxation rate. The prepared samples, with folic acid as the targeting group, were evaluated for their potentiality as tumor-targeting MRI contrast agents. A Siemens Tim Trio human MRI scanner at 3 T was used to test the concentration detection limits in vitro, contrast-enhanced MR imaging in the heart, kidney, and liver of mice and the metabolism action of FA-PEG-PAMAM-Gd. A transmission electron microscopy was used to determine the targeting to tumor cells. The toxicity was also assayed to evaluate the biocompatibility. The minimal detectable concentration for FA-PEG4k-PAMAM-Gd (PEG:4000 Da) was more than 15-fold lower than that for the commercially available contrast agent Gadopentetate dimeglumine. MRI images showed a gradual and prolonged tumor signal enhancement for FA-PEG4k-PAMAM-Gd. Millimeter-sized (-5 mm) tumors were well-visualized using the same agent. Our results indicate that the dendritic contrast agents, FA-PEG-PAMAM-Gd, have bonded highly to both KB and A549 cell lines, and the molecule targeting can be monitored by them in future.
However, the greatest risk from MRI contrast agents is the release of gadolinium from the chelate, which can lead to nephrogenic systemic fibrosis or acute metal toxicity. To decrease the toxicity of contrast agents, very recently, much attention was focused on polymeric nanomicelle MRI contrast agents. The polymeric nanomicelle MRI contrast agents can be dissociated into copolymer chains and excreted from kidney over a period, and so the toxicity could be reduced. In addition, polymeric nanomicelle MRI contrast agents exhibit a preferential pharmacokinetic profile during targeting of tumors, and their high structural stability in the bloodstream.
Another polymeric nanomicelle MRI contrast agent, Poly (ethylene glycol)-graft-α,β-poly (aspartic acid) derivatives (MAL-PEG-g-PAA-N3), were synthesized by sequential ring-opening reaction of polysuccinimide (PSI) with MAL-PEG-NH2 (PEG:2000 Da, MAL: N-(6-Maleimidocaproyloxy) succinimide) and 1-azido-3-aminopropane, respectively. Then N2-(hex-5-yne)-diethylenetriamine-tetra-t-butylacetate (DTTA-der) was conjugated to MAL-PEG-g-PAA-N3 by click cycloaddition. After deprotection of carboxylic groups, MAL-PEG-g-PAA-DTTA-COOH macromolecular ligands were obtained, which were then conjugated with targeting groups of peptides. Pep-PEG-g-PAA-(DTTA-Gd) (Pep:peptide) complex nanomicelles were fabricated from Pep-PEG-g-PAA-DTTA-COOH and gadolinium chloride. The formation of nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. All the nanomicelles showed spherical shapes with core-shell structures and narrow size distributions. Their sizes ranged from 50 to 80 nm, suggesting their passive targeting potential to tumor tissue. With the increase of graft degree (GD) of PEG, the sizes of Pep-PEG-g-PAA-(DTTA-Gd) nanomicelles showed a tendency to increase. Compared with gadopentetate dimeglumine (Gd-DTPA), Pep-PEG-g-PAA-(DTTA-Gd) nanomicelles showed decreased cytotoxicity, good biocompatibility and enhanced T1-weighted signal intensity, especially at low concentration of gadolinium (Ⅲ). Tumors with diameter of 5 mm were well-visualized using this contrast agent suggesting their great potentiality as MRI contrast agents.
本论文制备了两种靶向MRI造影剂用于肿瘤的早期诊断：一是以树状大分子PAMAM为核心的FA-PEG-PAMAM-Gd肺癌靶向MRI大分子造影剂；另一种是具有肝癌靶向功能的Pep-PEG-g-PAA-(DTTA-Gd)聚合物胶束MRI造影剂。
在第一种造影剂的制备过程中没有使用小分子配体。因为考虑到小分子配体的使用将增加制造成本,从而影响其批量应用。FA-PEG-PAMAM-Gd大分子MRI造影剂是以含32个端羧基的PAMAM-COOH为核,用聚乙二醇-叶酸(聚乙二醇的分子量分别为1000,2000和4000 Da)修饰端羧基,然后再与钆离子络合形成的大分子螯合物。大分子配体FA-PEG-PAMAM-COOH的结构通过核磁共振、红外以及质谱进行表征；FA-PEG-PAMAM-Gd造影剂中钆含量通过ICP-AES测定。大分子造影剂的粒径通过透射电镜表征大约在70 nm左右,这意味着它们对肿瘤具有被动靶向性。与小分子商用造影剂相比,FA-PEG-PAMAM-Gd表现出较低的毒性和高弛豫率。因该造影剂以叶酸为靶向基团,为此我们评价了其对A549实体肿瘤的靶向性。另外,也评价了该造影剂的毒性以及对小鼠体内各器官,如心脏、肝脏、肾脏的MRI增强效果。使用Siemens Tim Tri MRI扫描仪跟踪其代谢过程。结果表明FA-PEG-PAMAM-Gd造影剂的最低检测浓度比小分子造影剂低15倍左右,弛豫率比小分子造影剂高10倍左右FA-PEG4k-PAMAM-Gd的MRI影像显示出长效肿瘤信号增强效果,可以很好的显现5毫米左右的A549实体肿瘤。FA-PEG4k-PAMAM-Gd树状大分子MRI造影剂对KB细胞和A549细胞高度富集,将来可用于分子靶向造影。
然而,MRI造影剂的最大风险在于从配体中游离出的钆离子。游离的钆离子将引起肾源性系统纤维化或者急性金属中毒。临床上对造影剂的安全性要求较高。聚合物胶束MRI造影剂可在体内分散成共聚物分子,这些共聚物分子经过一段时间可以经肾脏等途径完全排出体外,所以此类造影剂的毒性较低,安全性较好。研究还发现,聚合物胶束MRI造影剂在靶向肿瘤的特定时间内表现出优先的动力学性能,而且在血液中的稳定性很好。
基于聚合物胶束MRI造影剂的优点,本论文合成了第二种造影剂,其合成步骤简述如下：MAL-PEG-NH2 (PEG分子量为2000 Da,MAL是6-(马来酰亚胺基)己酸琥珀酰亚胺酯的英文缩写)和叠氮丙胺分别连续开环聚天冬酰亚胺(PSI)得到MAL-PEG-g-PAA-N3接枝共聚物。然后再利用DTTA的炔基衍生物DTTA-der与MAL-PEG-g-PAA-N3发生Click反应得到共聚物MAL-PEG-g-PAA-DTTA,脱除DTTA-der上羧基的叔丁酯保护基团就得到大分子配体MAL-PEG-g-PAA-DTTA-COOH。该配体再与靶向基团-小分子肽(Pep)进行反应得到含有靶向基团的大分子配体Pep-PEG-g-PAA-DTTA-COOH。目标产物Pep-PEG-g-PAA-(DTTA-Gd)聚合物胶束是通过Pep-PEG-g-PAA-DTTA-COOH和钆离子络合反应得到。然后通过荧光光谱验证其胶束的形成；通过测量粒径大小验证其粒径的纳米尺度；透射电镜试验结果表明该螯合物呈壳核状球形胶束结构,粒径在50-80 nm之间,分布窄,意味着它们将具有肿瘤被动靶向性。随着PEG接枝量的增加,Pep-PEG-g-PAA-(DTTA-Gd)纳米胶束粒径呈增大趋势。与小分子造影剂Gd-DTPA相比,Pep-PEG-g-PAA-(DTTA-Gd)纳米胶束MRI造影剂的毒性小,生物相容性好,在低浓度时仍然表现出较好的T1加权成像增强效果。靶向性试验表明Pep-PEG-g-PAA-(DTTA-Gd)造影剂对肝癌实体肿瘤具有良好的靶向性,可以清晰呈现直径5mm左右的实体肿瘤。这样的试验结果表明了Pep-PEG-g-PAA-(DTTA-Gd)作为靶向MRI造影剂的可行性。
Magnetic resonance imaging (MRI) is currently one of the most useful noninvasive techniques in clinic for assessing anatomy and function of tissues and organs. The novel applications such as imaging of gene expression and real-time evaluation for drug delivery in vivo are actively studied. This technique is characterized by its excellent temporal and spatial resolution, its non-exposure to radiation and long effective imaging windows. However, MRI is less sensitive than nuclear medicine when used to monitor small tissue lesions, molecular activity, or cellular activities. With the appilication of paramagnetic contrast agents such as chelated Gd-diethylenetriaminepentaacetate (Gd-DTPA) or Gd-tetraazacyclododecanetetraacetic acid (Gd-DOTA), the imaging contrast and sensitivity can be increased by shortening the T1-relaxation time of water protons, and thus the tumor image appears brighter in the T1-weighted image. Several kinds of low molecular MRI contrast agents based on Gd-DTPA and Gd-DOTA have been approved by American Food and Drug Administration and widely used in clinical diagnosis of tumors. However, these low molecular weight contrast agents have serious drawbacks which limit their application for MRI contrast agents, such as short half-life in blood, low relaxivity rate, and lack of specificity to target organs and tissues for early diagnosis of tumor. To overcome the above disadvantages and achieve the early diagnosis of tumors, macromolecular MRI contrast agents have been developed by the conjugation of DTPA or other chelating units and polymer carriers. Polymers such as poly (ethylene glycol) (PEG), dextran, poly (L-lysine), poly (glutamic acid), poly [N-(2-hydroxypropyl) methacrylamide],α,β-poly [N-(2-aminoethyl) aspartamide], disulfide-based biodegradable synthetic polymers, dendrimer and polymeric micelles have been investigated as the carriers of gadolinium complexes. Macromolecular MRI contrast agents showed increased contrast, sensitivity, diagnostic imaging time, and specificity to tumor tissues for early dignosis after conjugated with targeting moieties such as folate, antibody or peptide.
In this study, we prepared two kinds of MRI contrast agents. One is FA-PEG-PAMAM-Gd nanoparticles as potential lung cancer-targeted macromolecular MRI contrast agent. Another one is polymer-gadolinium complex nanomicelle of Pep-PEG-g-PAA-(DTTA-Gd) as MRI contrast agent for early diagnosis of liver cancer.
FA-PEG-PAMAM-Gd MRI contrast agent was prepared without using low molecular ligands for the reason of increased cost in clinical applications. In particular, poly (amidoamine) (PAMAM) dendrimer with 32 carboxylic groups was modified with folate-conjugated poly (ethyleneglycol) amine (FA-PEG-NH2, Mw:1 k,2 k and 4 kDa). FA-PEG-PAMAM-Gd macromolecular MRI contrast agents were prepared by the complex reaction between the carboxylic groups in PAMAM and GdCl3. The structure of FA-PEG-PAMAM-COOH was confirmed by nuclear magnetic resonance (1H NMR), Fourier transform infrared (FT IR) spectra and electrospray ionization mass spectra (ESI-MS). The mass percentage content of Gd (Ⅲ) in FA-PEG-PAMAM-Gd was measured by inductively coupled plasma-atomic emission spectrometer (ICP-AES). The sizes of these nanoparticles were about 70 nm measured by transmission electron microscopy (TEM), suggesting their passive targeting potential to tumor tissue. In comparison with small molecular available in clinc, Gadopentetate dimeglumine, FA-PEG-PAMAM-Gd showed comparable cytotoxicity and higher relaxation rate. The prepared samples, with folic acid as the targeting group, were evaluated for their potentiality as tumor-targeting MRI contrast agents. A Siemens Tim Trio human MRI scanner at 3 T was used to test the concentration detection limits in vitro, contrast-enhanced MR imaging in the heart, kidney, and liver of mice and the metabolism action of FA-PEG-PAMAM-Gd. A transmission electron microscopy was used to determine the targeting to tumor cells. The toxicity was also assayed to evaluate the biocompatibility. The minimal detectable concentration for FA-PEG4k-PAMAM-Gd (PEG:4000 Da) was more than 15-fold lower than that for the commercially available contrast agent Gadopentetate dimeglumine. MRI images showed a gradual and prolonged tumor signal enhancement for FA-PEG4k-PAMAM-Gd. Millimeter-sized (-5 mm) tumors were well-visualized using the same agent. Our results indicate that the dendritic contrast agents, FA-PEG-PAMAM-Gd, have bonded highly to both KB and A549 cell lines, and the molecule targeting can be monitored by them in future.
However, the greatest risk from MRI contrast agents is the release of gadolinium from the chelate, which can lead to nephrogenic systemic fibrosis or acute metal toxicity. To decrease the toxicity of contrast agents, very recently, much attention was focused on polymeric nanomicelle MRI contrast agents. The polymeric nanomicelle MRI contrast agents can be dissociated into copolymer chains and excreted from kidney over a period, and so the toxicity could be reduced. In addition, polymeric nanomicelle MRI contrast agents exhibit a preferential pharmacokinetic profile during targeting of tumors, and their high structural stability in the bloodstream.
Another polymeric nanomicelle MRI contrast agent, Poly (ethylene glycol)-graft-α,β-poly (aspartic acid) derivatives (MAL-PEG-g-PAA-N3), were synthesized by sequential ring-opening reaction of polysuccinimide (PSI) with MAL-PEG-NH2 (PEG:2000 Da, MAL: N-(6-Maleimidocaproyloxy) succinimide) and 1-azido-3-aminopropane, respectively. Then N2-(hex-5-yne)-diethylenetriamine-tetra-t-butylacetate (DTTA-der) was conjugated to MAL-PEG-g-PAA-N3 by click cycloaddition. After deprotection of carboxylic groups, MAL-PEG-g-PAA-DTTA-COOH macromolecular ligands were obtained, which were then conjugated with targeting groups of peptides. Pep-PEG-g-PAA-(DTTA-Gd) (Pep:peptide) complex nanomicelles were fabricated from Pep-PEG-g-PAA-DTTA-COOH and gadolinium chloride. The formation of nanomicelles was confirmed by fluorescence spectrophotoscopy and particle size measurements. All the nanomicelles showed spherical shapes with core-shell structures and narrow size distributions. Their sizes ranged from 50 to 80 nm, suggesting their passive targeting potential to tumor tissue. With the increase of graft degree (GD) of PEG, the sizes of Pep-PEG-g-PAA-(DTTA-Gd) nanomicelles showed a tendency to increase. Compared with gadopentetate dimeglumine (Gd-DTPA), Pep-PEG-g-PAA-(DTTA-Gd) nanomicelles showed decreased cytotoxicity, good biocompatibility and enhanced T1-weighted signal intensity, especially at low concentration of gadolinium (Ⅲ). Tumors with diameter of 5 mm were well-visualized using this contrast agent suggesting their great potentiality as MRI contrast agents.
引文
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