~（99）Tc~m标记2PEG_4修饰RGD二聚体在神经胶质瘤动物模型的实验研究
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摘要
目的：
RGD多肽(RGD：含有氨基酸序列Arg-GIy-Asp的一小肽段的缩写)能与整合素αvβ特异性结合,从而进行肿瘤的诊断和治疗。为增强RGD多肽与整合素αvβ结合的亲和力,提高肿瘤对标记探针的摄取,我们在前期研究的基础上,对RGD二聚体进行结构改造,以联肼尼克酰胺(HYNIC)为双功能连接剂,N-三(羟甲基)甲基甘氨酸(tricine)和三苯基磷三磺酸钠(TPPTS)为协同配体(coligand),制备了99Tcm示记的由2PEG4修饰的RGD二聚体(Dimer:E[c(RGDfK)]2):99Tcm-HYNIC-2PEG4-Dimer,并与99Tcm-HYNIC-Dimer:进行比较,期望2PEG4的引入能有效改善标记探针的药代动力学性质,降低其在正常组织的摄取。
方法：
用免疫组化实验方法测定U87MG人神经胶质瘤细胞以及肿瘤组织中的整合素αvβ3的表达。通过U87MG细胞受体竞争结合实验测定RGD环肽单体c(RGDyK). HYNIC(联肼尼克酰胺)-Dimer和HYNIC-2PEG4-Dimer对125I-c(RGDyK)的半数抑制浓度(IC50)值。采用无亚锡一步法制备99Tcm-HYNIC-2PEG4-Dimer和99Tcm-HYNIC-Dimer,并测定各自的标记率和放化纯。评价99Tcm-HYNIC-2PEG4-Dimer和99Tcm-HYNIC-Dimer在荷U87MG瘤裸鼠的生物分布,进行γ显像。采用非配对t检验法对实验数据进行分析。
结果
免疫组化实验结果证实：在U87MG细胞和荷瘤裸鼠肿瘤组织中高表达整合素αvβ。HYNIC-2PEG4-Dimer比c(RGDyK)和IYNIC-Dimer有更高的整合素αvβ3亲和力(IC50值分别是0.8 nmol/L、27 nmol/L和2.4 nmol/L)。99Tcm-HYNIC-Dimer和99Tcm-HYNIC-2PEG4-Dimer的99Tcm标记率均>95%,经Sep-Pek C18柱纯化后其放化纯>99%。生物分布实验显示,两种标记物均主要经肾脏排泄,在注射后2 h,肿瘤对99Tcm-HYNIC-2PEG4-Dimer的摄取为99Tcm-HYNIC-Dimer的2.7倍(5.71±0.96%ID/g V.S.2.10±0.50%ID/g),摄取显著增高(t=4.80,P<0.05),与体外受体竞争结合实验数据相一致。γ显像结果显示,注射后99Tcm-HYNIC-2PEG4-Dimer 0.5h肿瘤即清晰可见,随时间延长,体内放射性本底明显减低,显像对比度增高。
结论
99Tcm-HYNIC-2PEG4-Dimer与整合素αvβ3的结合亲和力更高,肿瘤对其的摄取摄取率更高,是一个有应用前景的用于整合素αvβ3阳性肿瘤显像的放射性示踪剂。
Objective
RGD peptide (containing amino acid sequence Arg-Gly-Asp of a small peptide abbreviation) can specifically bind with the integrinαvβ3, which for the diagnosis and treatment of cancer. To enhance the RGD peptide and integrinαvβ3 binding affinity, and increase tumor uptake of the labeled probe, On the basis of preliminary studies on the RGD dimer structural transformation, we using joint hydrazine nicotinamide (HYNIC) as bifunctional agent, N-tris (hydroxymethyl) methyl glycine (tricine) and triphenylphosphine three sulfonate (TPPTS) as ligand coordination (coligand), prepared the 2PEG4 99Tcm-modified RGD dimer (Dimer:E [c (RGDfK)] 2): 99Tcm-HYNIC-2PEG4-Dimer, and with 99Tcm-HYNIC-Dimer comparison, expecting 2PEG4 can effectively improve the pharmacokinetic properties, reducing its normal tissue uptake.
Methods
The expression of integrinαvβ3 in the U87 human glioma cells as well as tumor tissues were determined by immunofluorescence staining. The 50% inhibitory concentration (IC50) values of c(RGDyK), HYNIC-Dimer and HYNIC-2PEG4-Dimer were determined on U87 human glioma cells with 125I-c(RGDyK) as the integrinαvβ3-pecific radiotracer。99Tcm-HYNIC-2PEG4-Dimer and 99Tcm-HYNIC-Dimer was prepared using non-SnCl2 formulation. The biodistribution and y imaging were performed in nude mice bearing human glioma xenografts.The unpaired t test were used for statistical analysis.
Results
High expression of integrinαvβ3 integrinαvβ3 in the U87 human glioma cells as well as tumor tissues can be seen. The labeling yield of the two radiotracers was more than 95%, and the radiochemical purity was more than 99% after purification with Sep-Pek C18 cartridge. HYNIC-2PEG4-Dimer had significantly higher integrinαvβ3 binding affinity than c(RGDyK) and HYNIC-Dimer (The IC50 values were 0.8 nmol/L,27 nmol/L and 2.4 nmol/L, respectively).Biodistribution data showed that 99mTc-HYNIC-2PEG4-Dimer was mainly excreted via the renal route. The tumor uptake of 99Tcm-HYNIC-2PEG4-Dimer was about 2.7 times higher than that of 99Tcm-HYNIC-Dimer at 2 h postinjection (5.71±0.96V.s.2.10±0.50%ID/g), t= 4.80, P< 0.05. y imaging revealed that the xenografted tumors were visible at 0.5 h postinjection, and the image contrast increased at 4 h postinjection with the rapid clearance of the radiotracer.
Conclusion
99Tcm-HYNIC-2PEG4-Dimer has higher integrinαvβ3 binding affinity,and the tumor uptake of its is higher, so it is a more promising radiotracer for integrinαvβ3-positive tumor imaging.
RGD多肽(RGD：含有氨基酸序列Arg-GIy-Asp的一小肽段的缩写)能与整合素αvβ特异性结合,从而进行肿瘤的诊断和治疗。为增强RGD多肽与整合素αvβ结合的亲和力,提高肿瘤对标记探针的摄取,我们在前期研究的基础上,对RGD二聚体进行结构改造,以联肼尼克酰胺(HYNIC)为双功能连接剂,N-三(羟甲基)甲基甘氨酸(tricine)和三苯基磷三磺酸钠(TPPTS)为协同配体(coligand),制备了99Tcm示记的由2PEG4修饰的RGD二聚体(Dimer:E[c(RGDfK)]2):99Tcm-HYNIC-2PEG4-Dimer,并与99Tcm-HYNIC-Dimer:进行比较,期望2PEG4的引入能有效改善标记探针的药代动力学性质,降低其在正常组织的摄取。
方法：
用免疫组化实验方法测定U87MG人神经胶质瘤细胞以及肿瘤组织中的整合素αvβ3的表达。通过U87MG细胞受体竞争结合实验测定RGD环肽单体c(RGDyK). HYNIC(联肼尼克酰胺)-Dimer和HYNIC-2PEG4-Dimer对125I-c(RGDyK)的半数抑制浓度(IC50)值。采用无亚锡一步法制备99Tcm-HYNIC-2PEG4-Dimer和99Tcm-HYNIC-Dimer,并测定各自的标记率和放化纯。评价99Tcm-HYNIC-2PEG4-Dimer和99Tcm-HYNIC-Dimer在荷U87MG瘤裸鼠的生物分布,进行γ显像。采用非配对t检验法对实验数据进行分析。
结果
免疫组化实验结果证实：在U87MG细胞和荷瘤裸鼠肿瘤组织中高表达整合素αvβ。HYNIC-2PEG4-Dimer比c(RGDyK)和IYNIC-Dimer有更高的整合素αvβ3亲和力(IC50值分别是0.8 nmol/L、27 nmol/L和2.4 nmol/L)。99Tcm-HYNIC-Dimer和99Tcm-HYNIC-2PEG4-Dimer的99Tcm标记率均>95%,经Sep-Pek C18柱纯化后其放化纯>99%。生物分布实验显示,两种标记物均主要经肾脏排泄,在注射后2 h,肿瘤对99Tcm-HYNIC-2PEG4-Dimer的摄取为99Tcm-HYNIC-Dimer的2.7倍(5.71±0.96%ID/g V.S.2.10±0.50%ID/g),摄取显著增高(t=4.80,P<0.05),与体外受体竞争结合实验数据相一致。γ显像结果显示,注射后99Tcm-HYNIC-2PEG4-Dimer 0.5h肿瘤即清晰可见,随时间延长,体内放射性本底明显减低,显像对比度增高。
结论
99Tcm-HYNIC-2PEG4-Dimer与整合素αvβ3的结合亲和力更高,肿瘤对其的摄取摄取率更高,是一个有应用前景的用于整合素αvβ3阳性肿瘤显像的放射性示踪剂。
Objective
RGD peptide (containing amino acid sequence Arg-Gly-Asp of a small peptide abbreviation) can specifically bind with the integrinαvβ3, which for the diagnosis and treatment of cancer. To enhance the RGD peptide and integrinαvβ3 binding affinity, and increase tumor uptake of the labeled probe, On the basis of preliminary studies on the RGD dimer structural transformation, we using joint hydrazine nicotinamide (HYNIC) as bifunctional agent, N-tris (hydroxymethyl) methyl glycine (tricine) and triphenylphosphine three sulfonate (TPPTS) as ligand coordination (coligand), prepared the 2PEG4 99Tcm-modified RGD dimer (Dimer:E [c (RGDfK)] 2): 99Tcm-HYNIC-2PEG4-Dimer, and with 99Tcm-HYNIC-Dimer comparison, expecting 2PEG4 can effectively improve the pharmacokinetic properties, reducing its normal tissue uptake.
Methods
The expression of integrinαvβ3 in the U87 human glioma cells as well as tumor tissues were determined by immunofluorescence staining. The 50% inhibitory concentration (IC50) values of c(RGDyK), HYNIC-Dimer and HYNIC-2PEG4-Dimer were determined on U87 human glioma cells with 125I-c(RGDyK) as the integrinαvβ3-pecific radiotracer。99Tcm-HYNIC-2PEG4-Dimer and 99Tcm-HYNIC-Dimer was prepared using non-SnCl2 formulation. The biodistribution and y imaging were performed in nude mice bearing human glioma xenografts.The unpaired t test were used for statistical analysis.
Results
High expression of integrinαvβ3 integrinαvβ3 in the U87 human glioma cells as well as tumor tissues can be seen. The labeling yield of the two radiotracers was more than 95%, and the radiochemical purity was more than 99% after purification with Sep-Pek C18 cartridge. HYNIC-2PEG4-Dimer had significantly higher integrinαvβ3 binding affinity than c(RGDyK) and HYNIC-Dimer (The IC50 values were 0.8 nmol/L,27 nmol/L and 2.4 nmol/L, respectively).Biodistribution data showed that 99mTc-HYNIC-2PEG4-Dimer was mainly excreted via the renal route. The tumor uptake of 99Tcm-HYNIC-2PEG4-Dimer was about 2.7 times higher than that of 99Tcm-HYNIC-Dimer at 2 h postinjection (5.71±0.96V.s.2.10±0.50%ID/g), t= 4.80, P< 0.05. y imaging revealed that the xenografted tumors were visible at 0.5 h postinjection, and the image contrast increased at 4 h postinjection with the rapid clearance of the radiotracer.
Conclusion
99Tcm-HYNIC-2PEG4-Dimer has higher integrinαvβ3 binding affinity,and the tumor uptake of its is higher, so it is a more promising radiotracer for integrinαvβ3-positive tumor imaging.
引文
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