肝组织特异性非离子型高分子磁共振造影剂的制备及性能评价  

PREPARATION AND EVALUATION OF LIVER SPECIFIC NON-IONIC POLYMERIC CONTRAST AGENT

作　　者：舒婕[1] 李建齐[1] 徐敏[1] 罗淑芳[2] 刘顺英[2] 余家会[2] 丛蓉[3] 杜冰[3] 

机构地区：[1]华东师范大学物理系 上海市功能磁共振成像重点实验室,上海200062 [2]华东师范大学新药创制先进技术研究院,上海200062 [3]华东师范大学生命科学学院,上海200062

出　　处：《高分子学报》2008年第2期116-122,共7页Acta Polymerica Sinica

基　　金：上海市纳米专项(项目号0652nm009,05nm05012,0452nm028,0452nm084);国家自然科学基金(基金号20504010)资助项目

摘　　要：L-酪氨酸甲酯与DTPA双N-羟基琥珀酰亚胺活性酯(SuO-DTPA-OSu)反应,合成了含L-酪氨酸甲酯残基的DTPA单N-羟基琥珀酰亚胺活性酯(SuO-DTPA-Tyr).以EDC/NHS为媒介,通过一步反应将不同量的乳糖酸偶联到α,β-聚[(2-氨乙基)-L-天冬酰胺]上,然后将含有苯环的结构的SuO-DTPA-Tyr与联有D-半乳糖的α,β-聚[(2-氨乙基)-L-天冬酰胺]反应,合成了3种含糖量不同的大分子配体,并制备了其Gd(III)螯合物.结果表明,EDC/NHS方法操作简便,产率高且易于提纯;而SuO-DTPA-Tyr上L-酪氨酸甲酯残基的引入,不仅实现了高分子造影剂的非离子化,同时L-酪氨酸甲酯残基上的苯环结构也可以方便核磁氢谱的指认.大分子配体的细胞毒性随含糖量降低而增加,但均小于同浓度聚(L-赖氨酸)的毒性;大分子螯合物的细胞毒性与商用小分子造影剂的细胞毒性相当,但其弛豫率明显高于小分子造影剂的弛豫率;大分子螯合物在小白鼠肝部有比商用小分子造影剂(钆喷酸葡胺)更好的成像增强效果及更长的停留时间,且在注射后前6h,含D-半乳糖酸残基的大分子螯合物比不含D-半乳糖酸残基的大分子螯合物在小白鼠肝部的代谢速率慢,并呈现出更清晰的造影效果.Contrast agents special for liver are always required to have a relatively longer metabolic time and astable contrast effect in liver tissue. Therefore, D-lactobionic acid residues, which are generally used as liver-targeted groups, were introduced here. Single N-hydroxysuccinimide active ester of DTPA （SuO-DTPA-Tyr） was synthesized as the ligand of gadolinium （Ⅲ） ion, forming the basic structure of non-ionic contrast agent. Three α,β-poly（ L- aspartic acid） derivatives （PD0, PD1 and PD3） with different D-lactobionic acid residue contents were synthesizedby conjugation of D-lactobionic acid and single N-hydroxysuccinimide active ester of DTPA with α,β-poly [ （2- aminoethyl）-L-aspartamide], respectively. Polymeric gadolinium （Ⅲ） complexes （ PD0-Gd, PD1-Gd and PD3-Gd ） were prepared by the reaction of α,β-poly（ L-aspartic acid） derivatives with GdCl3·6H2O. The contents of D- lactobionic residues and gadolinium （Ⅲ） were determined by quantitative ^13 C-NMR and ICP, respectively. Propertiesof these polymeric contrast agents were evaluated here. Cytotoxicity test shows that all the polymer ligands （ PC0, PC1 and PC3） have better cell viability rate than that of poly（L-lysine） with corresponding concentrations .The value of cell viability rate rises with the increase of D-lactobionic acid residue content. The reason is the D-lactobionic acid residues mostly shield the positive charge of backbone, which blocks the delivery of carrier to the cells. Compared with the commercial contrast agents, polymer complexes have the same level of cytotoxicity. However, their relaxivities（7.77,8.00 and 9.48 mmolL^-1 s^-1 for PD0-Gd, PD1-Gd and PD3-Gd, respectively） are obviously higher than that of commercial contrast agents （5.95 mmolL^-1 s^-1 for dimeglnmine gadopentetate）. That is because the mobility of polymer molecules is lower than that of small molecules, which leads to an increase of relaxivities. Experiments in vivo were carried out on ICR mice, which were di

关 键 词：聚(L-天冬氨酸)衍生物 大分子-钆螯合物 乳糖酸 磁共振成像 

分 类 号：R981[医药卫生—药品]