Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers
Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers
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DOI：
10.1007/s00775-006-0197-3
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发表时间：
2007-03-01
影响因子：
3
通讯作者：
Toth, Eva
中科院分区：
文献类型：
--
作者：
Jaszberenyi, Zoltan;Moriggi, Loick;Toth, Eva
第4代聚酰胺胺（PAMAM）和第一次超支化的聚乙烯亚胺或聚甘油树状大分子装载了Gd3+螯合物，并在体外和体内研究了这些大分子加合物在MRI造影剂中的应用。Gd3+螯合剂为四氮四羧酸DOTA-pBn（4-）上标停止剂或四氮四羧酸单酰胺DO3A-MA（3-）单元。水从O-17汇率决定的H - NMR和核磁弛豫分散研究相应的单体类似物(Gd (DO3A-AEM) (H2O)]和[Gd (DOTA-pBn-NH2) (H2O)] (-) (k(特异)(298)= 3.4和6.6 x 10(6)(1),分别),在H (3) DO3A-AEM {4 - [(2-acetylaminoethylcarbamoyl)甲基]7,10-bis (carboxymethyl-1 4 7, 10-tetraazacyclododec-1-yl)}乙酸酸和H (4) DOTA-pBn-NH2 2 - (4-aminobenzyl) 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic酸。对于大分子复合物，用Lipari-Szabo方法从局部和全局运动动力学的角度测量和分析了变场质子弛度。在低于100 MHz的频率下，带有负电荷Gd(DOTA-pBn)（-）的树状大分子的质子弛豫率是带有中性Gd（DO3A-MA）的类似分子的两倍。我们通过不同的旋转动力学来解释这种差异：与负载中性Gd（DO3A-MA）的树状大分子相比，负载Gd(DOTA-pBn)（-）的树状大分子的运动速度要慢得多，这可能与螯合物的负电荷有关，后者产生了更多的刚性，并增加了大分子的总体尺寸。枝状大分子上的聚乙二醇链不影响其弛豫性。在Gd3+配合物的质子弛豫度方面，这两种超支化结构都被发现是与常规PAMAM树状大分子一样好的支架。4.7 T荷瘤小鼠的体内MRI研究证明，所有树突复合物都适合血管造影，适合研究肿瘤血管的血容量、通透性等血管参数。
Generation 4 polyamidoamine (PAMAM) and, for the first time, hyperbranched poly(ethylene imine) or polyglycerol dendrimers have been loaded with Gd3+ chelates, and the macromolecular adducts have been studied in vitro and in vivo with regard to MRI contrast agent applications. The Gd3+ chelator was either a tetraazatetracarboxylate DOTA-pBn(4-)supercript stop or a tetraazatricarboxylate monoamide DO3A-MA(3-) unit. The water exchange rate was determined from a O-17 NMR and H-1 Nuclear Magnetic Relaxation Dispersion study for the corresponding monomer analogues [Gd(DO3A-AEM)(H2O)] and [Gd(DOTA-pBn-NH2)(H2O)](-) (k(ex)(298) = 3.4 and 6.6 x 10(6) s(-1), respectively), where H(3)DO3A-AEM is {4-[(2-acetylaminoethylcarbamoyl)methyl]-7,10-bis(carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)}-acetic acid and H(4)DOTA-pBn-NH2 is 2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. For the macromolecular complexes, variable-field proton relaxivities have been measured and analyzed in terms of local and global motional dynamics by using the Lipari-Szabo approach. At frequencies below 100 MHz, the proton relaxivities are twice as high for the dendrimers loaded with the negatively charged Gd(DOTA-pBn)(-) in comparison with the analogous molecule bearing the neutral Gd(DO3A-MA). We explained this difference by the different rotational dynamics: the much slower motion of Gd(DOTA-pBn)(-)-loaded dendrimers is likely related to the negative charge of the chelate which creates more rigidity and increases the overall size of the macromolecule compared with dendrimers loaded with the neutral Gd(DO3A-MA). Attachment of poly(ethylene glycol) chains to the dendrimers does not influence relaxivity. Both hyperbranched structures were found to be as good scaffolds as regular PAMAM dendrimers in terms of the proton relaxivity of the Gd3+ complexes. The in vivo MRI studies on tumor-bearing mice at 4.7 T proved that all dendrimeric complexes are suitable for angiography and for the study of vasculature parameters like blood volume and permeability of tumor vessels.