Rotational dynamics account for pH-dependent relaxivities of PAMAM dendrimeric, Gd-based potential MRI contrast agents
Rotational dynamics account for pH-dependent relaxivities of PAMAM dendrimeric, Gd-based potential MRI contrast agents
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DOI：
10.1002/chem.200401326
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发表时间：
2005-05-06
影响因子：
4.3
通讯作者：
Merbach, AE
中科院分区：
文献类型：
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作者：
Laus, S;Sour, A;Merbach, AE
确保Gd-III络合物快速水交换的EPTPA(5-)通过苄基硫脲键(H(5)EPTPA=乙三胺-N，N，N‘，N“，N”-五乙酸)偶联到三代(5，7和9代)聚酰胺-胺(PAMAM)树枝状大分子上。在pH 7.4时测得的树状大分子络合物G5-(GdEPTPA)(111)G7-(GdEPTPA)(253)和G9-(GdEPTPA)(1157)的质子弛豫度随着温度的升高而减小，这表明对于树枝状大分子来说，缓慢的水交换第一次没有限制松弛。在给定的磁场和温度下，弛豫系数从G5到G7逐渐增大，然后在G9略有下降(在37℃，30 MHz下，r(1)分别为20.5，28.3和27.9 mm(-1)S(-1))。结果表明，这三种树枝状大分子络合物的弛豫度都与pH有很强的可逆性依赖关系。这源于树枝状大分子骨架的pH依赖的旋转动力学，这被在G5-(GdEPTPA)(111)上分别在pH 6.0和9.9下进行的变温和多场O-17核磁共振和H-1弛豫度研究所证实。[Gd(EPTPA)(H2O)](2-)单体络合物的O-17和H-1纵向松弛速率与pH有很强的依赖关系。用Lipari-Szabo谱密度函数分析了O-17和H-1的纵向弛豫速率，计算了大分子整体运动(Tau(Go))和Gd-III络合物在表面的局部运动(Tau(Lo))的关联时间，并用序参数S进行了关联。树状大分子络合物G5(GdEPTPA)(111)在酸性条件下的tau(Go)比在碱性条件下(T-Go(298)=4040ps和2950ps)高得多，而局部运动受pH的影响较小(tau(298)(Lo)为150和125ps)。表征大分子刚性的有序参数在pH为6.0时也比在pH为9.9时高(S-2=0.43vs0.36)。全局关联时间的pH依赖关系可能与PAMAM骨架中叔胺基团的质子化有关，这导致了较低pH下的树枝状结构扩张和更刚性。随着pH的降低，tau(Go)的增加是引起质子弛豫的pH依赖性的原因。G5-(GdEPTPA)(111)(k(Ex)(298)=150×10(6)S(-1))的水交换速率没有明显的pH依赖性，与单体[Gd(EPTPA)(H2O)](2-)的水交换速率相似。(2)G5-(GdEPTPA)(111)的质子弛豫度主要受树枝状大分子结构的重要柔性限制，并在很小程度上受快于最佳水交换速率。
The EPTPA(5-) chelate, which ensures fast water exchange in Gd-III complexes, has been coupled to three different generations (5, 7, and 9) of polyamidoamine (PAMAM) dendrimers through benzylthiourea linkages (H(5)EPTPA = ethylenepropylenetriamine-N,N,N',N",N"-pentaacetic acid). The proton relaxivities measured at pH 7.4 for the dendrimer complexes G5-(GdEPTPA)(111) G7-(GdEPTPA)(253) and G9-(GdEPTPA)(1157) decrease with increasing temperature, indicating that, for the first time for dendrimers, slow water exchange does not limit relaxivity. At a given field and temperature, the relaxivity increases from G5 to G7, and then slightly decreases for G9 (r(1) = 20.5, 28.3 and 27.9 mm(-1)s(-1), respectively, at 37 degrees C, 30 MHz). The relaxivities show a strong and reversible pH dependency for all three dendrimer complexes. This originates from the pH-dependent rotational dynamics of the dendrimer skeleton, which was evidenced by a combined variable-temperature and multiple-field O-17 NMR and H-1 relaxivity study performed at pH 6.0 and 9.9 on G5-(GdEPTPA)(111). The longitudinal O-17 and H-1 relaxation rates of the dendrimeric complex are strongly pH-dependent, whereas they are not for the [Gd(EPTPA)(H2O)](2-) monomer chelate. The longitudinal O-17 and H-1 relaxation rates have been analysed by the Lipari-Szabo spectral density functions and correlation times have been calculated for the global motion of the entire macromolecule (tau(gO)) and the local motion of the Gd-III chelates on the surface (tau(lO)), correlated by means of an order parameter S'. The dendrimer complex G5(GdEPTPA)(111) has a considerably higher tau(gO) under acidic than under basic conditions (T-gO(298)=4040ps and 2950ps, respectively), while local motions are less influenced by pH (tau(298)(lO) to 150 and 125 ps). The order parameter, characterizing the rigidity of the macromolecule, is also higher at pH 6.0 than at pH 9.9 (S-2 = 0.43 vs 0.36, respectively). The pH dependence of the global correlation time can be related to the protonation of the tertiary amine groups in the PAMAM skeleton, which leads to an expanded and more rigid dendrimeric structure at lower pH. The increase of tau(gO) with decreasing pH is responsible for the pH dependent proton relaxivities. The water exchange rate on G5-(GdEPTPA)(111) (k(ex)(298) = 150 x 10(6) s(-1)) shows no significant pH dependency and is similar to the one measured for the monomer [Gd(EPTPA)(H2O)](2-) The proton relaxivity of G5-(GdEPTPA)(111) is mainly limited by the important flexibility of the dendrimer structure, and to a small extent, by a faster than optimal water exchange rate.