The synthesis of poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) dendrons Gd-based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons (G-0 or dendron's core, and G-1) with peripheral NH2 groups to conjugate a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivative and afterwards to chelate with Gd3+ paramagnetic ions. These complexes, which have a well-defined molecular weight, are of relevance to MRI as an attempt to gain higher 1 H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water 1 H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature 17 O-NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting 1 H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast-Enhanced MRI (DCE-MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16-F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post-injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.

中文翻译：

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新型聚[N，N-双（3-氨基丙基）甘氨酸]（PAPGly）树枝状Gd造影剂的合成，弛豫特性及其在低场（1 T）下使用动态对比度增强MRI技术的体内研究。

聚[N，N-双（3-氨基丙基）甘氨酸]（PAPGly）树突的Gd基造影剂（GdCA）的合成是通过不同官能团的正交保护和活化/偶联策略进行的，其中特定数量的合成已经描述了将步骤添加到现有树状结构的步骤。该协议的目的是建立带有外围NH2基团的两代不同的树枝状分子（G-0或树枝状核，以及G-1），以共轭1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸（DO3A）衍生物，然后与Gd3 +顺磁性离子螯合。这些配合物具有明确的分子量，与MRI相关的是，与用作造影剂的单体Gd（III）配合物相比，通过放慢分子的旋转来获得更高的1 H弛豫性，并增加一个分子结构中存在的顺磁中心的数量，这些都与MRI相关。通过研究它们在不同磁场下的水1 H纵向弛豫率（NMRD，核磁弛豫色散），并通过评估可变温度17 O-NMR数据，我们确定了表征每种物质的水交换率和旋转相关时间的参数复杂，都影响1 H弛豫。此外，这两个新颖的PAPGly GdCA是以下对象：i）体内研究，以确定它们在几个时间点在健康C57小鼠中的生物分布，ii）动态对比增强MRI（DCE-MRI）方法，以评估在皮下移植有B16-F10黑色素瘤细胞的C57BL / 6小鼠的肿瘤区域中测得的对比效率。比较具有不同分子量（MW）的这两个树突GdCA的目的是了解MW和弛豫性如何影响低磁场（1 T）下的体内对比度增强能力。对于所研究的CA，在注射后5分钟时已经在几个器官（血管，脾脏和肝脏）中观察到明显的对比度增强。此外，由于这些大分子结构增强的通透性保持作用，这些CA在肿瘤区域中引起明显的对比度增强。比较具有不同分子量（MW）的这两个树突GdCA的目的是了解MW和弛豫性如何影响低磁场（1 T）下体内的对比增强能力。对于所研究的CA，注射后5分钟已在几个器官（血管，脾脏和肝脏）中观察到明显的对比度增强。此外，由于这些大分子结构增强的通透性保持作用，这些CA在肿瘤区域中引起明显的对比度增强。比较具有不同分子量（MW）的这两个树突GdCA的目的是了解MW和弛豫性如何影响低磁场（1 T）下体内的对比增强能力。对于所研究的CA，注射后5分钟已在几个器官（血管，脾脏和肝脏）中观察到明显的对比度增强。此外，由于这些大分子结构增强的通透性保持作用，这些CA在肿瘤区域中引起明显的对比度增强。对于所研究的CA，在注射后5分钟就已经存在。此外，由于这些大分子结构增强的通透性保持作用，这些CA在肿瘤区域中引起明显的对比度增强。对于所研究的CA，在注射后5分钟就已经存在。此外，由于这些大分子结构增强的通透性保持作用，这些CA在肿瘤区域中引起明显的对比度增强。