Voisin Pierre, Ribot Emeline Julie, Miraux Sylvain, Bouzier-Sore Anne-Karine, Lahitte Jean-François, Bouchaud Véronique, Mornet Stéphane, Thiaudière Eric, Franconi Jean-Michel, Raison Lydia, Labrugère Christine, Delville Marie-Hélène
Résonance Magnétique des Systèmes Biologiques, UMR CNRS 5536, 146 rue Léo Saignat, F-33076 Bordeaux cedex France.
Bioconjug Chem. 2007 Jul-Aug;18(4):1053-63. doi: 10.1021/bc060269t. Epub 2007 May 19.
The improvement of commonly used Gd3+ -based MRI agents requires the design of new systems with optimized in vivo efficacy, pharmacokinetic properties, and specificity. To design these contrast agents, two parameters are usually considered: increasing the number of coordinated water molecules or increasing the rotational correlation time by increasing molecular weight and size. This has been achieved by noncovalent or covalent binding of low-molecular weight Gd3+ chelates to macromolecules or polymers. The grafting of these high-spin paramagnetic gadolinium chelates on metal oxide nanoparticles (SiO2, Al2O3) is proposed. This new synthetic strategy presents at least two main advantages: (1) a high T1-relaxivity for MRI with a 275% increase of the MRI signal and (2) the ability of nanoparticles to be internalized in cells. Results indicate that these new contrast agents lead to a huge reconcentration of Gd3+ paramagnetic species inside microglial cells. This reconcentration phenomenon gives rise to high signal-to-noise ratios on MR images of cells after particle internalization, from 1.4 to 3.75, using Al2O3 or SiO2 particles, respectively. The properties of these new particles will be further used to get new insight into gene therapy against glioma, using microglial cells as vehicles to simultaneously transport a suicide gene and contrast agents. Since microglia are chemoattracted to brain tumors, the presence of these new contrast agents inside the cells will lead to a better MRI determination of the in vivo location, shape, and borders of the tumors. These Gd3+-loaded microglia can therefore provide effective localization of tumors by MRI before applying any therapeutic treatment. The rate of carcinoma remission following a suicide gene strategy is also possible.
改进常用的基于钆（Gd3+）的磁共振成像（MRI）造影剂需要设计新的系统，使其在体内功效、药代动力学特性和特异性方面达到最佳。为了设计这些造影剂，通常会考虑两个参数：增加配位水分子的数量，或者通过增加分子量和尺寸来延长旋转相关时间。这可以通过低分子量钆螯合物与大分子或聚合物的非共价或共价结合来实现。有人提出将这些高自旋顺磁性钆螯合物接枝到金属氧化物纳米颗粒（二氧化硅、氧化铝）上。这种新的合成策略至少有两个主要优点：（1）用于MRI时具有高T1弛豫率，MRI信号增加275%；（2）纳米颗粒能够被细胞内化。结果表明，这些新的造影剂会导致小胶质细胞内钆顺磁性物质大量重新聚集。这种重新聚集现象使得颗粒内化后细胞的磁共振图像上具有高信噪比，分别使用氧化铝或二氧化硅颗粒时，信噪比从1.4提高到3.75。这些新颗粒的特性将进一步用于深入了解针对胶质瘤的基因治疗，利用小胶质细胞作为载体同时运输自杀基因和造影剂。由于小胶质细胞会被脑肿瘤化学吸引，细胞内这些新造影剂的存在将有助于通过MRI更好地确定肿瘤在体内的位置、形状和边界。因此，这些负载钆的小胶质细胞可以在应用任何治疗之前通过MRI有效定位肿瘤。采用自杀基因策略后癌症缓解率也是有可能的。
