Du Hongli, Yu Jiani, Guo Dongcai, Yang Weitao, Wang Jun, Zhang Bingbo
Shanghai Skin Disease Hospital, The Institute for Photomedicine, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine , Shanghai 200443, China.
School of Materials Science and Engineering, School of Life Science, Collaborative Innovation Center of Chemical Science and Engineering, Tianjin University , Tianjin 300072, China.
Langmuir. 2016 Feb 2;32(4):1155-65. doi: 10.1021/acs.langmuir.5b04186. Epub 2016 Jan 19.
Gd(3+)-ion-doped upconversion nanoparticles (UCNPs), integrating the advantages of upconversion luminescence and magnetic resonance imaging (MRI) modalities, are capturing increasing attention because they are promising to improve the accuracy of diagnosis. The embedded Gd(3+) ions in UCNPs, however, have an indistinct MRI enhancement owing to the inefficient exchange of magnetic fields with the surrounding water protons. In this study, a novel approach is developed to improve the MR imaging sensitivity of Gd(3+)-ion-doped UCNPs. Bovine serum albumin (BSA) bundled with DTPA-Gd(3+) (DTPA(Gd)) is synthesized both as the MR imaging sensitivity synergist and phase-transfer ligand for the surface engineering of UCNPs. The external Gd(3+) ion attachment strategy is found to significant improve the MR imaging sensitivity of Gd(3+)-ion-doped UCNPs. The relaxivity analysis shows that UCNPs@BSA·DTPA(Gd) exhibit higher relaxivity values than do UCNPs@BSA without DTPA(Gd) moieties. Another relaxivity study discloses a striking message that the relaxivity value does not always reflect the realistic MRI enhancement capability. The high concentration of Gd(3+)-ion-containing UCNPs with further surface-engineered BSA·DTPA(Gd) (denoted as UCNPs-H@BSA·DTPA(Gd)) exhibits a more pronounced MRI enhancement capability compared to the other two counterparts [UCNPs-N@BSA·DTPA(Gd) and UCNPs-L@BSA·DTPA(Gd) (-N and -L are denoted as zero and low concentrations of Gd(3+) ion doping, respectively)], even though it holds the lowest r1 of 1.56 s(-1) per mmol L(-1) of Gd(3+). The physicochemical properties of UCNPs are essentially maintained after BSA·DTPA(Gd) surface decoration with good colloidal stability, in addition to improving the MR imaging sensitivity. In vivo T1-weighted MRI shows potent tumor-enhanced MRI with UCNPs-H@BSA·DTPA(Gd). An in vivo biodistribution study indicates that it is gradually excreted from the body via hepatobiliary and renal processing with no obvious toxicity. It could therefore be concluded, with improved MR imaging sensitivity by an internal and external incorporation of Gd(3+) strategy, that UCNPs-H@BSA·DTPA(Gd) presents great potential as an alternative in tumor-targeted MR imaging.
掺钆（Gd(3+)）离子的上转换纳米粒子（UCNPs）结合了上转换发光和磁共振成像（MRI）模式的优点，因其有望提高诊断准确性而受到越来越多的关注。然而，UCNPs中嵌入的Gd(3+)离子由于与周围水质子的磁场交换效率低下，其MRI增强效果不明显。在本研究中，开发了一种新方法来提高掺Gd(3+)离子的UCNPs的磁共振成像灵敏度。合成了与二乙烯三胺五乙酸钆（DTPA-Gd(3+)，即DTPA(Gd)）结合的牛血清白蛋白（BSA），作为UCNPs表面工程的磁共振成像灵敏度增效剂和相转移配体。发现外部Gd(3+)离子附着策略能显著提高掺Gd(3+)离子的UCNPs的磁共振成像灵敏度。弛豫率分析表明，UCNPs@BSA·DTPA(Gd)的弛豫率值高于不含DTPA(Gd)部分的UCNPs@BSA。另一项弛豫率研究揭示了一个惊人的信息，即弛豫率值并不总是反映实际的MRI增强能力。与其他两种对应物[UCNPs-N@BSA·DTPA(Gd)和UCNPs-L@BSA·DTPA(Gd)（-N和-L分别表示Gd(3+)离子掺杂的零浓度和低浓度）]相比，具有进一步表面工程化BSA·DTPA(Gd)的高浓度含Gd(3+)离子的UCNPs（表示为UCNPs-H@BSA·DTPA(Gd)）表现出更明显的MRI增强能力，尽管其每毫摩尔升Gd(3+)的最低r1为1.56 s(-1)。除了提高磁共振成像灵敏度外，在进行BSA·DTPA(Gd)表面修饰后，UCNPs的物理化学性质基本保持，具有良好的胶体稳定性。体内T1加权MRI显示UCNPs-H@BSA·DTPA(Gd)具有强大的肿瘤增强MRI效果。体内生物分布研究表明，它通过肝胆和肾脏处理逐渐从体内排出，无明显毒性。因此，可以得出结论，通过内部和外部掺入Gd(3+)策略提高了磁共振成像灵敏度，UCNPs-H@BSA·DTPA(Gd)在肿瘤靶向磁共振成像中具有巨大的替代潜力。
