Zielhuis S W, Seppenwoolde J H, Bakker C J G, Jahnz U, Zonnenberg B A, van het Schip A D, Hennink W E, Nijsen J F W
Department of Nuclear Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
J Biomed Mater Res A. 2007 Sep 15;82(4):892-8. doi: 10.1002/jbm.a.31183.
In this paper the preparation and characterization of holmium-loaded alginate microspheres is described. The rapid development of medical imaging techniques offers new opportunities for the visualisation of (drug-loaded) microparticles. Therefore, suitable imaging agents have to be incorporated into these particles. For this reason, the element holmium was used in this study in order to utilize its unique imaging characteristics. The paramagnetic behaviour of this element allows visualisation with MRI and holmium can also be neutron-activated resulting in the emission of gamma-radiation, allowing visualisation with gamma cameras, and beta-radiation, suitable for therapeutic applications. Almost monodisperse alginate microspheres were obtained by JetCutter technology where alginate droplets of a uniform size were hardened in an aqueous holmium chloride solution. Ho(3+) binds via electrostatic interactions to the carboxylate groups of the alginate polymer and as a result alginate microspheres loaded with holmium were obtained. The microspheres had a mean size of 159 microm and a holmium loading of 1.3 +/- 0.1% (w/w) (corresponding with a holmium content based on dry alginate of 18.3 +/- 0.3% (w/w)). The binding capacity of the alginate polymer for Ho(3+) (expressed in molar amounts) is equal to that for Ca(2+), which is commonly used for the hardening of alginate. This indicates that Ho(3+) has the same binding affinity as Ca(2+). In line herewith, dynamic mechanical analyses demonstrated that alginate gels hardened with Ca(2+) or Ho(3+) had similar viscoelastic properties. The MRI relaxation properties of the microspheres were determined by a MRI phantom experiment, demonstrating a strong R(2)* effect of the particles. Alginate microspheres could also be labelled with radioactive holmium by adding holmium-166 to alginate microspheres, previously hardened with calcium (labelling efficiency 96%). The labelled microspheres had a high radiochemical stability (94% after 48 h incubation in human serum), allowing therapeutic applications for treatment of cancer. The potential in vivo application of the microspheres for a MR-guided renal embolization procedure was illustrated by selective administration of microspheres to the left kidney of a pig. Anatomic MR-imaging showed the presence of holmium-loaded microspheres in the kidney. In conclusion, this study demonstrates that the incorporation of holmium into alginate microspheres allows their visualisation with a gamma camera and MRI. Holmium-loaded alginate microspheres can be used therapeutically for embolization and, when radioactive, for local radiotherapy of tumours.
本文描述了载钬藻酸盐微球的制备及特性。医学成像技术的迅速发展为（载药）微粒的可视化提供了新机遇。因此，必须将合适的成像剂掺入这些微粒中。出于这个原因，本研究使用了钬元素以利用其独特的成像特性。该元素的顺磁行为使其可通过磁共振成像（MRI）进行可视化，并且钬还可被中子激活，从而产生γ辐射，可通过γ相机进行可视化，同时还能产生适用于治疗应用的β辐射。通过喷射切割技术获得了几乎单分散的藻酸盐微球，在氯化钬水溶液中使大小均匀的藻酸盐液滴硬化。Ho(3+) 通过静电相互作用与藻酸盐聚合物的羧基结合，从而得到载钬的藻酸盐微球。微球的平均大小为159微米，钬负载量为1.3±0.1%（w/w）（相当于基于干藻酸盐的钬含量为18.3±0.3%（w/w））。藻酸盐聚合物对Ho(3+) 的结合能力（以摩尔量表示）与对常用于藻酸盐硬化的Ca(2+) 的结合能力相同。这表明Ho(3+) 具有与Ca(2+) 相同的结合亲和力。与此一致，动态力学分析表明用Ca(2+) 或Ho(3+) 硬化的藻酸盐凝胶具有相似的粘弹性特性。通过MRI体模实验测定了微球的MRI弛豫特性，证明了微粒具有很强的R(2)* 效应。通过向先前用钙硬化的藻酸盐微球中添加钬 - 166，藻酸盐微球也可用放射性钬进行标记（标记效率96%）。标记的微球具有高放射化学稳定性（在人血清中孵育48小时后为94%），可用于癌症治疗的治疗应用。通过将微球选择性地给予猪的左肾，说明了微球在磁共振引导下肾栓塞手术中的潜在体内应用。解剖学磁共振成像显示肾脏中存在载钬微球。总之，本研究表明将钬掺入藻酸盐微球中可使其通过γ相机和MRI进行可视化。载钬藻酸盐微球可用于栓塞治疗，当具有放射性时，可用于肿瘤的局部放射治疗。
