标题: | 钆金属错合物及氧化铁表面修饰做为分子影像之磁振造影对比剂 Mri Contrast Agents of Gadolinium(Iii) Complexes and Surface Modified Iron Oxide for Molecular Imaging |
作者: | 王云铭 WANG YUN-MING 国立交通大学生物科技学系(所) |
关键字: | 磁振造影对比剂;热力学;动力学;弛缓率;钆金属错合物;水交换速率;Magnetic resonance imaging contrast agent;thermodynamic;kinetic;relaxivity;gadolinium complex;water exchange rate |
公开日期: | 2009 |
摘要: | 近年來磁振造影(MRI)已被发展至应用于人体到细胞及分子的层级。为了完全开发 MRI 技术应用于细胞、分子与功能性影像,能够标帜活体细胞的目标化、区域化及數量 化之新一代MRI 对比剂与技术是目前最迫切需要的。因此,目前兩种最主要的MRI 对 比剂是研究与发展的方向:小型分子量之钆金属错合物及氧化铁奈米粒子。高度表现于 人類肿瘤上新颖的MMP-7、Legumain 蛋白酶(protease)或α v β3 受体与肿瘤侵犯及转移有 关,目标化之MMP-7、Legumain 或cRGD 之胜肽片段可当作标的,目标化至表现这些 蛋白酶或受体類型之肿瘤。本研究之目的为调节不同亲脂性之钆金属错合物,并将此钆 金属错合物键结上目标化之MMP-7、Legumain 或cRGD 蛋白酶表现之肿瘤,找出最佳 的脂溶性之钆金属错合物,胜肽片段能使钆金属错合物目标化沈积于MMP-7 蛋白酶、 Legumain 或cRGD 相关的肿瘤位置。亲脂性之钆金属错合物能够安定的沈积于肿瘤细 胞膜表面而应用于MRI 上,可用于标帜与追踪癌细胞。这些钆金属错合物能用于以非 侵入造影追踪蛋白酶表现。此钆金属错合物之物性、化性探讨,包括热力学稳定度、弛 缓率(r1)、内层水分子數、水分子交换速率、转动相关时间及与蛋白酶或膜蛋白受体作 用之探讨是本研究的重点。最后,体外相关实验与MR 影像也将被研究探讨。在氧化铁 奈米粒子方面,先前研究中有发展出具良好生物相容性的超顺磁氧化铁奈米粒子,其在 磁振造影的显影上具有较高之靈敏度,无毒性又兼具生物可降解性,我们利用先前的经 验作为研究T2 磁振造影对比剂的一基本平台。本计划目的为将超顺磁氧化铁奈米粒子 表面修饰上具生物相容性之高分子聚合物,再键结贺癌平(Herceptin)或其他具目标化之 胜肽片段,藉以目标化到肿瘤(乳癌或其他癌症)位置。我们首先合成奈米级之超顺磁氧 化铁粒子及研究其物、化性质,包括氧化铁奈米粒子粒径大小、稳定性、磁化率、XRD 晶型研究等,并藉由缩短其横向弛缓时间(T2)來提高其将來在MRI 上讯号强度的对比。 纵向(T1)及横向(T2)弛缓率则利用20MHz 弛缓仪在37°C 下测得。最后利用流式细胞仪及 MR 影像來证明已修饰超顺磁氧化铁奈米粒子之效能。 Recently, MRI has been developed to examine living organisms down to the cellular and molecule level. To exploit the advancement of MRI technique for cellular, molecule and functional imaging, there are increasing needs for developing new MRI contrast agents and techniques for cell and molecule labeling to report the localization, movement, mass, and functions of cells in vivo. Therefore, two major classes of contrast agents are available for MRI such as small molecular weight Gd3+ chelates and iron oxide nanoparticles. The purpose of research is tuning the lipophilicity of Gd3+ complexes and conjugating with peptide substrates of MMP-7, Legumain protease or cRGD. MMP-7, Legumain protease and αv β3 receptor are greatly related to tumor invasion and metastasis, and are also highly expressed in majority of human tumors, which make them as the very representative cancer proteases and membrance receptor. To find the optimum lipophilicity of Gd3+ complexes that can be stably incorporated into cell membranes may serve as a useful tool for tumor cell labeling and tracking. Ideally, these Gd3+ chelates should label intact cell membranes noninvasively at low concentrations and with fast kinetics, and should remain on labeled cells over a period of time to allow repetitive imaging. The chemical and physical properties of these Gd3+ complexes will be characterized, including thermodynamic stability constant, relaxivity (r1), the number of inner-sphere water and kinetic parameter (water exchange rate and rotational correlation time). Finally, the MR imaging will be conducted as well. On the other hand, in the case of targeting to tumor cell, the surface of iron oxide nanoparticles modified with dextrin or PEG (polyethylene glycol) and then conjugated with herceptin or targeting peptide will be synthesized. The nano-sized superparamagnetic iron oxide(SPIO) particulates selectively shorten the transverse relaxation time (T2) of nearby water protons and generally produce negative enhancement by decreasing signal intensity. The geometry, structural features, and physical properties of magnetite nanoparticles will be characterized. The longitudinal relaxivity (r1) and transverse relaxivity (r2) will be measured by 20 MHz relaxometer at 37.0 ± 0.1℃. To prove effectiveness of this MR probe, the flow-cytometric analysis and MR imaging will be used. |
官方说明文件#: | NSC97-2113-M009-016-MY3 |
URI: | http://hdl.handle.net/11536/100967 https://www.grb.gov.tw/search/planDetail?id=1758547&docId=300146 |
显示于类别: | Research Plans |
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