Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Int J Nanomedicine. 2013;8:1385-91. doi: 10.2147/IJN.S42003. Epub 2013 Apr 10.
Increased expression of cellular membrane bound glucose-regulated protein 78 (GRP78) is considered to be one of the biomarkers for gastric cancers. Therefore, peptides or molecules with specific recognition to GRP78 can act as a guiding probe to direct conjugated imaging agents to localized cancers. Based on this rationale, GRP78-guided polymeric micelles were designed and manufactured for nuclear imaging detection of tumors. Thiolated GRP78 binding peptide (GRP78BP) was first labeled with maleimide-terminated poly(ethylene glycol)- poly(ɛ-caprolactone) and then mixed with diethylenetriaminepentaacetic acid (DTPA)-linked poly(ethylene glycol)-poly(ɛ-caprolactone) to form DTPA/GRP78BP-conjugated micelles. The coupling efficiency of micelles with radioisotope indium-111 ((111)In) was measured and analyzed by instant thin layer chromatography. The coupling efficiency of DTPA-conjugated micelles and DTPA/GRP78BP-conjugated micelles with (111)In was 85% and 93%, respectively. For characterization and trace imaging, the radioisotope (111)In-targeting tumors were detected and imaged in a xenograft murine model using nano single photon emission computed tomography/computed tomography. The results revealed that the radioactive intensity measured in the animals administered with GRP78BP-guided (111)In-labeled micelles was statistically higher than that in animals administered with (111)In-labeled micelles, demonstrating that GRP78BP more than doubled the accumulation of micelles to the tumor tissue (P < 0.05). The results indicate that the gastric cancer biomarker GRP78 is a probing target in the application of nuclear imaging for tumor diagnosis. This novel GRP78BP-guided micelle agent may be applied in clinical practice to complement the histological diagnosis.
细胞表面结合葡萄糖调节蛋白 78（GRP78）的表达增加被认为是胃癌的生物标志物之一。因此，具有与 GRP78 特异性识别的肽或分子可以作为导向探针将共轭成像剂引导至局部癌症。基于这一原理，设计并制造了 GRP78 导向的聚合物胶束用于肿瘤的核成像检测。首先用马来酰亚胺封端的聚乙二醇-聚（ε-己内酯）标记硫醇化的 GRP78 结合肽（GRP78BP），然后将其与二乙三胺五乙酸（DTPA）-连接的聚乙二醇-聚（ε-己内酯）混合形成 DTPA/GRP78BP 共轭胶束。通过即时薄层层析法测量并分析放射性同位素铟-111（（111）In）与胶束的偶联效率。DTPA 共轭胶束和 DTPA/GRP78BP 共轭胶束与（111）In 的偶联效率分别为 85%和 93%。为了进行特征和示踪成像，使用纳米单光子发射计算机断层扫描/计算机断层扫描在异种移植小鼠模型中检测和成像靶向肿瘤的放射性同位素（111）In。结果表明，给予 GRP78BP 导向（111）In 标记的胶束的动物的放射性强度明显高于给予（111）In 标记的胶束的动物，表明 GRP78BP 使胶束对肿瘤组织的积累增加了一倍以上（P<0.05）。结果表明，胃癌生物标志物 GRP78 是肿瘤核成像诊断应用中的探测靶点。这种新型的 GRP78BP 导向胶束剂可应用于临床实践，以补充组织学诊断。
