Pu Fan, Qiao Jingjuan, Xue Shenghui, Yang Hua, Patel Anvi, Wei Lixia, Hekmatyar Khan, Salarian Mani, Grossniklaus Hans E, Liu Zhi-Ren, Yang Jenny J
Departments of Chemistry and Biology, Center for Diagnostics &Therapeutics, Georgia State University, Atlanta, GA 30303.
Department of Ophthalmology, Emory University, Atlanta, GA, 30322.
Sci Rep. 2015 Nov 18;5:16214. doi: 10.1038/srep16214.
Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR-targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd(3+) binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM(-1)s(-1) at 1.5 T and 25 °C) and strong Gd(3+) selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects.
胃泌素释放肽受体（GRPR）在包括前列腺癌和肺癌在内的多种病变细胞表面存在差异表达。然而，由于缺乏具有高弛豫率、靶向能力和肿瘤穿透性的造影剂，通过临床磁共振成像（MRI）监测体内GRPR的时空表达受到严重阻碍。在此，我们报告了一种通过将GRPR靶向部分嫁接到具有设计的钆（Gd(3+)）结合位点的支架蛋白上（ProCA1.GRPR）来开发GRPR靶向MRI造影剂的方法。除了对GRPR具有强结合亲和力（解离常数Kd = 2.7 nM）外，ProCA1.GRPR还具有高弛豫率（在1.5 T和25°C下r1 = 42.0 mM(-1)s(-1)）以及对生理金属离子具有强钆（Gd(3+)）选择性。ProCA1.GRPR能够利用MRI在体内检测小鼠PC3和H441肿瘤中GRPR的表达及空间分布。ProCA1.GRPR有望对癌症的早期检测和治疗效果监测具有重要的临床前和临床意义。
