In vivo phage display selection of an ovarian cancer targeting peptide for SPECT/CT imaging.
In vivo phage display selection of an ovarian cancer targeting peptide for SPECT/CT imaging.
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DOI：
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发表时间：
2014-09
影响因子：
2.5
通讯作者：
M. Soendergaard;Jessica R. Newton-Northup;S. Deutscher
中科院分区：
文献类型：
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作者：
M. Soendergaard;Jessica R. Newton-Northup;S. Deutscher
卵巢癌(OC)往往致命的结果与检测方法不足有关，而核显像剂的开发可能会克服这一点。利用体内噬菌体展示技术已经确定了肿瘤靶向性多肽；然而，这些配体大多针对肿瘤血管系统。为了克服这一问题，采用两层噬菌体展示方法筛选出具有良好药代动力学和成像特性的卵巢癌靶向多肽。筛选抗人卵巢癌SKOV-3小鼠移植瘤的fUSE5 15氨基酸多肽文库，并对浓缩的SKOV-3细胞进行筛选。用Gsg-间隔物和1，4，7，10-tetraazacyclodecane-1，4，7，10-tetraacetic酸(DOTA)螯合剂合成了RSLWSDFYASASRGP(J18)，并用~(111)In标记。用SKOV-3异种移植小鼠评价放射性标记多肽的生物分布和单光子发射计算机断层扫描(SPECT)成像能力。与(111)In-DOTA-GSG-J18的竞争结合实验表明，该多肽的半数最大抑制浓度(IC50值)为10.5±1.1μM。生物分布研究表明，注射后30min、1 h、2 h和4 h的肿瘤摄取分别为1.63±0.68、0.60±0.32、0.31±0.12和0.10±0.02%。SPECT/CT显示良好的肿瘤摄取和最小的本底结合。这项研究展示了成功地利用两层噬菌体展示选择过程来鉴定具有出色SPECT/CT成像能力的卵巢癌亲和肽。
The often fatal outcome of ovarian cancer (OC) is related to inadequate detection methods, which may be overcome by development of nuclear imaging agents. Cancer targeting peptides have been identified using in vivo bacteriophage (phage) display technology; however, the majority of these ligands target tumor vasculature. To overcome this problem, a two-tier phage display method was employed to select an ovarian cancer targeting peptide with good pharmacokinetic and imaging properties. A fUSE5 15-amino acid peptide library was screened against xenografted human OC SKOV-3 tumors in mice, which was followed by selection against enriched SKOV-3 cells. The selected peptide RSLWSDFYASASRGP (J18) was synthesized with a GSG-spacer and a 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) chelator and radiolabeled with (111)In. SKOV-3 xenografted mice were used to evaluate the biodistribution and single photon emission computed tomography (SPECT) imaging capabilities of the radiolabeled peptide. Competitive binding experiments using (111)In-DOTA-GSG-J18 indicated that the peptide displayed a half maximal inhibitory concentration (IC50) value of 10.5 ± 1.1 μM. Biodistribution studies revealed that tumor uptake was 1.63 ± 0.68, 0.60 ± 0.32, 0.31 ± 0.12 and 0.10 ± 0.02% injected dose/g at 30 min, 1 h, 2 h and 4 h post-injection of (111)In-DOTA-GSG-J18, respectively. SPECT/CT imaging demonstrated good tumor uptake and minimal background binding. This study demonstrated successful utilization of a two-tier phage display selection process to identify an ovarian cancer avid peptide with excellent SPECT/CT imaging capabilities.