PEG 化对 HER2 靶向复古 A9 肽类似物的影响。

IF 3.6 4区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Nuclear medicine and biology Pub Date : 2024-10-05 DOI:10.1016/j.nucmedbio.2024.108963
Sushree Arpitabala Yadav , V. Kusum Vats , Rohit Sharma , Archana Mukherjee , Drishty Satpati
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引用次数: 0

摘要

乳腺癌中 HER2 受体水平的升高可以通过受体特异性肽作为靶标,以核医学方法进行精确检测和治疗。此前报道的A9肽复古类似物显示了HER2特异性和良好的药代动力学特征。因此,为了进一步改善 rL-A9 多肽的循环时间,我们在固相合成过程中在多肽的 N 端引入了长聚乙二醇链(PEG12),并研究了 PEG 化对生物特征的影响。在表达 HER2 的人类乳腺癌 SKBR3 细胞中,[177Lu]Lu-DOTA-PEG12-rL-A9 表现出较高的特异性细胞摄取率(5.94 ± 0.09 %)和较低的纳摩尔结合亲和力(Kd = 34.58 ± 12.78 nM)。在所有研究时间点(3、24、48 小时),雌性 SCID 小鼠诱导的 SKBR3 肿瘤对[177Lu]Lu-DOTA-rL-A9 的摄取量均高于非 PEG 化的放射多肽。通过阻断研究,肿瘤中的放射性积累减少了 51%,这表明放射肽具有特异性。与[177Lu]Lu-DOTA-rL-A9相比,[177Lu]Lu-DOTA-PEG12-rL-A9在48小时内的肿瘤胃比和肿瘤肠比均有所提高,这将为更好地对比和划分转移部位铺平道路。
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Influence of PEGylation on HER2-targeting retro A9 peptide analogue
Elevated levels of HER2 receptor in breast cancer can be targeted through receptor-specific peptides for precise detection and therapy by nuclear medicine approach. Previously reported retro analogue of A9 peptide had shown HER2-specificity with promising pharmacokinetic features. Hence, with an aim of further improving the circulation time of rL-A9 radiopeptide, long polyethylene glycol chain (PEG12) was introduced at the N-terminus of the peptide during solid phase synthesis and influence of PEGylation on biological profile was studied. [177Lu]Lu-DOTA-PEG12-rL-A9 demonstrated high specific cellular uptake (5.94 ± 0.09 %) in HER2-expressing human breast carcinoma SKBR3 cells and low nanomolar binding affinity (Kd = 34.58 ± 12.78 nM). Uptake in SKBR3 tumors induced in female SCID mice was higher at all the time points investigated (3, 24, 48 h) in comparison to the non-PEGylated radiopeptide, [177Lu]Lu-DOTA-rL-A9. Blocking studies led to 51 % reduction in accumulation of radioactivity in the tumor indicating specificity of the radiopeptide. Improved tumor-to-stomach and tumor-to-intestine ratios for [177Lu]Lu-DOTA-PEG12-rL-A9 compared to [177Lu]Lu-DOTA-rL-A9 at 48 h shall pave the way for better contrast and delineation of metastatic sites.
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来源期刊
Nuclear medicine and biology
Nuclear medicine and biology 医学-核医学
CiteScore
6.00
自引率
9.70%
发文量
479
审稿时长
51 days
期刊介绍: Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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