{"title":"PEG 化对 HER2 靶向复古 A9 肽类似物的影响。","authors":"Sushree Arpitabala Yadav , V. Kusum Vats , Rohit Sharma , Archana Mukherjee , Drishty Satpati","doi":"10.1016/j.nucmedbio.2024.108963","DOIUrl":null,"url":null,"abstract":"<div><div>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 (PEG<sub>12</sub>) was introduced at the N-terminus of the peptide during solid phase synthesis and influence of PEGylation on biological profile was studied. [<sup>177</sup>Lu]Lu-DOTA-PEG<sub>12</sub>-rL-A9 demonstrated high specific cellular uptake (5.94 ± 0.09 %) in HER2-expressing human breast carcinoma SKBR3 cells and low nanomolar binding affinity (K<sub>d</sub> = 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, [<sup>177</sup>Lu]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 [<sup>177</sup>Lu]Lu-DOTA-PEG<sub>12</sub>-rL-A9 compared to [<sup>177</sup>Lu]Lu-DOTA-rL-A9 at 48 h shall pave the way for better contrast and delineation of metastatic sites.</div></div>","PeriodicalId":19363,"journal":{"name":"Nuclear medicine and biology","volume":"138 ","pages":"Article 108963"},"PeriodicalIF":3.6000,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Influence of PEGylation on HER2-targeting retro A9 peptide analogue\",\"authors\":\"Sushree Arpitabala Yadav , V. Kusum Vats , Rohit Sharma , Archana Mukherjee , Drishty Satpati\",\"doi\":\"10.1016/j.nucmedbio.2024.108963\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 (PEG<sub>12</sub>) was introduced at the N-terminus of the peptide during solid phase synthesis and influence of PEGylation on biological profile was studied. [<sup>177</sup>Lu]Lu-DOTA-PEG<sub>12</sub>-rL-A9 demonstrated high specific cellular uptake (5.94 ± 0.09 %) in HER2-expressing human breast carcinoma SKBR3 cells and low nanomolar binding affinity (K<sub>d</sub> = 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, [<sup>177</sup>Lu]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 [<sup>177</sup>Lu]Lu-DOTA-PEG<sub>12</sub>-rL-A9 compared to [<sup>177</sup>Lu]Lu-DOTA-rL-A9 at 48 h shall pave the way for better contrast and delineation of metastatic sites.</div></div>\",\"PeriodicalId\":19363,\"journal\":{\"name\":\"Nuclear medicine and biology\",\"volume\":\"138 \",\"pages\":\"Article 108963\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-10-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nuclear medicine and biology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0969805124000891\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nuclear medicine and biology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0969805124000891","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
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.
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.