探索聚乙二醇化对药代动力学的影响:聚乙二醇对前列腺特异性膜抗原抑制剂的大小依赖性影响。

IF 3.1 3区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Yang Liu, Li Xia, Haiyang Li, Ping Cai, Sufan Tang, Yue Feng, Guangfu Liu, Yue Chen, Nan Liu, Wei Zhang, Zhijun Zhou
{"title":"探索聚乙二醇化对药代动力学的影响:聚乙二醇对前列腺特异性膜抗原抑制剂的大小依赖性影响。","authors":"Yang Liu, Li Xia, Haiyang Li, Ping Cai, Sufan Tang, Yue Feng, Guangfu Liu, Yue Chen, Nan Liu, Wei Zhang, Zhijun Zhou","doi":"10.1186/s13550-024-01071-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer-related deaths in men. Prostate-specific membrane antigen (PSMA) as a target has gained increasing attention. This research aims to investigate and understand how altering size of PEG impacts the in vitro and in vivo behavior and performance of PSMA inhibitors, with a specific focus on their pharmacokinetic characteristics and targeting properties.</p><p><strong>Results: </strong>Two <sup>68</sup>Ga-labeled PSMA-targeted radiotracers were developed, namely [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD, with varying sizes of polyethylene glycol (PEG). [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD had excellent affinity for PSMA with IC50 being 8.06 ± 0.91, 6.13 ± 0.79 nM, respectively. Both tracers enabled clear visualization of LNCaP tumors in PET images with excellent tumor-to-background contrast. They also revealed highly efficient uptake and internalization into LNCaP cells, increasing over time. The biodistribution studies demonstrated that both radioligands exhibited significant and specific uptake into LNCaP tumors. Furthermore, they were rapidly cleared through the renal pathway, as evidenced by [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD showing a tenfold and a fivefold less in renal uptake, respectively, compared to [<sup>68</sup>Ga]Ga-Flu-1 in 30 min. Both in vitro and in vivo experiments demonstrated that PEG size significantly impacted tumor-targeting and pharmacokinetic properties.</p><p><strong>Conclusions: </strong>These radiotracers have demonstrated their effectiveness in significantly reducing kidney uptake while maintaining the absorbed dose in tumors. Both radiotracers exhibited strong binding and internalization characteristics in vitro, displayed high specificity and affinity for PSMA in vivo.</p>","PeriodicalId":11611,"journal":{"name":"EJNMMI Research","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10850047/pdf/","citationCount":"0","resultStr":"{\"title\":\"Exploring the impact of PEGylation on pharmacokinetics: a size-dependent effect of polyethylene glycol on prostate-specific membrane antigen inhibitors.\",\"authors\":\"Yang Liu, Li Xia, Haiyang Li, Ping Cai, Sufan Tang, Yue Feng, Guangfu Liu, Yue Chen, Nan Liu, Wei Zhang, Zhijun Zhou\",\"doi\":\"10.1186/s13550-024-01071-z\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer-related deaths in men. Prostate-specific membrane antigen (PSMA) as a target has gained increasing attention. This research aims to investigate and understand how altering size of PEG impacts the in vitro and in vivo behavior and performance of PSMA inhibitors, with a specific focus on their pharmacokinetic characteristics and targeting properties.</p><p><strong>Results: </strong>Two <sup>68</sup>Ga-labeled PSMA-targeted radiotracers were developed, namely [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD, with varying sizes of polyethylene glycol (PEG). [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD had excellent affinity for PSMA with IC50 being 8.06 ± 0.91, 6.13 ± 0.79 nM, respectively. Both tracers enabled clear visualization of LNCaP tumors in PET images with excellent tumor-to-background contrast. They also revealed highly efficient uptake and internalization into LNCaP cells, increasing over time. The biodistribution studies demonstrated that both radioligands exhibited significant and specific uptake into LNCaP tumors. Furthermore, they were rapidly cleared through the renal pathway, as evidenced by [<sup>68</sup>Ga]Ga-PP4-WD and [<sup>68</sup>Ga]Ga-PP8-WD showing a tenfold and a fivefold less in renal uptake, respectively, compared to [<sup>68</sup>Ga]Ga-Flu-1 in 30 min. Both in vitro and in vivo experiments demonstrated that PEG size significantly impacted tumor-targeting and pharmacokinetic properties.</p><p><strong>Conclusions: </strong>These radiotracers have demonstrated their effectiveness in significantly reducing kidney uptake while maintaining the absorbed dose in tumors. Both radiotracers exhibited strong binding and internalization characteristics in vitro, displayed high specificity and affinity for PSMA in vivo.</p>\",\"PeriodicalId\":11611,\"journal\":{\"name\":\"EJNMMI Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-02-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10850047/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJNMMI Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13550-024-01071-z\",\"RegionNum\":3,\"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":"EJNMMI Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13550-024-01071-z","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
引用次数: 0

摘要

背景:前列腺癌是第二大高发癌症,也是导致男性癌症相关死亡的第五大原因。前列腺特异性膜抗原(PSMA)作为一种靶标已受到越来越多的关注。本研究旨在调查和了解改变 PEG 的大小如何影响 PSMA 抑制剂在体外和体内的行为和性能,特别关注其药代动力学特征和靶向特性:结果:研究人员开发了两种68Ga标记的PSMA靶向放射性racer,即[68Ga]Ga-PP4-WD和[68Ga]Ga-PP8-WD,其中聚乙二醇(PEG)的大小各不相同。[68Ga]Ga-PP4-WD和[68Ga]Ga-PP8-WD与PSMA的亲和力极佳,IC50分别为8.06 ± 0.91和6.13 ± 0.79 nM。这两种示踪剂都能在 PET 图像中清晰显示 LNCaP 肿瘤,肿瘤与背景对比度极佳。它们还显示了 LNCaP 细胞的高效摄取和内化,并随着时间的推移而增加。生物分布研究表明,这两种放射性配体在 LNCaP 肿瘤中都表现出显著的特异性摄取。此外,与[68Ga]Ga-Flu-1相比,[68Ga]Ga-PP4-WD和[68Ga]Ga-PP8-WD在30分钟内的肾脏摄取量分别减少了10倍和5倍,这证明它们能通过肾脏途径迅速清除。体外和体内实验都表明,PEG的大小对肿瘤靶向性和药动学特性有显著影响:结论:这些放射性racers在保持肿瘤吸收剂量的同时,显著降低了肾脏摄取量。这两种放射性racers在体外表现出很强的结合和内化特性,在体内对PSMA具有很高的特异性和亲和力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Exploring the impact of PEGylation on pharmacokinetics: a size-dependent effect of polyethylene glycol on prostate-specific membrane antigen inhibitors.

Background: Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer-related deaths in men. Prostate-specific membrane antigen (PSMA) as a target has gained increasing attention. This research aims to investigate and understand how altering size of PEG impacts the in vitro and in vivo behavior and performance of PSMA inhibitors, with a specific focus on their pharmacokinetic characteristics and targeting properties.

Results: Two 68Ga-labeled PSMA-targeted radiotracers were developed, namely [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD, with varying sizes of polyethylene glycol (PEG). [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD had excellent affinity for PSMA with IC50 being 8.06 ± 0.91, 6.13 ± 0.79 nM, respectively. Both tracers enabled clear visualization of LNCaP tumors in PET images with excellent tumor-to-background contrast. They also revealed highly efficient uptake and internalization into LNCaP cells, increasing over time. The biodistribution studies demonstrated that both radioligands exhibited significant and specific uptake into LNCaP tumors. Furthermore, they were rapidly cleared through the renal pathway, as evidenced by [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD showing a tenfold and a fivefold less in renal uptake, respectively, compared to [68Ga]Ga-Flu-1 in 30 min. Both in vitro and in vivo experiments demonstrated that PEG size significantly impacted tumor-targeting and pharmacokinetic properties.

Conclusions: These radiotracers have demonstrated their effectiveness in significantly reducing kidney uptake while maintaining the absorbed dose in tumors. Both radiotracers exhibited strong binding and internalization characteristics in vitro, displayed high specificity and affinity for PSMA in vivo.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
EJNMMI Research
EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-
CiteScore
5.90
自引率
3.10%
发文量
72
审稿时长
13 weeks
期刊介绍: EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信