Preliminary Evaluation of Astatine-211-Labeled Bombesin Derivatives for Targeted Alpha Therapy
Preliminary Evaluation of Astatine-211-Labeled Bombesin Derivatives for Targeted Alpha Therapy
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DOI：
10.1248/cpb.c20-00077
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发表时间：
2020-06-01
影响因子：
1.7
通讯作者：
Ogawa, Kazuma
中科院分区：
文献类型：
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作者：
Aoki, Miho;Zhao, Songji;Ogawa, Kazuma
目前有多种前列腺癌的诊断和治疗药物使用bombesin （BBN）衍生物，但astastine -211 （At-211）标记的BBN衍生物尚未被研究。本研究对At-211标记的BBN衍生物进行了初步评价。合成了几种具有不同连接体的非放射性碘引入BBN衍生物（ib -BBN），并测定了它们的结合亲和力。由于IB-3表现出与天然BBN相当的亲和力，合成了[At-211]AB-3， [At-211]AB-3的放射化学产率为28.2 +/- 2.4%，放射化学纯度为bbb90 %。进行了稳定性研究和细胞内化/外化实验。[At-211]AB-3被细胞吸收并内化；然而，随着时间的推移，放射性从细胞中流出。此外，我们还在PC-3荷瘤小鼠体内评估了[At-211]AB-3在有或没有过量BBN的情况下的生物分布。尽管在小鼠血浆中的稳定性较差，但在PC-3荷瘤小鼠中，[At-211]AB-3在肿瘤组织中积累（4.05 +/- 0.73%ID/g），被过量的天然BBN （2.56 +/- 0.24%ID/g）抑制。在各个器官中积累的放射性可能是由于游离的At-211。小鼠血浆中的肽降解和细胞的放射性外排是改进的领域。开发at -211标记的BBN衍生物需要修改BBN序列并防止破坏。
There are various diagnostic and therapeutic agents for prostate cancer using bombesin (BBN) derivatives, but astatine-211 (At-211)-labeled BBN derivatives have yet to be studied. This study presented a preliminary evaluation of At-211- labeled BBN derivative. Several nonradioactive iodine-introduced BBN derivatives (IB-BBNs) with different linkers were synthesized and their binding affinities measured. Because IB-3 exhibited a comparable affinity to native BBN, [At-211]AB-3 was synthesized and the radiochemical yields of [At-211] AB-3 was 28.2 +/- 2.4%, with a radiochemical purity of >90%. The stability studies and cell internalization/externalization experiments were performed. [At-211]AB-3 was taken up by cells and internalized; however, radioactivity effluxed from cells over time. In addition, the biodistribution of [At-211]AB-3, with and without excess amounts of BBN, were evaluated in PC-3 tumor-bearing mice. Despite poor stability in murine plasma, [At-211]AB-3 accumulated in tumor tissue (4.05 +/- 0.73%ID/g) in PC-3 tumor-bearing mice, which was inhibited by excess native BBN (2.56 +/- 0.24%ID/g). Accumulated radioactivity in various organs is probably due to free At-211. Peptide degradation in murine plasma and radioactivity efflux from cells are areas of improvement. The development of At-211-labeled BBN derivatives requires modifying the BBN sequence and preventing deastatination.