Department of Oncology, University of Alberta, Edmonton, AB, Canada.
Department of Oncology, University of Alberta, Edmonton, AB, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada.
Nucl Med Biol. 2020 Nov-Dec;90-91:74-83. doi: 10.1016/j.nucmedbio.2020.10.005. Epub 2020 Oct 29.
Radiolabeled peptides play a central role in nuclear medicine as radiotheranostics for targeted imaging and therapy of cancer. We have recently proposed the use of metabolically stabilized GRPR antagonist BBN2 for radiolabeling with F and Ga and subsequent PET imaging of GRPRs in prostate cancer. The present work studied the impact of Sc- and Ga-labeled DOTA complexes attached to GRPR antagonist BBN2 on the in vitro GRPR binding affinity, and their biodistribution and tumor uptake profiles in MCF7 breast and PC3 prostate cancer models.
DOTA-Ava-BBN2 was radiolabeled with radiometals Ga and Sc. Gastrin-releasing peptide receptor (GRPR) affinities of peptides were assessed in PC3 prostate cancer cells. GRPR expression profiles were studied in human breast cancer tissue samples and MCF7 breast cancer cells. PET imaging of Ga- and Sc-labeled peptides was performed in MCF7 and PC3 xenografts as breast and prostate cancer models.
Radiopeptides [Ga]Ga-DOTA-Ava-BBN2 and [Sc]Sc-DOTA-Ava BBN2 were prepared in radiochemical yields of 70-80% (decay-corrected), respectively. High binding affinities were found for both peptides (IC = 15 nM (Ga) and 5 nM (Sc)). Gene expression microarray analysis revealed high GRPR mRNA expression levels in estrogen receptor (ER)-positive breast cancer, which was further confirmed with Western blot and immunohistochemistry. However, PET imaging showed only low tumor uptake of both radiotracers in MCF7 xenografts ([Ga]Ga-DOTA-BBN2 (SUV 0.27 ± 0.06); [Sc]Sc-DOTA-BBN2 (SUV 0.20 ± 0.03)). In contrast, high tumor uptake and retention were found for both radiopeptides in PC3 tumors ([Ga]Ga-DOTA-BBN2 (SUV 0.46 ± 0.07); [Sc]Sc-DOTA-BBN2 (SUV 0.51 ± 0.11)).
Comparison of Ga- and Sc-labeled DOTA-Ava-BBN2 peptides revealed slight but noticeable differences of the radiometal with an impact on the in vitro GRPR receptor binding properties in PC3 cells. No differences were found in their in vivo biodistribution profiles in MCF7 and PC3 xenografts. Radiopeptides [Ga]Ga-DOTA-Ava-BBN2 and [Sc]Sc-DOTA-Ava-BBN2 displayed comparable tumor uptake and retention profiles with rapid blood and renal clearance profiles in both tumor models.
The favorable PET imaging performance of [Sc]Sc-DOTA-Ava-BBN2 in prostate cancer should warrant the development of an [Sc]Sc-DOTA-Ava-BBN2 analog for clinical translation which comes with a main γ-line of much lower energy and intensity compared to Sc.
放射性标记肽在核医学中作为靶向成像和癌症治疗的放射治疗剂发挥着核心作用。我们最近提出使用代谢稳定的 GRPR 拮抗剂 BBN2 进行 F 和 Ga 的放射性标记，随后对前列腺癌中的 GRPR 进行 PET 成像。本研究研究了 GRPR 拮抗剂 BBN2 上附着的 Sc 和 Ga 标记的 DOTA 络合物对体外 GRPR 结合亲和力的影响，以及它们在 MCF7 乳腺癌和 PC3 前列腺癌模型中的生物分布和肿瘤摄取特征。
用放射性金属 Ga 和 Sc 标记 DOTA-Ava-BBN2。在 PC3 前列腺癌细胞中评估肽的胃泌素释放肽受体 (GRPR) 亲和力。在人乳腺癌组织样本和 MCF7 乳腺癌细胞中研究 GRPR 表达谱。在 MCF7 和 PC3 异种移植瘤中进行 Ga 和 Sc 标记肽的 PET 成像，作为乳腺癌和前列腺癌模型。
放射性肽 [Ga]Ga-DOTA-Ava-BBN2 和 [Sc]Sc-DOTA-Ava-BBN2 的放射化学产率分别为 70-80%（衰减校正）。两种肽均具有高结合亲和力（IC = 15 nM（Ga）和 5 nM（Sc））。基因表达微阵列分析显示，雌激素受体 (ER) 阳性乳腺癌中 GRPR mRNA 表达水平较高，Western blot 和免疫组化进一步证实了这一点。然而，PET 成像仅显示两种放射性示踪剂在 MCF7 异种移植瘤中的肿瘤摄取率均较低[Ga]Ga-DOTA-BBN2（SUV 0.27 ± 0.06）；[Sc]Sc-DOTA-BBN2（SUV 0.20 ± 0.03）]。相比之下，两种放射性肽在 PC3 肿瘤中均显示出较高的肿瘤摄取和保留[Ga]Ga-DOTA-BBN2（SUV 0.46 ± 0.07）；[Sc]Sc-DOTA-BBN2（SUV 0.51 ± 0.11）]。
比较 Ga 和 Sc 标记的 DOTA-Ava-BBN2 肽显示出轻微但明显的放射性金属差异，对 PC3 细胞中 GRPR 受体结合特性有影响。在 MCF7 和 PC3 异种移植瘤中，它们的体内生物分布特征没有差异。放射性肽 [Ga]Ga-DOTA-Ava-BBN2 和 [Sc]Sc-DOTA-Ava-BBN2 在两种肿瘤模型中均表现出相似的肿瘤摄取和保留特征，具有快速的血液和肾脏清除特征。
[Sc]Sc-DOTA-Ava-BBN2 在前列腺癌中的良好 PET 成像性能应保证开发用于临床转化的 [Sc]Sc-DOTA-Ava-BBN2 类似物，与 Sc 相比，它具有更低的主 γ 线能量和强度。
