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NeoBOMB1,一种用于乳腺癌治疗学的 GRPR 拮抗剂:[Ga]NeoBOMB1 在 T-47D 细胞和荷瘤小鼠中进行的临床前研究的初步结果。

NeoBOMB1, a GRPR-Antagonist for Breast Cancer Theragnostics: First Results of a Preclinical Study with [Ga]NeoBOMB1 in T-47D Cells and Tumor-Bearing Mice.

机构信息

Molecular Radiopharmacy, INRASTES/NCSR "Demokritos", 15310 Athens, Greece.

Department of Radiology, Erasmus MC, 3015 CN Rotterdam, The Netherlands.

出版信息

Molecules. 2017 Nov 11;22(11):1950. doi: 10.3390/molecules22111950.

Abstract

The GRPR-antagonist-based radioligands [Ga/In/Lu]NeoBOMB1 have shown excellent theragnostic profiles in preclinical prostate cancer models, while [Ga]NeoBOMB1 effectively visualized prostate cancer lesions in patients. We were further interested to explore the theragnostic potential of NeoBOMB1 in GRPR-positive mammary carcinoma, by first studying [Ga]NeoBOMB1 in breast cancer models; Methods: We investigated the profile of [Ga]NeoBOMB1, a [Ga]NeoBOMB1 surrogate, in GRPR-expressing T-47D cells and animal models; : NeoBOMB1 (ICs of 2.2 ± 0.2 nM) and [Ga]NeoBOMB1 (ICs of 2.5 ± 0.2 nM) exhibited high affinity for the GRPR. At 37 °C [Ga]NeoBOMB1 strongly bound to the T-47D cell-membrane (45.8 ± 0.4% at 2 h), internalizing poorly, as was expected for a radioantagonist. [Ga]NeoBOMB1 was detected >90% intact in peripheral mouse blood at 30 min pi. In mice bearing T-47D xenografts, [Ga]NeoBOMB1 specifically localized in the tumor (8.68 ± 2.9% ID/g vs. 0.6 ± 0.1% ID/g during GRPR-blockade at 4 h pi). The unfavorably high pancreatic uptake could be considerably reduced (206.29 ± 17.35% ID/g to 42.46 ± 1.31% ID/g at 4 h pi) by increasing the NeoBOMB1 dose from 10 pmol to 200 pmol, whereas tumor uptake remained unaffected. Notably, tumor values did not decline from 1 to 24 h pi; Conclusions: [Ga]NeoBOMB1 can successfully target GRPR-positive breast cancer in animals with excellent prospects for clinical translation.

摘要

基于 GRPR 拮抗剂的放射性配体 [Ga/In/Lu]NeoBOMB1 在前列腺癌模型的临床前研究中表现出优异的治疗诊断学特性,而 [Ga]NeoBOMB1 可有效显示患者的前列腺癌病变。我们进一步有兴趣探索 NeoBOMB1 在 GRPR 阳性乳腺癌中的治疗诊断学潜力,首先研究 [Ga]NeoBOMB1 在乳腺癌模型中的作用;方法:我们研究了 [Ga]NeoBOMB1 ( NeoBOMB1 替代品)在表达 GRPR 的 T-47D 细胞和动物模型中的特征;: NeoBOMB1(IC50 为 2.2 ± 0.2 nM)和 [Ga]NeoBOMB1(IC50 为 2.5 ± 0.2 nM)对 GRPR 具有高亲和力。在 37°C 时,[Ga]NeoBOMB1 强烈结合至 T-47D 细胞膜(在 2 h 时为 45.8 ± 0.4%),内化作用较差,这与放射性拮抗剂一致。在注射后 30 分钟时,在周围的小鼠血液中检测到 >90%的完整的 [Ga]NeoBOMB1。在携带 T-47D 异种移植瘤的小鼠中,[Ga]NeoBOMB1 特异性地定位于肿瘤(在注射后 4 h 时,与 GRPR 阻断时的 0.6 ± 0.1% ID/g 相比,为 8.68 ± 2.9% ID/g)。通过将 NeoBOMB1 剂量从 10 pmol 增加至 200 pmol,可大大降低胰腺摄取量(从注射后 4 h 的 206.29 ± 17.35% ID/g 降低至 42.46 ± 1.31% ID/g),而肿瘤摄取量保持不变。值得注意的是,肿瘤值在 1 至 24 h 期间并未下降;结论:[Ga]NeoBOMB1 可成功靶向 GRPR 阳性乳腺癌,具有良好的临床转化前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b2d9/6150197/560157aab5e1/molecules-22-01950-g001.jpg

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