Department of Radiology, Biophysics, Stanford University School of Medicine, Stanford, CA94305-5484, USA.
Bioconjug Chem. 2009 May 20;20(5):1016-25. doi: 10.1021/bc9000245.
Radiolabeled RGD (Arg-Gly-Asp) and bombesin (BBN) radiotracers that specifically target integrin alpha(v)beta(3) and gastrin releasing peptide receptor (GRPR) are both promising radiopharmaceuticals for tumor imaging. We recently designed and synthesized a RGD-BBN heterodimeric peptide with both RGD and BBN motifs in one single molecule. The (18)F-labeled RGD-BBN heterodimer exhibited dual integrin alpha(v)beta(3) and GRPR targeting in a PC-3 prostate cancer model. In this study we investigated whether radiolabeled RGD-BBN tracers can be used to detect breast cancer by using microPET. Cell binding assay demonstrated that the high GRPR expressing breast cancer cells typically express low to moderate level of integrin alpha(v)beta(3), while high integrin alpha(v)beta(3) expressing breast cancer cells have negligible level of GRPR. We labeled RGD-BBN heterodimer with three positron emitting radionuclides (18)F, (64)Cu, and (68)Ga and investigated the corresponding PET radiotracers in both orthotopic T47D (GRPR(+)/low integrin alpha(v)beta(3)) and MDA-MB-435 (GRPR(-)/integrin alpha(v)beta(3)(+)) breast cancer models. The three radiotracers all possessed in vitro dual integrin alpha(v)beta(3) and GRPR binding affinity. The advantages of the RGD-BBN radiotracers over the corresponding BBN analogues are obvious for imaging MDA-MB-435 (GRPR(-)/integrin alpha(v)beta(3)(+)) tumor. (18)F-FB-PEG(3)-RGD-BBN showed lower tumor uptake than (64)Cu-NOTA-RGD-BBN and (68)Ga-NOTA-RGD-BBN but was able to visualize breast cancer tumors with high contrast. Synthesis of (64)Cu-NOTA-RGD-BBN and (68)Ga-NOTA-RGD-BBN is much faster and easier than (18)F-FB-PEG(3)-RGD-BBN. (64)Cu-NOTA-RGD-BBN showed prolonged tumor uptake but also higher liver retention and kidney uptake than (68)Ga-NOTA-RGD-BBN and (18)F-FB-PEG(3)-RGD-BBN. (68)Ga-NOTA-RGD-BBN possessed high tumor signals but also relatively high background uptake compared with the other two radiotracers. In summary, the prosthetic labeling groups, chelators, and isotopes all have a profound effect on the tumor targeting efficacy and in vivo kinetics of the RGD-BBN tracers for dual integrin and GRPR recognition. Further development of suitably labeled RGD-BBN tracers for PET imaging of cancer is warranted.
放射性标记的 RGD（精氨酸-甘氨酸-天冬氨酸）和 bombesin（BBN）放射性示踪剂特异性靶向整合素 alpha(v)beta(3)和胃泌素释放肽受体（GRPR），都是肿瘤成像有前途的放射性药物。我们最近设计并合成了一种 RGD-BBN 杂二聚体肽，其中一个分子中同时具有 RGD 和 BBN 基序。（18）F 标记的 RGD-BBN 杂二聚体在 PC-3 前列腺癌模型中表现出双重整合素 alpha(v)beta(3)和 GRPR 靶向性。在这项研究中，我们使用 microPET 研究了放射性标记的 RGD-BBN 示踪剂是否可用于检测乳腺癌。细胞结合实验表明，高 GRPR 表达的乳腺癌细胞通常表达低至中度水平的整合素 alpha(v)beta(3)，而高整合素 alpha(v)beta(3)表达的乳腺癌细胞几乎没有 GRPR 表达。我们用三种正电子发射放射性核素（18）F、（64）Cu 和（68）Ga 标记了 RGD-BBN 杂二聚体，并在同源性 T47D（GRPR(+)/低整合素 alpha(v)beta(3)）和 MDA-MB-435（GRPR(-)/整合素 alpha(v)beta(3)(+))乳腺癌模型中研究了相应的 PET 放射性示踪剂。三种放射性示踪剂均具有体外双重整合素 alpha(v)beta(3)和 GRPR 结合亲和力。与相应的 BBN 类似物相比，RGD-BBN 放射性示踪剂在成像 MDA-MB-435（GRPR(-)/整合素 alpha(v)beta(3)(+))肿瘤方面具有明显优势。（18）F-FB-PEG(3)-RGD-BBN 的肿瘤摄取低于（64）Cu-NOTA-RGD-BBN 和（68）Ga-NOTA-RGD-BBN，但能够以高对比度可视化乳腺癌肿瘤。（64）Cu-NOTA-RGD-BBN 和（68）Ga-NOTA-RGD-BBN 的合成比（18）F-FB-PEG(3)-RGD-BBN 快得多，也容易得多。（64）Cu-NOTA-RGD-BBN 显示出延长的肿瘤摄取，但与（68）Ga-NOTA-RGD-BBN 和（18）F-FB-PEG(3)-RGD-BBN 相比，肝脏保留和肾脏摄取更高。（68）Ga-NOTA-RGD-BBN 具有高肿瘤信号，但与其他两种放射性示踪剂相比，背景摄取也相对较高。总之，假体标记基团、螯合剂和同位素都对 RGD-BBN 示踪剂用于双重整合素和 GRPR 识别的肿瘤靶向效果和体内动力学有深远影响。需要进一步开发适合 PET 成像的 RGD-BBN 放射性示踪剂用于癌症。
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