111In-labeled galectin-3-targeting peptide as a SPECT agent for imaging breast tumors
111In-labeled galectin-3-targeting peptide as a SPECT agent for imaging breast tumors
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DOI：
10.2967/jnumed.107.048751
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发表时间：
2008-05-01
影响因子：
9.3
通讯作者：
Deutscher, Susan L.
中科院分区：
文献类型：
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作者：
Kumar, Senthil R.;Deutscher, Susan L.
Galectin-3是β-半乳糖苷结合动物凝集素Galectin家族的成员。Galectin-3在多种肿瘤中高表达，与肿瘤生长和转移有关。鉴于这一事实，放射性标记的Galectin-3靶向分子可能对表达Galectin-3的肿瘤的非侵入性成像以及靶向放射性核素治疗有用。在这项研究中，评价了从噬菌体展示中鉴定的Galectin-3-Avid多肽在人乳腺癌细胞和人乳腺肿瘤荷瘤小鼠中的肿瘤细胞靶向性和SPECT特性。方法：以甘氨酸-丝氨酸-甘氨酸(Gly-Ser-Gly，GSG)为连接基合成半乳凝素-3-亲和肽G3-C12(ANTPCGPYTHDCPVKR)。与1，4，7，10-四氮杂环十二烷-N，N‘，N’‘，N’-四乙酸偶联后，用In-111标记。用高效液相色谱法对化合物的放化纯度和稳定性进行了评价。用表达Galectin-3的人乳腺癌细胞MDA-MB-435来表征该放射性标记化合物的体外结合特性。以携带MDA-MB-435异种移植瘤的SCID小鼠作为体内模型，用In-111标记的多肽进行体内分布和成像研究。结果：In-111-DOTA(GSG)-G3-C12可与表达Galectin-3的MDA-MB-435细胞特异性结合。该标记多肽在血清中稳定存在，在尿液中保持不变，竞争结合实验表明，该标记多肽对培养的乳腺癌细胞的抑制浓度为200.00+/-6.70 nM，抑制率为50%。体内生物分布研究表明，肿瘤在注射示踪剂后30min、1.0h和2.0h的摄取百分率分别为1.2+/-0.24、0.75+/-0.05和0.6+/-0.04(平均+/-SD)。In-111-DOTA(GSG)-G3-C12的SPECT/CT研究显示，荷瘤小鼠对肿瘤具有良好的摄取和对比度。在注射后2小时，在非放射性标记的对应物存在下，成功阻断(52%)In-111-DOTA(GSG)G3-C12的体内摄取，证明了多肽结合的特异性。结论：本研究证明了一种新的放射性标记多肽用于Galectin-3阳性乳腺肿瘤的非侵入性成像是成功的。这种多肽可能是未来临床应用的一个有前途的候选者。
Galectin-3 is a member of the galectin family of beta-galactoside-binding animal lectins. Galectin-3 is overexpressed in a wide range of neoplasms and is associated with tumor growth and metastases. Given this fact, radiolabeled galectin-3-targeting molecules may be useful for the noninvasive imaging of tumors expressing galectin-3, as well as for targeted radionuclide therapy. In this study, the tumor cell-targeting and SPECT properties of a galectin-3-avid peptide identified from bacteriophage display were evaluated in human breast carcinoma cells and in human breast tumor-bearing mice. Methods: The galectin-3-avid peptide G3-C12 (ANTPCGPYTHDCPVKR) was synthesized with a Gly-Ser-Gly (GSG) linker at the amino terminus. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N',N '',N'''-tetraacetic acid (DOTA), the peptide was labeled with In-111. The radiochemical purity and stability of the compound was assessed by high-performance liquid chromatography. MDA-MB-435 human breast carcinoma cells expressing galectin-3 were used to characterize the in vitro binding properties of the radiolabeled compound. SCID mice bearing MDA-MB-435 xenografts were used as an in vivo model for biodistribution and imaging studies with the In-111-labeled peptide. Results: In-111-DOTA(GSG)-G3-C12 bound specifically to galectin-3-expressing MDA-MB-435 cells. The radiolabeled peptide was stable in serum and was found intact in excreted urine for at least 1 h. Competitive binding experiments indicated that the radiolabeled peptide exhibited an inhibitory concentration of 50% of 200.00 +/- 6.70 nM for culture breast carcinoma cells. In vivo biodistribution studies revealed that tumor uptake was 1.2 +/- 0.24, 0.75 +/- 0.05, and 0.6 +/- 0.04 (mean +/- SD) percentage injected dose per gram at 30 min, 1.0 h, and 2.0 h after injection of the radiotracer, respectively. SPECT/CT studies with In-111-DOTA(GSG)-G3-C12 showed excellent tumor uptake and contrast in the tumor-bearing mice. Specificity of peptide binding was demonstrated by successful blocking (52%) of in vivo tumor uptake of In-111-DOTA(GSG)G3-C12 in the presence of its nonradiolabeled counterpart at 2 h after injection. Conclusion: This study demonstrated the successful use of a new radiolabeled peptide for the noninvasive imaging of galectin-3-positive breast tumors. This peptide may be a promising candidate for future clinical applications.