Comparison of a monomeric and dimeric radiolabeled RGD-peptide for tumor targeting
Comparison of a monomeric and dimeric radiolabeled RGD-peptide for tumor targeting
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DOI：
10.1089/108497802320970244
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发表时间：
2002-12-01
影响因子：
3.4
通讯作者：
Boerman, OC
中科院分区：
文献类型：
--
作者：
Janssen, M;Oyen, WJG;Boerman, OC
α（v）β（3）整联蛋白是一种在萌芽内皮细胞上表达的跨膜异二聚体蛋白，与细胞外基质蛋白如玻连蛋白的精氨酸-甘氨酸-天冬氨酸（RGD）氨基酸序列结合。不断生长的恶性肿瘤需要血管生成。因此，alpha（v）beta（3）在生长的肿瘤中优先表达，并且是放射性标记的RGD肽的潜在靶点。在这项研究中，我们比较了单体放射性标记的RGD肽与二聚体类似物的肿瘤靶向特性。两种肽均通过肼基烟酰胺（=HYNIC）部分用Tc-99 m进行放射性标记，形成Tc-99 m-HYNIC-c（RGDfK）和Tc-99 m-HYNIC-E-[c（RGDfK）]（2）。在体外，IC 50显示二聚体对α（v）β（3）整联蛋白的亲和力是单体的10倍（0.1与1.0 nM）。在皮下生长OVCAR-3卵巢癌异种移植物的无胸腺雌性BALB/c小鼠中，二聚体和单体的肿瘤摄取峰值分别为5.8 +/-0.7% ID/g和5.2 +/-0.6% ID/g。在注射后1、2和4 h（p.i.）肿瘤中二聚体的摄取显著高于单体类似物的摄取。肿瘤-血液比在感染后24小时最高。两种化合物的值均为63。在所有时间点，二聚体的肾脏保留显著高于单体的肾脏保留。总之，在该小鼠模型中，二聚体RGD-肽在肿瘤中的保留比单体类似物更好，这很可能是由于与靶细胞的二价相互作用。此外，二聚体肽的肾保留高于单体肽。
The alpha(v)beta(3) integrin, a transmembrane heterodimeric protein expressed on sprouting endothelial cells, binds to the arginine-glycine-aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin. Growing malignant tumors continuously require angiogenesis. As a result, alpha(v)beta(3) is preferentially expressed in growing tumors and is a potential target for radiolabeled RGD-peptides.In this study we compared the tumor targeting characteristics of a monomeric radiolabeled RGD-peptide with those of a dimeric analogue. Both peptides were radiolabeled with Tc-99m via the hydrazinonicotinamid (=HYNIC) moiety to form Tc-99m-HYNIC-c(RGDfK) and Tc-99m-HYNIC-E-[c(RGDfK)](2). In vitro, the IC50 showed a 10-fold higher affinity of the dimer for the alpha(v)beta(3) integrin as compared to the monomer (0.1 vs. 1.0 nM). In athymic female BALB/c mice with subcutaneously growing OVCAR-3 ovarian carcinoma xenografts, tumor uptake peaked at 5.8 +/- 0.7 %ID/g and 5.2 +/- 0.6 %ID/g for the dimer and the monomer, respectively. At 1, 2, and 4 h postinjection (p.i.) uptake of the dimer in the tumor was significantly higher than that of the monomeric analogue. Tumor-to-blood ratios were highest at 24 h p.i. at a value of 63 for both compounds. At all timepoints kidney retention of the dimer was significantly higher as compared to kidney retention of the monomer. In conclusion, in this mouse model the dimeric RGD-peptide showed better retention in the tumor than the monomeric analogue, most likely due to the bivalent interaction with the target cell. Furthermore, kidney retention of the dimeric peptide was higher than that of the monomeric peptide.