An Integrin Alpha 6-Targeted Radiotracer with Improved Receptor Binding Affinity and Tumor Uptake.,Bioconjugate Chemistry

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An Integrin Alpha 6-Targeted Radiotracer with Improved Receptor Binding Affinity and Tumor Uptake.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-05-07 , DOI: 10.1021/acs.bioconjchem.0c00170
Qi Luo _{1,

2} , Guangjie Yang ₃ , Hannan Gao ₃ , Yanpu Wang ₃ , Chuangwei Luo ₃ , Xiaotu Ma _{1,

2} , Yu Gao _{1,

2} , Xiaoda Li ₄ , Huiyun Zhao ₄ , Bing Jia ₃ , Jiyun Shi ₁ , Fan Wang _{1,

3}

Affiliation

In this study, we reported a 99mTc-labeled integrin α6-targeted peptide as the molecular imaging probe for tumor imaging by single-photon emission computed tomography (SPECT). We found that replacing Cys-Cys cyclized RWY peptide (sequence: cCRWYDENAC) with lactam-bridged cyclic cKiE peptide (sequence: cKRWYDENAisoE) did not sacrifice the integrin α6-binding affinity and specificity of cKiE radiotracer. To further improve the radiotracer's tumor targeting capability, the dimerized cKiE peptide (termed cKiE2) was designed, and the corresponding radiotracer 99mTc-cKiE2 was evaluated for tumor uptake and in vivo pharmacokinetics properties in tumor models. We found that cKiE2 showed higher binding affinity to integrin α6 than did monomeric RWY or cKiE peptide. The biodistribution results showed that the tumor uptake of 99mTc-cKiE2 was twice higher than that of 99mTc-RWY (3.20 ± 0.12 vs 1.26 ± 0.06 %ID/g, P < 0.001) at 0.5 h postinjection. The tumor to nontargeting tissue ratios were also enhanced in most normal organs. Specificity of 99mTc-cKiE2 for integrin α6 was demonstrated by competitive blocking of tumor uptake with excess cold peptide (3.20 ± 0.24 to 1.38 ± 0.23 %ID/g, P < 0.001). The integrin α6-positive tumors were clearly visualized by 99mTc-cKiE2/SPECT with low background except with a relatively high kidney uptake. The tumor uptake of 99mTc-cKiE2 correlates well with the tumor integrin α6 expression levels in a linear fashion (R2 = 0.9623). We also compared 99mTc-cKiE2 with an integrin αvβ3-targeted radiotracer 99mTc-3PRGD2 in the orthotopic hepatocellular carcinoma tumor models. We found that the orthotopic tumor was clearly visualized with 99mTc-cKiE2. 99mTc-3PRGD2 imaging did not show tumor contours in situ as clearly as 99mTc-cKiE2. The tumor-to-liver ratios of 99mTc-cKiE2 and 99mTc-3PRGD2 were 2.20 ± 0.17 and 0.85 ± 0.20. In conclusion, 99mTc-cKiE2 is an improved SPECT radiotracer for imaging integrin α6-positive tumors and has great potential for further clinical application.

中文翻译：

具有改善的受体结合亲和力和肿瘤吸收的整合素α6靶向放射性示踪剂。

在这项研究中，我们报道了99mTc标记的整联蛋白α6靶向肽作为通过单光子发射计算机断层扫描（SPECT）进行肿瘤成像的分子成像探针。我们发现，用内酰胺桥环cKiE肽（序列：cKRWYDENAisoE）代替Cys-Cys环化的RWY肽（序列：cCRWYDENAC）不会牺牲整联蛋白α6-结合亲和力和cKiE放射性示踪剂的特异性。为了进一步提高放射性示踪剂的肿瘤靶向能力，设计了二聚化的cKiE肽（称为cKiE2），并评估了相应的放射性示踪剂99mTc-cKiE2在肿瘤模型中的肿瘤吸收和体内药代动力学特性。我们发现与单体RWY或cKiE肽相比，cKiE2对整联蛋白α6的结合亲和力更高。生物分布结果表明，注射后0.5 h，99mTc-cKiE2的肿瘤摄取是99mTc-RWY的两倍（3.20±0.12 vs 1.26±0.06％ID / g，P <0.001）。在大多数正常器官中，肿瘤与非靶向组织的比率也有所提高。99mTc-cKiE2对整联蛋白α6的特异性通过过量的冷肽（3.20±0.24至1.38±0.23％ID / g，P <0.001）竞争性阻断肿瘤摄取来证明。通过99mTc-cKiE2 / SPECT可以清晰地观察到整合素α6阳性肿瘤，其背景较低，但肾脏摄取相对较高。肿瘤摄取99mTc-cKiE2与肿瘤整合素α6表达水平呈线性相关（R2 = 0.9623）。我们还在原位肝细胞癌肿瘤模型中比较了99mTc-cKiE2与靶向整联蛋白αvβ3的放射性示踪剂99mTc-3PRGD2。我们发现，使用99mTc-cKiE2可以清晰地观察到原位肿瘤。99mTc-3PRGD2成像未像99mTc-cKiE2一样清晰地显示肿瘤轮廓。99mTc-cKiE2和99mTc-3PRGD2的肿瘤-肝脏比率为2.20±0.17和0.85±0.20。总之，99mTc-cKiE2是一种改进的SPECT放射性示踪剂，可用于对整合素α6阳性肿瘤进行成像，并具有进一步临床应用的巨大潜力。

更新日期：2020-04-29

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