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HYNIC和DOMA偶联的放射性标记蛙皮素类似物作为用于乳腺肿瘤闪烁显像检测的受体靶向探针。

HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor.

作者信息

De Kakali, Mukherjee Dibyanti, Sinha Samarendu, Ganguly Shantanu

机构信息

Infectious Diseases and Immunology Division (Nuclear Medicine Laboratory), CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata, West Bengal, 700032, India.

Regional Radiation Medicine Center, Thakurpukur Cancer Research Center and Welfare Home Campus, Kolkata, West Bengal, 700 060, India.

出版信息

EJNMMI Res. 2019 Mar 18;9(1):25. doi: 10.1186/s13550-019-0493-x.

DOI:10.1186/s13550-019-0493-x
PMID:30887136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6423188/
Abstract

BACKGROUND

Among the many peptide receptor systems, gastrin-releasing-peptide (GRP) receptors, the mammalian equivalent of bombesin (BN) receptors, are potential targets for diagnosis and therapy of breast tumors due to their overexpression in various frequently occurring human cancers. The aim of this study was to synthesize and comparative evaluation of Tc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH, BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH, BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH, BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH, BN4 were synthesized and biologically evaluated for targeted imaging of GRP receptor-positive breast-tumors.

METHODS

Solid-phase synthesis using Fmoc-chemistry was adopted for the synthesis of peptides. BN1-BN4 analogs were better over the standard Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using Tc-labeled analogs. Biodistribution and imaging analyses were performed on MDA-MB-231 cell-induced tumor-bearing mice. BN-analogs induced angiogenesis; tumor formation and GRP-receptor-expression were confirmed by histology and immunohistochemistry analyses of tumor sections and important tissue sections.

RESULTS

All the analogs displayed ≥ 97% purity after the HPLC purification. BN-peptide-conjugates exhibited high serum stability and significant binding affinity to GRP-positive tumor; rapid internalization/externalization in/from MDA-MB-231 cells were noticed for the BN analogs. BN4 and BN3 exhibited higher binding affinity, stability than BN1 and BN2. Highly specific in vivo uptakes to the tumor were clearly visualized by scintigraphy; rapid excretion from non-target tissues via kidneys suggests a higher tumor-to-background ratio. BN4, among all the analogs, stimulates the expression of angiogenic markers to a maximum.

CONCLUSION

Considering its most improved pharmacological characteristics, BN4 is thus considered as most promising probes for early non-invasive diagnosis of GRP receptor-positive breast tumors.

摘要

背景

在众多肽受体系统中，胃泌素释放肽（GRP）受体是蛙皮素（BN）受体的哺乳动物对应物，由于其在各种常见人类癌症中过度表达，因而成为乳腺肿瘤诊断和治疗的潜在靶点。本研究旨在合成并比较评估锝标记的新型BN肽类似物。合成了四种新型BN类似物，即HYNIC-Asp[PheNle]BN(7-14)NH，BN1；HYNIC-Pro-Asp[TyrMet]BN(7-14)NH，BN2；HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH，BN3；以及DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH，BN4，并对其进行生物学评估，以用于GRP受体阳性乳腺肿瘤的靶向成像。

方法

采用Fmoc化学法进行固相合成肽。BN1-BN4类似物优于标准的Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH（BNS）。使用锝标记的类似物进行亲脂性、血清稳定性、内化和结合亲和力研究。对MDA-MB-231细胞诱导的荷瘤小鼠进行生物分布和成像分析。通过对肿瘤切片和重要组织切片进行组织学和免疫组织化学分析，证实BN类似物诱导血管生成、肿瘤形成和GRP受体表达。

结果

经过高效液相色谱纯化后，所有类似物的纯度均≥97%。BN肽缀合物表现出高血清稳定性以及对GRP阳性肿瘤的显著结合亲和力；在MDA-MB-231细胞中，BN类似物表现出快速的内化/外化。BN4和BN3表现出比BN1和BN2更高的结合亲和力和稳定性。通过闪烁显像可清晰观察到肿瘤在体内具有高度特异性摄取；通过肾脏从非靶组织快速排泄表明肿瘤与背景的比值更高。在所有类似物中，BN4对血管生成标志物的表达刺激作用最大。

结论

鉴于其最优化的药理学特性，BN4被认为是GRP受体阳性乳腺肿瘤早期无创诊断最有前景的探针。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/58890cbc2f6f/13550_2019_493_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/daefc18af187/13550_2019_493_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/4877109b97b9/13550_2019_493_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/39795b2ee863/13550_2019_493_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/c1809f063972/13550_2019_493_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/9d525e7a90f9/13550_2019_493_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/47aa228fe0d9/13550_2019_493_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/819896308e60/13550_2019_493_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/40d532090d8d/13550_2019_493_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f82c/6423188/0df791d23342/13550_2019_493_Fig12_HTML.jpg

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