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HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor
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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423188/ https://www.ncbi.nlm.nih.gov/pubmed/30887136 http://dx.doi.org/10.1186/s13550-019-0493-x |
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author | De, Kakali Mukherjee, Dibyanti Sinha, Samarendu Ganguly, Shantanu |
author_facet | De, Kakali Mukherjee, Dibyanti Sinha, Samarendu Ganguly, Shantanu |
author_sort | De, Kakali |
collection | PubMed |
description | 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 (99m)Tc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH(2), BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH(2), BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH(2), BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH(2), 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(2) (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using (99m)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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13550-019-0493-x) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6423188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-64231882019-04-05 HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor De, Kakali Mukherjee, Dibyanti Sinha, Samarendu Ganguly, Shantanu EJNMMI Res Original Research 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 (99m)Tc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH(2), BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH(2), BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH(2), BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH(2), 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(2) (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using (99m)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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13550-019-0493-x) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2019-03-18 /pmc/articles/PMC6423188/ /pubmed/30887136 http://dx.doi.org/10.1186/s13550-019-0493-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Research De, Kakali Mukherjee, Dibyanti Sinha, Samarendu Ganguly, Shantanu HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title | HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title_full | HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title_fullStr | HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title_full_unstemmed | HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title_short | HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
title_sort | hynic and doma conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423188/ https://www.ncbi.nlm.nih.gov/pubmed/30887136 http://dx.doi.org/10.1186/s13550-019-0493-x |
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