Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting

Aim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 rec...

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Main Author: Subhani M. Okarvi
Format: Article
Language:English
Published: MDPI AG 2023-11-01
Series:Pharmaceuticals
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Online Access:https://www.mdpi.com/1424-8247/16/11/1550
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author Subhani M. Okarvi
author_facet Subhani M. Okarvi
author_sort Subhani M. Okarvi
collection DOAJ
description Aim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 receptor (AT1) and AngII type 2 receptor (AT2). Overexpression of the AT1 receptor in breast cancer cells seems to promote tumor growth and angiogenesis, thus targeting the AT1 receptor using AngII peptide would facilitate the detection of breast carcinoma. We developed an AngII peptide intending to assess whether the peptide of the renin–angiotensin system holds the ability to target AT1 receptor-overexpressing breast cancer in vivo. Methods: DOTA-coupled AngII peptide was synthesized by conventional solid-phase peptide synthesis according to Fmoc/HATU chemistry. <sup>68</sup>Ga/<sup>177</sup>Lu labeled AngII peptide was evaluated for its binding with TNBC MDA-MB-231 and ER+ MCF7 cell lines. Pharmacokinetics was studied in healthy balb/c mice and in vivo tumor targeting in nude mice with MDA-MB-231 tumors xenografts. Results: DOTA-AngII peptide was labeled efficiently with <sup>68</sup>Ga/<sup>177</sup>Lu with high labeling efficiency (≥90%). The stability of the radiopeptide in human plasma was found to be high. The AngII peptide analog showed nanomolar (<40 nM) AT1 receptor-specific binding affinity. The radioactivity internalized into MDA-MBA-231 and MCF7 cells were 14.97% and 11.75%, respectively. In vivo, biodistribution in balb/c mice exhibited efficient clearance of <sup>68</sup>Ga/<sup>177</sup>Lu-DOTA-AngII peptide from the blood and elimination predominantly by the renal system due to its hydrophilic nature. A low amount of radioactivity was seen in the major organs including lungs, liver, stomach, spleen, and intestines (<3% ID/g) except the kidneys. A high renal-urinary excretion was observed for the radiotracer. In the TNBC MDA-MB-231 xenografts model, radiolabeled AngII peptide exhibited specific and effective AT1-based targeting in vivo. A rapid and efficient tumor targeting (2.18% ID/g at 45 min p.i.) together with fast renal excretion (~67% ID) highlights the tumor-targeting potential of the radiotracer. The AT1 receptor specificity of the radiotracer was validated by blocking assays. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in nude mice. Conclusion: Our findings suggest that <sup>68</sup>Ga/<sup>177</sup>Lu-DOTA-AngII peptide can be useful for the theranostic application of breast carcinomas. This study suggests the potential of this innovative class of peptides for rapid and efficient targeting of tumors and warrants further evaluation.
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spelling doaj.art-425aa9f7ab2642baa036a79c3c8932942023-11-24T15:00:12ZengMDPI AGPharmaceuticals1424-82472023-11-011611155010.3390/ph16111550Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer TargetingSubhani M. Okarvi0Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, MBC-03, P.O. Box 3354, Riyadh 11211, Saudi ArabiaAim: Angiotensin II (AngII) is known to play a significant part in the development of breast cancer by triggering cell propagation of breast cancer, tumor angiogenesis, and regulating tumor invasion and cell migration. AngII arbitrates its action via two G-protein-coupled receptors, AngII type 1 receptor (AT1) and AngII type 2 receptor (AT2). Overexpression of the AT1 receptor in breast cancer cells seems to promote tumor growth and angiogenesis, thus targeting the AT1 receptor using AngII peptide would facilitate the detection of breast carcinoma. We developed an AngII peptide intending to assess whether the peptide of the renin–angiotensin system holds the ability to target AT1 receptor-overexpressing breast cancer in vivo. Methods: DOTA-coupled AngII peptide was synthesized by conventional solid-phase peptide synthesis according to Fmoc/HATU chemistry. <sup>68</sup>Ga/<sup>177</sup>Lu labeled AngII peptide was evaluated for its binding with TNBC MDA-MB-231 and ER+ MCF7 cell lines. Pharmacokinetics was studied in healthy balb/c mice and in vivo tumor targeting in nude mice with MDA-MB-231 tumors xenografts. Results: DOTA-AngII peptide was labeled efficiently with <sup>68</sup>Ga/<sup>177</sup>Lu with high labeling efficiency (≥90%). The stability of the radiopeptide in human plasma was found to be high. The AngII peptide analog showed nanomolar (<40 nM) AT1 receptor-specific binding affinity. The radioactivity internalized into MDA-MBA-231 and MCF7 cells were 14.97% and 11.75%, respectively. In vivo, biodistribution in balb/c mice exhibited efficient clearance of <sup>68</sup>Ga/<sup>177</sup>Lu-DOTA-AngII peptide from the blood and elimination predominantly by the renal system due to its hydrophilic nature. A low amount of radioactivity was seen in the major organs including lungs, liver, stomach, spleen, and intestines (<3% ID/g) except the kidneys. A high renal-urinary excretion was observed for the radiotracer. In the TNBC MDA-MB-231 xenografts model, radiolabeled AngII peptide exhibited specific and effective AT1-based targeting in vivo. A rapid and efficient tumor targeting (2.18% ID/g at 45 min p.i.) together with fast renal excretion (~67% ID) highlights the tumor-targeting potential of the radiotracer. The AT1 receptor specificity of the radiotracer was validated by blocking assays. Furthermore, PET imaging provided sufficient visualization of MDA-MB-231 tumors in nude mice. Conclusion: Our findings suggest that <sup>68</sup>Ga/<sup>177</sup>Lu-DOTA-AngII peptide can be useful for the theranostic application of breast carcinomas. This study suggests the potential of this innovative class of peptides for rapid and efficient targeting of tumors and warrants further evaluation.https://www.mdpi.com/1424-8247/16/11/1550angiotensinbreast cancerradiolabelingpeptide synthesisbiodistributionpreclinical
spellingShingle Subhani M. Okarvi
Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
Pharmaceuticals
angiotensin
breast cancer
radiolabeling
peptide synthesis
biodistribution
preclinical
title Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
title_full Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
title_fullStr Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
title_full_unstemmed Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
title_short Preparation, Radiolabeling with <sup>68</sup>Ga/<sup>177</sup>Lu and Preclinical Evaluation of Novel Angiotensin Peptide Analog: A New Class of Peptides for Breast Cancer Targeting
title_sort preparation radiolabeling with sup 68 sup ga sup 177 sup lu and preclinical evaluation of novel angiotensin peptide analog a new class of peptides for breast cancer targeting
topic angiotensin
breast cancer
radiolabeling
peptide synthesis
biodistribution
preclinical
url https://www.mdpi.com/1424-8247/16/11/1550
work_keys_str_mv AT subhanimokarvi preparationradiolabelingwithsup68supgasup177supluandpreclinicalevaluationofnovelangiotensinpeptideanaloganewclassofpeptidesforbreastcancertargeting