Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-A...
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| Format: | Article |
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MDPI AG
2020-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/10/977 |
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| author | Ayman Abouzayed Hanna Tano Ábel Nagy Sara S. Rinne Fadya Wadeea Sharmishtaa Kumar Kristina Westerlund Vladimir Tolmachev Amelie Eriksson Karlström Anna Orlova |
| author_facet | Ayman Abouzayed Hanna Tano Ábel Nagy Sara S. Rinne Fadya Wadeea Sharmishtaa Kumar Kristina Westerlund Vladimir Tolmachev Amelie Eriksson Karlström Anna Orlova |
| author_sort | Ayman Abouzayed |
| collection | DOAJ |
| description | The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH<sub>2</sub>) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC<sub>50</sub>) of <sup>nat</sup>In-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [<sup>111</sup>In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate. |
| first_indexed | 2024-03-10T15:34:56Z |
| format | Article |
| id | doaj.art-d25f32a395b44c4fa313e977f06c4356 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T15:34:56Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-d25f32a395b44c4fa313e977f06c43562023-11-20T17:21:12ZengMDPI AGPharmaceutics1999-49232020-10-01121097710.3390/pharmaceutics12100977Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of CancerAyman Abouzayed0Hanna Tano1Ábel Nagy2Sara S. Rinne3Fadya Wadeea4Sharmishtaa Kumar5Kristina Westerlund6Vladimir Tolmachev7Amelie Eriksson Karlström8Anna Orlova9Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, SwedenDepartment of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, SwedenDepartment of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, SwedenThe targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH<sub>2</sub>) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC<sub>50</sub>) of <sup>nat</sup>In-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [<sup>111</sup>In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.https://www.mdpi.com/1999-4923/12/10/977prostate cancergastrin-releasing peptide receptorRM26albumin-binding domaintargeted therapygastrin-releasing peptide receptors (GRPR) antagonist |
| spellingShingle | Ayman Abouzayed Hanna Tano Ábel Nagy Sara S. Rinne Fadya Wadeea Sharmishtaa Kumar Kristina Westerlund Vladimir Tolmachev Amelie Eriksson Karlström Anna Orlova Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer Pharmaceutics prostate cancer gastrin-releasing peptide receptor RM26 albumin-binding domain targeted therapy gastrin-releasing peptide receptors (GRPR) antagonist |
| title | Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer |
| title_full | Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer |
| title_fullStr | Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer |
| title_full_unstemmed | Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer |
| title_short | Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer |
| title_sort | preclinical evaluation of the grpr targeting antagonist rm26 conjugated to the albumin binding domain for grpr targeting therapy of cancer |
| topic | prostate cancer gastrin-releasing peptide receptor RM26 albumin-binding domain targeted therapy gastrin-releasing peptide receptors (GRPR) antagonist |
| url | https://www.mdpi.com/1999-4923/12/10/977 |
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