Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
Ayman Abouzayed,
Hanna Tano,
Ábel Nagy,
Sara S. Rinne,
Fadya Wadeea,
Sharmishtaa Kumar,
Kristina Westerlund,
Vladimir Tolmachev,
Amelie Eriksson Karlström,
Anna Orlova
Affiliations
Ayman Abouzayed
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
Hanna Tano
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, Sweden
Ábel Nagy
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, Sweden
Sara S. Rinne
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
Fadya Wadeea
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
Sharmishtaa Kumar
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, Sweden
Kristina Westerlund
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, Sweden
Vladimir Tolmachev
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
Amelie Eriksson Karlström
Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, AlbaNova University Center, 106 91 Stockholm, Sweden
Anna Orlova
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden
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-NH2) 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 (IC50) of natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [111In]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.
