title: New small99mTc-labeled peptides for HER2 receptor imaging.
abstract: The high expression of the human epidermal growth factor receptor 2 (HER2) and the accessibility of its extracellular domain make it an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. In this study, the heptapeptide leucine-threonine-valine-serine-proline-tryptophan-tyrosine (LTVSPWY) as a new small peptide for an anti-HER2 target was labeled by incorporating99mTc to the cysteine-based ligands CGGG (Cys-Gly-Gly-Gly) and CSSS (Cys-Ser-Ser-Ser) linked to this peptide. Both99mTc-labeled peptides were evaluated for HER2 bindings as well as pharmacokinetics and tumor targeting. CGGG- and CSSS-LTVSPWY peptides were labeled with99mTc using a gluconate ligand exchange. Cellular specific binding, affinities, and internalization of both peptides to the HER2 receptor were evaluated in the SKOV-3 cell line. Specific targeting of both peptides to the HER2 receptor was assessed in three cell lines with different levels of HER2 expression. Studies were performed in SKOV-3 tumor bearing mice for tumor targeting. Both peptides were labeled with99mTc with more than 99% efficiency and showed favorable stability in solution and serum. The HER2 binding affinities of both the radiolabeled peptides were inhibited up to 60% by the unlabeled peptide, as well as with trastuzumab antibody. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 4.95 ± 4.84% and 3.84 ± 2.53% for the CSSS and CGGG chelators, respectively, at 1 h after injection. However, tumor uptakes were similar for both peptides at 4 h postinjection, although a higher tumor to background ratio and lower radioactivity retention in the kidney were observed for CSSS, leading to a clearer tumor image with injection of this peptide. These small new peptides were selectively targeted to the HER2 receptor, and introduction of a serine residue into the chelator improved the pharmacokinetics of99mTc labeled LTVSPWY for clear tumor imaging in animals.
authors.affiliation: Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran; Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Hamideh
authors.initials: H
authors.lastname: Sabahnoo
authors.affiliation: Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran; Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Zohreh
authors.initials: Z
authors.lastname: Noaparast
authors.affiliation: Department of Radiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Abedi
authors.affiliation: Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran; Pharmaceutical Sciences Research Center, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: sjhosseinim@yahoo.com.
authors.forename: Seyed Jalal
authors.initials: SJ
authors.lastname: Hosseinimehr
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D015609:Organotechnetium Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: (99m)Tc; Cysteine-based ligand; HER2 receptor; LTVSPWY; Peptide; Tumor uptake