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177 Lu-labeling of nuclear localization sequence (NLS)-grafted HER2-receptor affine peptide.

Authors :
Yadav SA
Vats VK
Sharma R
Chauhan N
Subramanian M
Das A
Satpati D
Source :
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Oct 01; Vol. 112, pp. 117883. Date of Electronic Publication: 2024 Aug 21.
Publication Year :
2024

Abstract

Tagging of cell permeable nuclear localization sequence (NLS) with receptor targeting peptide vectors is an attractive strategy for selectively targeted translocation of therapeutic cargoes. The present study aimed at grafting nuclear localization sequence (NLS) onto breast cancer targeting rL-A9 peptide. Molecular docking analysis revealed higher binding affinity of the peptide, DOTA-NLS-rL-A9 (-26.1 kJ/mol) towards HER2 receptor in comparison to DOTA-rL-A9 peptide (-22.2 kJ/mol). Confocal microscopy data suggested significantly enhanced cellular internalization of NLS-tagged peptide. The engineered HER2-selective, DOTA-NLS-rL-A9 peptide scaffold was radiolabeled with Lu-177 for intracellular delivery of the theranostic radionuclide into tumor cells. [ <superscript>177</superscript> Lu]Lu-DOTA-NLS-rL-A9 exhibited significantly enhanced binding affinity (4.58 ± 1.77 nM) towards human breast carcinoma SKBR3 cells and cellular internalization (85 % at 24 h) compared to its original analog, [ <superscript>177</superscript> Lu]Lu-DOTA-rL-A9. In vivo biodistribution studies showed consistent retention of [ <superscript>177</superscript> Lu]Lu-DOTA-NLS-rL-A9 in the tumor with negligible washout of radioactivity (∼4.1 % ID/g at 48 h). Prolonged tumor activity with rapid off-target tissue clearance resulted in significantly high tumor-to-background ratios. The radiopeptide, [ <superscript>177</superscript> Lu]Lu-DOTA-NLS-rL-A9 thus, being precisely confined into HER2-expressing tumor cells and exhibiting favourable pharmacokinetic features is an efficient candidate for further screening.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Details

Language :
English
ISSN :
1464-3391
Volume :
112
Database :
MEDLINE
Journal :
Bioorganic & medicinal chemistry
Publication Type :
Academic Journal
Accession number :
39180861
Full Text :
https://doi.org/10.1016/j.bmc.2024.117883