Squalene-PEG-Exendin as High-Affinity Constructs for Pancreatic Beta-Cells

Novel drug delivery systems targeting native, transplanted, or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chem...

Full description

Saved in:
Bibliographic Details
Published in:Bioconjugate chemistry 2018-08, Vol.29 (8), p.2531-2540
Main Authors: Babič, Andrej, Vinet, Laurent, Chellakudam, Vineetha, Janikowska, Karolina, Allémann, Eric, Lange, Norbert
Format: Article
Language:English
Subjects:
Affinity
Amino acids
Beta cells
Conjugates
Drug delivery
Drug delivery systems
Fluorescence
Fluorescent indicators
Liver
Organic chemistry
Organs
Pancreas
Pancreas transplantation
Pancreatic islet transplantation
Peptides
Polypeptides
Probes
Squalene
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Novel drug delivery systems targeting native, transplanted, or cancerous beta-cells are of utmost importance. Herein, we present new exendin-4 derivatives with modified unnatural amino acids at strategic positions within the polypeptide sequence. The modified peptides allowed modular orthogonal chemical modifications to attach imaging agents and amphiphilic squalene-PEG groups. The resulting conjugates, SQ-PEG-ExC1-Cy5 and SQ-PEG-ExC40-Cy5 fluorescence probes, display low nanomolar affinity to GLP-1R in fluorescence-based binding assays with EC50 at 1.1 ± 0.2 and 0.8 ± 0.2 nM, respectively. Naturally expressing GLP-1R MIN6 cells and recombinantly transfected CHL-GLP-1R positive cells were specifically targeted by all of the new beta-cell probes in vitro. Specific islet targeting was observed after i.v. injection of SQ-PEG-ExC1-Cy5 with SQ-PEG in normoglycemic mice ex vivo. Semiquantitative biodistribution analysis by epifluorescence indicated prolonged blood half-life (3.8 h) for the amphiphilic Ex conjugate. Liver and pancreas were identified as main biodistribution organs for SQ-PEG-ExC1-Cy5.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.8b00186