Blood-Brain Barrier Penetrating Luminescent Conjugates Based on Cyclometalated Platinum(II) Complexes

Herein we report on the synthesis, structural characterization and photophysical properties of cyclometalated Pt­(II) complexes [Pt­(N^C)­(PPh2(C6H4COOH))­Cl] (where N^C ligands are 2-phenylpyridine, (2-benzofuran-3-yl)­pyridine, and (2-benzo­[b]­tiophen-3-yl)­pyridine) and their conjugates with the...

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Bibliographic Details
Published in:Bioconjugate chemistry 2020-11, Vol.31 (11), p.2628-2637
Main Authors: Solomatina, Anastasia I, Slobodina, Aleksandra D, Ryabova, Elena V, Bolshakova, Olga I, Chelushkin, Pavel S, Sarantseva, Svetlana V, Tunik, Sergey P
Format: Article
Language:English
Subjects:
Aqueous solutions
Benzofuran
Biocompatibility
Blood-brain barrier
Cell culture
Cell membranes
Conjugates
Conjugation
Cytotoxicity
Histidine
Magnetic resonance spectroscopy
Mass spectrometry
Mass spectroscopy
Medical imaging
Neuroimaging
NMR
NMR spectroscopy
Nuclear magnetic resonance
Peptides
Phosphorescence
Platinum
Pyridines
Structural analysis
Toxicity
Translocation
β-Amyloid
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Summary:Herein we report on the synthesis, structural characterization and photophysical properties of cyclometalated Pt­(II) complexes [Pt­(N^C)­(PPh2(C6H4COOH))­Cl] (where N^C ligands are 2-phenylpyridine, (2-benzofuran-3-yl)­pyridine, and (2-benzo­[b]­tiophen-3-yl)­pyridine) and their conjugates with the histidine-containing RRRRRRRRRRHVLPKVQA peptide. This peptide contains the RHVLPKVQA sequence, which is responsible for antiamyloid activity, and the Arg9 RRRRRRRRR domain, which shows improved translocation through cell membranes. The chemistry underpinning the conjugation is regioselective complexation between Pt­(II) complexes and histidine residue in the peptide. The prepared conjugates have been characterized using high-resolution mass spectrometry and NMR spectroscopy. It was shown that the conjugates are easily soluble in aqueous media and display emission band profiles essentially similar to those of the starting complexes but considerably higher luminescence quantum yield and much longer phosphorescence lifetime. MTT assay on HeLa cell culture revealed no cytotoxicity up to 10 μM after 24 h of incubation. Ex vivo and in vivo neuroimaging experiments on both wild and amyloid peptide expressing strains of Drosophila melanogaster revealed that the conjugates penetrate the blood-brain barrier and are evenly distributed throughout the brain independently of the strain used.
ISSN:1043-1802
1520-4812
DOI:10.1021/acs.bioconjchem.0c00542