An osmium(ii)-terpyridine bipeptide conjugate FrFKFrFK was found to target the mitochondria in a concentration dependent manner and mechanism of cytotoxicity was found, in turn, to depend on targeting.
The preparation of
two polyarginine conjugates of the complex Os(II)
[bis-(4′-(4-carboxyphenyl)-2,2′:6′,2″-terpyridine)]
[Os-(R
n
)
2
]
x
+
(
n
= 4 and 8;
x
= 10 and
18) is reported, to explore whether the R8 peptide sequence that promotes
cell uptake requires a contiguous amino acid sequence for membrane
permeation or if this can be accomplished in a linearly bridged structure
with the additive effect of shorter peptide sequences. The conjugates
exhibit NIR emission centered at 754 nm and essentially oxygen-insensitive
emission with a lifetime of 89 ns in phosphate-buffered saline. The
uptake, distribution, and cytotoxicity of the parent complex and peptide
derivatives were compared in 2D cell monolayers and a three-dimensional
(3D) multicellular tumor spheroid (MCTS) model. Whereas, the bis-octaarginine
sequences were impermeable to cells and spheroids, and the bis-tetraarginine
conjugate showed excellent cellular uptake and accumulation in two
2D monolayer cell lines and remarkable in-depth penetration of 3D
MCTSs of pancreatic cancer cells. Overall, the data indicates that
cell permeability can be promoted via non-contiguous sequences of
arginine residues bridged across the metal centre.
Nitrosamine metabolites resulting from cigarette smoking and E-cigarette (E-cig) vaping cause DNA damage that can lead to genotoxicity. While DNA adducts of metabolites of nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) are well-known tobacco-related cancer biomarkers, only a few studies implicate NNN and NNK in DNA oxidation in humans. NNK and NNN were found in the urine of E-cigarette users who never smoked cigarettes. This paper proposes the first chemical pathways of DNA oxidation driven by NNK and NNN metabolites in redox reactions with Cu 2+ and NADPH leading to reactive oxygen species (ROS). A microfluidic array with thin films of DNA and metabolic enzymes that make metabolites of NNN and NNK in the presence of Cu 2+ and NADPH was used to estimate relative rates of DNA oxidation. Detection by electrochemiluminescence (ECL) employed a new ECL dye [Os(tpy-benz-COOH) 2 ] 2+ that is selective for and sensitive to the primary DNA oxidation product 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) in DNA. Enzyme−DNA films on magnetic beads were used to produce nitrosamine metabolites that enter ROS-forming redox cycles with Cu 2+ and NADPH, and liquid chromatography−mass spectrometry (LC−MS) was used to quantify 8-oxodG and identify metabolites. ROS were detected by optical sensors. Metabolites of NNK and NNN + Cu 2+ + NADPH generated relatively high rates of DNA oxidation. Lung is the exposure route in smoking and vaping, human lung tissue contains Cu 2+ and NADPH, and lung microsomal enzymes gave the highest rates of DNA oxidation in this study. Also, E-cigarette vapor contains 6-fold more copper than that in cigarette smoke, which could exacerbate DNA oxidation.
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