N‐Heterocyclic Carbene–Gold(I) Complexes Conjugated to a Leukemia‐Specific DNA Aptamer for Targeted Drug Delivery

Abstract

This report describes the synthesis and characterization of novel N-heterocyclic carbene (NHC) gold(I) complexes and their bioconjugation to the CCRF-CEM leukemia specific aptamer sgc8c. Confirmation of successful bioconjugation was achieved by using fluorescent tags on both the NHC-Au(I) complex and the aptamer. Cell viability assays indicate the NHC-Au(I)-aptamer conjugate is more cytotoxic than the NHC-gold complex alone. A combination of flow cytometry, confocal microscopy, and cell viability assays provide clear evidence that the NHC-Au(I)-aptamer conjugate is selective for targeted CCRF-CEM leukemia cells. Graphical Abstract KeywordsNHC; DNA aptamer; bioconjugation; cancer cell; selectivity; carbene; cytotoxicity N-heterocyclic carbenes (NHCs) are an interesting class of ligands with strong σ-donating properties. [1] The resulting strong bond between transition metals and the NHCs render their metal complexes stable to air, heat, water, and acid. [2] In the context of potentially reducing the side effects caused by metallo-drug demetalation and degradation in the body, NHCmetal complexes offer a promising alternative, especially considering their ease of synthesis and vast structural diversity. [3,4] In the last decade, NHC-Au complexes have drawn attention as a new generation of potential anticancer agents due to their impressively high cytotoxicity and stability. A series of neutral and cationic NHC-Au complexes with a wide diversity of ligand structures were synthesized and characterized in recent years. [3][4][5] Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptAu(I) complexes can induce cell apoptosis by targeting mitochondrial-related cellular pathways [6,7] that involve thioredoxin reductase (TrxR) and Estrogen Receptor (ER). [3,7] Though NHC-Au(I) complexes inhibit the growth of tumor cells, they also interact with human normal cells, a characteristic common for metal based drugs, [8] thus limiting their potential as cancer therapeutics. [9] [10] Cell-selectivity is an obvious area in need of improvement.This report describes a strategy to target cancer cells efficiently while potentially reducing metal-based side effects. The strategy involves covalently binding a cytotoxic NHC-Au(I) complex to a DNA aptamer. Aptamers are short single-stranded oligonucleotides which are biocompatible, stable and more importantly, they are able to specifically recognize and effectively bind to their targets-in this case-cancer cells. [11] With all these advantages, DNA-aptamers are one of the most attractive drug delivery agents. [12][13][14] Currently, several reports feature aptamer-drug conjugates, but most rely on noncovalent association of the drug with specific DNA sequences. [13] Non-covalent strategies have disadvantages such as complicated syntheses, uncontrollable drug loading, and uncontrollable drug release. [15] One of the reports of covalent attachment involves tethering the anti-cancer agent Doxorubicin (Dox) to an aptamer. [14] However, Dox causes side effects, such as ...

Multistimuli-Responsive Fluorescent Organometallic Assemblies Based on Mesoionic Carbene-Decorated Tetraphenylethene Ligands and Their Applications in Cell Imaging

“…We were inspired by previous examples of NHC-Au I complexes used in cell imaging and anticancer applications. [68][69][70][71][72][73] Considering that the fluorescence behavior and stability of MIC-Au I complex and organometallic cages [M 4 (2) 2 ](OTf) 4 (M = Ag and Au) are significantly improved, we report the first confocal laser scanning microscopy (CLSM) studies of organometallic cages [M 4 (2) 2 ](OTf) 4 (M = Ag and Au) clearly demonstrating cell imaging ability. These studies used three different cancer cell lines representing different types of cancer: A549 (nonsmall cell lung cancer), HeLa (cervical cancer), and SMMC-7721 (hepatocellular cancer).…”