Metal complexes for the detection of disease-related protein biomarkers

Highlights

• Metal complexes used in construction of DNA-based sensing platforms are described.

• Recent chemosensors for disease-related protein biomarkers are summarized.

• Applications of metal complex for the detection of protein biomarkers are discussed.

Abstract

The detection of pathological biomarkers can allow for the early diagnosis and treatment of human disease, lowering morbidity and improving quality of life. Transition metal complexes have recently found use as luminescent probes for the detection of protein biomarkers. In this review, we highlight recent examples of metal complexes that have been used in DNA-based sensing platforms or as chemosensors for protein biomarkers.

Introduction

The utilization of luminescent transition metal complexes for various applications has witnessed tremendous growth over the past several decades, particularly as luminescent probes [1], [2], for photochemical applications [3], [4], or for constructing organic optoelectronics [5], [6]. Metal complexes have several salient advantages which make them capable as attractive alternatives to organic fluorophores for use in luminescent sensing applications [7], [8], [9], [10]. Firstly, luminescent metal complexes can exhibit a high quantum yield, increasing the intensity of the emission signal for the same excitation intensity. Second, the phosphorescence of luminescent metal complexes is generally more long-lived than fluorescent emission modes, which can allow the emission of metal complexes to be recognized from an autofluorescent background via time-resolved fluorescent spectroscopy. Third, their large Stokes shifts allows excitation and emission wavelengths to be more easily separated. Fourth, metal complexes are often synthesized in a modular fashion, which makes it easier to generate analogues of a complex for optimization of its photophysical or chemical properties. Finally, their luminescent emission is sensitive to shifts in their ambient environment, as allowing them to serve as signal transducers for a wide range of analytical applications.

Transition metal complexes exhibit relatively complex excited states, including metal-to-ligand charge-transfer (MLCT), ligand-to-metal charge transfer (LMCT), intraligand charge-transfer (ILCT), ligand-to-ligand charge-transfer (LLCT), ligand-to-metal–metal charge transfer (LMMCT), metal–metal-to-ligand charge-transfer (MMLCT) and metal-to-ligand–ligand charge-transfer (MLLCT) [11], [12]. Furthermore, these excited states can be influenced by the type of metal center, the nature of ligands, and changes in the ambient environment, allowing metal complexes to exhibit a diverse range of photophysical properties including emission wavelength, lifetime, and quantum yield.

In sensing application, the transition metal complex plays the role of a “signaling unit”, for transducing the analyte binding event into an optical (luminescent) signal in both chemosensing and DNA-based sensing. In a chemosensor, the binding unit is generally a motif that is attached to the metal complex through either a σ-linker or a π-linker. The binding units selectively bind to the target analyte and result in the enhancement or reduction of the luminescence intensity of the signaling unit for “switch–on” or “switch–off” sensing, respectively (Fig. 1a).

For DNA-based sensing, the metal complex generally contains a DNA binding motif that selectively binds to a specific DNA structure such as the G-quadruplex. Thus, the DNA acts as the binding unit that selectively binds to the target analyte, which then induces a conformational change of DNA. The structure selective metal complex acts as the signaling unit and generates a luminescence signal upon binding to the specific DNA conformation, thus achieve the sensing of target analyte (Fig. 1b).

The progression of a disease in a person is often accompanied by changes in various physiological parameters in the human body. These signals, known as “biomarkers”, can be described as gauges of ordinary biological processes, pathological processes, physiological responses to therapeutic intervention or any other measurable diagnostic indicator for evaluating the risk or the existence of a disease [13]. Many types of biomarkers have been documented, including proteins, metabolites, lipids, mRNA, DNA, or circulating tumor cells, and they can be obtained from sources such as human blood, urine or tissues [14]. Therefore, the ability to accurately and reliably detect pathologically relevant biomarkers would aid in the early diagnosis of human diseases, allowing for timely treatment, reduction in patient morbidity and improvement of quality of life.

Conventional techniques for the sensing of macromolecular biomarkers include the enzyme linked immunosorbent assay (ELISA) [15], [16], Western blotting [17], gel electrophoresis [18], immunofluorescence [19], [20], polymerase chain reaction (PCR) [21], or flow cytometry [22], [23]. For the detection of small molecular biomarkers, chromatographic techniques such as gas-liquid chromatography coupled to mass spectrometry are often employed [24]. However, most of these assays are tedious, time-consuming and/or require expensive instrumentation or complex sample preparation. This has inspired the design of alternative detection strategies for biomarker detection, with a preference towards detection platforms with the potential to perform in-field measurement for point-of-care diagnosis.

This review describes the application of metal complexes for the detection of disease-related protein biomarkers, with a particular focus on luminescent and electrochemiluminescent (ECL) modes of output. For ease of access, the examples in this review have been divided into two classes. The first includes metal complexes that have been utilized for the DNA-based detection of protein biomarkers, while the second class of metal complexes does not require DNA oligonucleotides for protein biomarker detection. This review aims not to be exhaustive, but instead attempts to highlight the diverse range of metal complexes that have been used for detecting biomarkers relevant for human diseases in the last three years (2014–2016). While no such review article on this specific topic has yet been presented in the literature, more general reviews on the application of metal complexes for sensing have been published by various groups [1], [12], [25], [26], [27], [28]. Meanwhile, various other transition metal complexes such as platinum, gold, rhenium, osmium and other complexes display luminescent properties [1], [12], researchers have mostly employed iridium(III) and ruthenium(II) complexes for protein biomarker sensing in the last few years. As the consequence, we will mainly focus on examples of iridium(III) and ruthenium(II) complexes in the following sections.