Rapid progress in identifying biomarkers that are hallmarks of disease has increased demand for high-performance detection technologies. Implementation of electrochemical methods in clinical analysis may provide an effective answer to the growing need for rapid, specific, inexpensive, and fully automated means of biomarker analysis. This Review summarizes advances from the past 5 years in the development of electrochemical sensors for clinically relevant biomolecules, including small molecules, nucleic acids, and proteins. Various sensing strategies are assessed according to their potential for reaching relevant limits of sensitivity, specificity, and degrees of multiplexing. Furthermore, we address the remaining challenges and opportunities to integrate electrochemical sensing platforms into point-of-care solutions.

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Electrochemical Methods for the Analysis of Clinically Relevant Biomolecules

Metal ions are essential to many chemical, biological, and environmental processes. In the past two decades, many DNA-based metal sensors have emerged. While the main biological role of DNA is to store genetic information, its chemical structure is ideal for metal binding via both the phosphate backbone and nucleobases. DNA is highly stable, cost-effective, easy to modify, and amenable to combinatorial selection. Two main classes of functional DNA were developed for metal sensing: aptamers and DNAzymes. While a few metal binding aptamers are known, it is generally quite difficult to isolate such aptamers. On the other hand, DNAzymes are powerful tools for metal sensing since they are selected based on catalytic activity, thus bypassing the need for metal immobilization. In the last five years, a new surge of development has been made on isolating new metal-sensing DNA sequences. To date, many important metals can be selectively detected by DNA often down to the low parts-per-billion level. Herein, each me...

Metal Sensing by DNA

With over 2,000 publications, including about 250 reviews, resulting from a SciFinder search in just a two year period (2009–2010), the field of aptamer research has continuously generated lots of interest in the scientific community. Aptamers, first reported by three groups independently in 1990,1–3 are the artificial single-stranded DNA or RNA sequences (more recently, peptides) that fold into secondary and tertiary structures making them bind to certain targets with extremely high specificity. Owing to the high specific affinity of an aptamer to its target molecule (small molecules, proteins and even entire cells), it is thought to resemble chemical antibodies, with the dissociation constants ranging from nanomolar to picomolar level. Aptamers have a number of unique features which make them a more effective choice than antibodies. First, aptamers can be screened via in vitro process against a synthetic library, making it possible to target any molecules (from small inorganic ions to intact cells), overcoming the limit of having to use cell lines or animals, as is necessary for antibodies. Second, aptamers, once selected, can undergo subsequent amplification through polymerase chain reaction to produce a large quantity with high purity. Third, the simple chemical structure of aptamer makes it easily amendable to further modifications with functional groups according to different purposes. Finally, aptamers are much more stable than antibodies, making them suitable in applications requiring harsh conditions (e.g., high temperature or extreme pH).

The applications of aptamers remain very dynamic, with increasing explorations in the fields of biosensing, diagnostics and therapeutics (some aptamer-based applications are illustrated in Figure 1). There have been a numbers of excellent reviews in recent years with different emphases.4–8 Herein, as the first review of aptamers on Analytical Chemistry, we attempt to cover major progresses in bioanalytical applications of aptamers in the past 2 years.



Figure 1

The widespread use of aptamers for numerous analytical and biological applications. Bioanalytical applications of aptamers are highlighted in red.

Aptamer in bioanalytical applications.

Publisher Summary The electroactivity of nucleic acids was discovered several years ago. It was shown that at mercury electrodes, adenine and cytosine were reduced in ssDNA while guanine produced an anodic signal due to the oxidation of guanine reduction product. The DNA signals at mercury electrodes are highly sensitive to changes in DNA structure due to DNA denaturation and renaturation, as well as to minor structural changes resulting from DNA premelting and DNA damage. The changes in DNA structure are reflected not only by the DNA faradaic responses but also by non-faradaic signals due to adsorption/desorption of DNA. Several interesting principles have been used in the development of the DNA sensors—such as amplified electrochemical analysis, investigation of charge transport, and tracing of changes in conformation of DNA. The s ensors for DNA hybridization and DNA damage lead the field of the electrochemistry of nucleic acids. The chapter briefly summarizes some properties of the elimination voltammetry with linear scan (EVLS) method. Oscillographic polarography, at controlled alternating current, was used in the electrochemical analysis of nucleic acids.

Electrochemistry of nucleic acids.

The combination of nanostructures with biomolecules leading to the generation of functional nanosystems holds great promise for biotechnological and biomedical applications. As a naturally occurring biomacromolecule, DNA exhibits excellent biocompatibility and programmability. Also, scalable synthesis can be readily realized through automated instruments. Such unique properties, together with Watson–Crick base-pairing interactions, make DNA a particularly promising candidate to be used as a building block material for a wide variety of nanostructures. In the past few decades, various DNA nanostructures have been developed, including one-, two- and three-dimensional nanomaterials. Aptamers are single-stranded DNA or RNA molecules selected by Systematic Evolution of Ligands by Exponential Enrichment (SELEX), with specific recognition abilities to their targets. Therefore, integrating aptamers into DNA nanostructures results in powerful tools for biosensing and bioimaging applications. Furthermore, owing to their high loading capability, aptamer-modified DNA nanostructures have also been altered to play the role of drug nanocarriers for in vivo applications and targeted cancer therapy. In this review, we summarize recent progress in the design of aptamers and related DNA molecule-integrated DNA nanostructures as well as their applications in biosensing, bioimaging and cancer therapy. To begin with, we first introduce the SELEX technology. Subsequently, the methodologies for the preparation of aptamer-integrated DNA nanostructures are presented. Then, we highlight their applications in biosensing and bioimaging for various targets, as well as targeted cancer therapy applications. Finally, we discuss several challenges and further opportunities in this emerging field.

Aptamer-integrated DNA nanostructures for biosensing, bioimaging and cancer therapy

Oligonucleotides were once considered only functional as molecules for the storage of genetic information. However, the discovery of RNAzymes, and later, DNAzymes, unravelled the innate potential of oligonucleotides in many other biological applications. In the last two decades, these applications have been further expanded through the introduction of Systematic Evolution of Ligands by EXponential enrichment (SELEX) which has generated, by repeated rounds of in vitro selection, a type of molecular probe termed aptamers. Aptamers are oligonucleic acid (or peptide) molecules that can bind to various molecular targets and are viewed as complements to antibodies. Aptamers have found applications in many areas, such as bio-technology, medicine, pharmacology, microbiology, and analytical chemistry, including chromatographic separation and biosensors. In this review, we focus on the use of aptamers in the development of biosensors. Coupled with their ability to bind a variety of targets, the robust nature of oligonucleotides, in terms of synthesis, storage, and wide range of temperature stability and chemical manipulation, makes them highly suitable for biosensor design and engineering. Among the many design strategies, we discuss three general paradigms that have appeared most frequently in the literature: structure-switching, enzyme-based, and aptazyme-based designs.

Nucleic acid aptamers for biosensors and bio-analytical applications

DNA aptamers for molecular imaging and profiling of cancer

In recent decades, tremendous progress has been made in understanding origination and development of human cancers. Despite our increasing understanding of cancers, finding a cure for cancers remains a great challenge. This article focuses on the use of aptamer probes for molecular diagnosis of cancer.


Keywords:

molecular diagnosis;
cancer;
positron emission tomography (PET);
aptamer;
tumor detection

Cancer Cell Proteomics using Molecular Aptamers

Aptamers are ssDNA, RNA, or modified nucleic acids, usually consisting of short strands of oligonucleotides. Aptamers have the ability to bind specifically to a range of targets, from small organic molecules to proteins. However, by using cell-based aptamer selection, we have developed a strategy to identify the molecular signatures on the surface of targeted cells by exploiting the differences at the molecular level between any two given cell types. By applying this method, we have generated a panel of aptamers for the specific recognition of leukemia cells, and we report the results in this study. The selected aptamers were found to bind to target cells with an equilibrium dissociation constant (K (d)) in the nanomolar-to-picomolar range. Overall, the cell-based selection process is simple, fast, straightforward, and reproducible. Most importantly, since this strategy can be implemented without prior knowledge of a target's specific molecular signature, cell-based aptamer selection holds great promise for the development of specific molecular probes for cancer diagnosis and cancer biomarker discovery.

Using Live Cells to Generate Aptamers for Cancer Study

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Nucleic acid aptamers for biosensors and bio-analytical applications

DNA aptamers for molecular imaging and profiling of cancer

Cancer Cell Proteomics using Molecular Aptamers

Using Live Cells to Generate Aptamers for Cancer Study