Nanotechnologies for biomolecular detection and medical diagnostics

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Nanotechnology-based platforms for the high-throughput, multiplexed detection of proteins and nucleic acids in heretofore unattainable abundance ranges promise to bring substantial advances in molecular medicine. The emerging approaches reviewed in this article, with reference to their diagnostic potential, include nanotextured surfaces for proteomics, a two-particle sandwich assay for the biological amplification of low-concentration biomolecular signals, and silicon-based nanostructures for the transduction of molecular binding into electrical and mechanical signals, respectively.

Introduction

As medicine steadily progresses toward diagnostics based on molecular markers, and highly specific therapies aimed at molecular targets, the necessity for high-throughput methods for the detection of biomolecules, and their abundance, concomitantly increases. Technology platforms that provide the reliable, rapid, quantitative, low-cost and multi-channel identification of biomarkers such as genes and proteins are de facto the rate-limiting steps for the clinical deployment of personalized medicine [1], in domains such as the early detection and the treatment of malignant disease. Early detection is particularly important in the case of cancer and other pathologies, because the early stages of disease are typically treated with the greatest probability of success.

The repeated screening of large populations for signs of precancerous developments, or the establishment of early malignant lesions is only conceivable in the context of the analysis of biological fluids such as blood, urine and sputum samples. To date, this has been impossible, largely because there are no contemporary approaches for the reliable, quantitative detection of multiple low-abundance protein markers, comprised within a formidable complexity of diverse biomolecular species in each bio-fluid specimen.

Nanotechnology offers promise, as a broad spectrum of highly innovative approaches emerges for the overcoming of this challenge [2, 3•, 4, 5, 6, 7, 8, 9, 10, 11]. Four emerging approaches are reviewed below: nanostructured surfaces for the enhancement of proteomic analysis via mass spectrometry (MS) and reverse-phase protein microarrays; the bio-bar code method for the amplification of protein signatures via the use of two-particle, sandwich assay; nanowires as biologically gated transistors, transducing molecular binding events into real-time electrical signals; and silicon cantilevers for the mechanics-based recognition of biomolecular populations.

Section snippets

Nanostructured surfaces for proteomic analyses via MS and reverse-phase protein microarrays

MS is currently the gold standard for the protein expression profiling of biological fluids and tissues [12, 13, 14], with mounting evidence that matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS can be employed for the early detection of malignant disease. Current limitations of this approach include the complexity and reproducibility of the 2-D gel electrophoresis pre-fractionation steps required for its implementation on biological fluids. It is also recognized that

The bio-bar-code assay

The bio-bar-code assay (Figure 3) is a powerful amplification and detection system for nucleic acids and proteins [3•, 18, 19, 20, 21]. It utilizes two types of particles to accomplish sample purification, detection and amplification. The first is a microparticle with a recognition agent. In the case of nucleic acids, the recognition agent is an oligonucleotide that is complementary to a statistically unique region of a target [19]. In the case of proteins, the recognition agent is a monoclonal

Nanowires: label-free electronic sensors of genes and proteins

Nanowire sensors operate on the basis that the change in chemical potential accompanying a target/analyte binding event, such as DNA hybridization [8], can act as a field-effect gate upon the nanowire, thereby changing its conductance. This is similar, in principle, to how a field-effect transistor operates. The ideal nanowire sensor is a lightly doped, high-aspect ratio, single-crystal nanowire with a diameter between 10 nm and 20 nm. If it is much smaller, it will be too noisy a sensor, and if

Cantilevers: nanomechanical detection of biological molecules

Detection of extremely small forces using micro- and nanoelectromechanical systems (MEMS and NEMS) is well established. Recently, it has been demonstrated that molecular adsorption also results in measurable mechanical forces. Detecting biomolecular interactions by measuring nanomechanical forces offers an exciting opportunity for the development of highly sensitive, miniature and label-free biological sensors [11, 30]. For example, micron-sized silicon cantilever beams undergo bending due to

Conclusion

Nanotechnology-based platforms offer promise for the attainment of multiple elusive goals in biomolecular analysis. Primary examples of emerging approaches include surface nanotexturing for MS and RPMAs, the bio-bar code assay, biologically gated nanowire sensors, and nanomechanical devices such as bio-derivatized cantilever arrays. Through their individual or combined uses it is envisioned that progress will be accomplished in the high-throughput multiplexing of analyses of nucleic acids and

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

MCC, NJ and MF are grateful to the National Cancer Institute for funding under National Institute of Health Contract No. NO1-CO-12400. TT is grateful to the DOE Office of Biological and Environmental Research for financial support.

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    These authors contributed equally to this work.

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