Elsevier

Analytica Chimica Acta

Volume 1041, 24 December 2018, Pages 1-24
Analytica Chimica Acta

Review
Cancer biomarker determination by resonance energy transfer using functional fluorescent nanoprobes

https://doi.org/10.1016/j.aca.2018.07.060Get rights and content

Highlights

  • Explanations of methods used to prepare, overcoat and bioconjugate nanoparticles.

  • Identification of biomarkers that indicate cancers and nanoparticle RET methods for transduction.

  • Performance comparisons of various luminescent RET-based nanoparticle methods.

Abstract

The development of bioanalytical methods that provide early detection of the presence of cancer by sensitive and specific determination of biomarkers such as small biomolecules, nucleic acids, proteins, enzymes, and even whole cells are essential to improve opportunity for improved patient treatment and to diminish the rate of cancer mortality. Förster resonance energy transfer (FRET) methods have been increasingly used to develop bioassays that offer speed, selectivity and low detection levels with practicality that is appropriate for providing point-of-care measurements for screening. The unique optical and photophysical properties of fluorescent nanoparticles such as semiconductor quantum dots (QDs), upconversion nanoparticles (UCNPs), graphene quantum dots (GQDs) and other materials have been reported to operate as efficient donors and/or acceptors for replacement of fluorescent organic dye molecules in various FRET-based assays. This review is focused on the recent progress that has been made in the development of nanoparticle-based FRET bioassays, and considers nanoparticle synthesis, design of optical properties, conjugation chemistry and approaches to fluorescence detection that provide for selective and sensitive quantification of cancer biomarkers.

Introduction

Cancer is a complex class of diseases that are characterized by uncontrolled growth of cells, invasion of normal tissues and eventual spread throughout the body [1]. Despite the tremendous resources that have been dedicated to the treatment of cancer, the disease remains one of the leading causes of death worldwide, a situation that is expected to only exacerbate in the future [2]. Many of the current diagnostic techniques (e.g. imaging, cytology) rely on morphological changes in tissues and cells, which often appear at the later stages of the disease [3]. In contrast, changes at the molecular level occur at the early stages, often before clinical symptoms develop [4]. Therefore, cancer diagnosis using molecular biomarkers can substantially improve early detection and therapeutic intervention. Cancer biomarkers can be biomolecules or even an entire cell that allow for differentiation between a normal and abnormal biological state that can be used to evaluate the overall outcome for a patient, or to predict response to a therapy.

A large number of cancer biomarkers have been reported and different assays have been developed for qualitative and quantitative determination of such biomarkers in cancerous tissues or biofluids [5]. However, relatively few proposed assays have been successful in the validation process for approved clinical use [6]. The primary reason for the failure of these assays is the complexity and heterogeneity of cancer tissue together with the insufficient attention to proper assay designs and stringent analytical validation required for such analysis. For instance, an ideal sample matrix for noninvasive cancer diagnosis for early stage screening is blood. However, biomarkers in blood are present in trace amount and are typically masked by blood components that are present at concentrations that are several orders of magnitude higher [7]. Therefore, assays for detection of cancer biomarkers should have both exceptional sensitivity and specificity.

Among different detection techniques used for cancer biomarker assays, fluorescence detection offers high sensitivity with signal typically appearing with minimal background (noise) by appropriate selection of wavelengths, polarization and/or time resolution. Förster resonance energy transfer (FRET) is a fluorescence method that offers signal that is based on molecular proximity and through-space energy exchange rather than simply on the presence of a label, and can be multiplexed for simultaneous analysis of targets. FRET-based detection using organic dyes is limited by the intrinsic broad band emission of such molecules, sensitivity to photobleaching, as well as by scattering and autofluorescence from biological samples, which occurs over a wide range of UV-visible wavelengths [8]. Fluorescent nanoparticles such as semiconductor quantum dots (QDs), upconversion nanoparticles (UCNPs), and fluorescence carbon nanomaterials can participate in FRET. Such materials offer photo-optical stability, relatively narrow emission bands to improve the potential for multiplexing, and tend to have high signal-to-noise [9]. This review begins with an overview of the challenges of developing assays for cancer biomarkers, and then examines how the optical properties, surface chemistries and bioconjugation strategies of fluorescent nanoparticles combine to make possible advances in FRET-based assays of cancer biomarkers.

Section snippets

Type, origin, and level of biomarker for cancer detection

According to World Health Organization (WHO) definition “a biomarker is any substance, structure or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease” [10]. As a subcategory, cancer biomarkers may be defined as any biological entity in blood or other biofluids that can allow for differentiation of a normal or abnormal biological state of an organism, evaluate the overall outcome of the patients, or predict responses to a

Förster resonance energy transfer (FRET) and inner filter effect (IFE)

Förster resonance energy transfer (FRET) is a distance-dependent physical phenomenon involving the radiationless transfer of energy typically in the range of 1–10 nm via non-radiative dipole-dipole coupling from the excited state of a fluorescent donor molecule to a proximal acceptor molecule in the ground state as shown in Fig. 1 [44,45]. The FRET efficiency depends on three main factors: i) the distance between donor and acceptor molecules, ii) the spectral overlap between the emission

Fluorescent nanoparticles for FRET-based bioassay

Fluorescent nanoparticles have physicochemical and optical properties that are well suited to address the challenges confronted in FRET bioassays including excitation/emission in the near-infrared (NIR) window, multiplexing capabilities and excellent photostability [27]. The following is an overview of different types of fluorescent nanoparticles that have recently been used in cancer diagnostics. Table 2 lists various properties of fluorescent nanoparticles that are important in FRET

Cancer biomarker detection by FRET using functionalized nanoparticles

In this section we consider recent reports of FRET-based bioassay for detection of various cancer biomarkers using different luminescent functional nanoparticles. The focus is on bioassays that use QDs, UCNPs and GQDs as a donor and/or an acceptor for enhancing the efficiency, sensitivity, and stability of the assay. The reported nanoparticle based FRET bioassays were mainly described as being either turn ‘on’ or turn ‘off’. Turn ‘on’ indicates that fluorescence was recovered after binding of

Conclusions

The availability of new materials has accelerated the development of bioassays for biomarkers that provide early detection of cancers. New antibodies and aptamers of low dissociation constants continue to increase the breadth of accessible targets and the sensitivity of assays. Sensitivity is also dependent on the technology used for transduction of the selective binding interaction into an analytical signal. Fluorescence methods represent one of the most commonly used approaches for

Acknowledgements

We acknowledge the Natural Sciences and Engineer Research Council of Canada (NSERC) (STPGP-479222-15) (RGPIN-2014-04121) for financial support of our research programs.

Pradip Das received his B.Sc. in 2009 and M.Sc. in 2011 in Chemistry from Vidyasagar University, India and Indian Institute of Technology Kharagpur, India, respectively. He received his Ph.D. in Chemistry from Indian Association for the Cultivation of Science, India in 2016. He completed his first postdoctoral research with Prof. Ulrich J. Krull in 2017 from University of Toronto Mississauga, Canada. Currently, he joined as a postdoctoral fellow at the University of Milano-Bicocca, Italy. His

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    Pradip Das received his B.Sc. in 2009 and M.Sc. in 2011 in Chemistry from Vidyasagar University, India and Indian Institute of Technology Kharagpur, India, respectively. He received his Ph.D. in Chemistry from Indian Association for the Cultivation of Science, India in 2016. He completed his first postdoctoral research with Prof. Ulrich J. Krull in 2017 from University of Toronto Mississauga, Canada. Currently, he joined as a postdoctoral fellow at the University of Milano-Bicocca, Italy. His research interests focus on the synthesis of functional nanoprobes for biological applications.

    Abootaleb Sedighi received his M.Sc. degree from Shahid Beheshti University in 2008 and his Ph.D. degree in chemistry from Simon Fraser University, Canada in 2015. In his Ph.D. research under the supervision of Prof. Paul C. H. Li, he employed nanoparticle-DNA interactions to enhance the specificity of diagnostic assays. Abootaleb has been a postdoctoral fellow at University of Toronto, Canada since 2015. His current research under the supervision of Prof. Ulrich J. Krull focuses on the development of nanomaterial-biomolecule constructs for diagnostic and theranostic applications.

    Ulrich Krull is appointed as a Professor of Analytical Chemistry at the University of Toronto, and holds the endowed AstraZeneca Chair in Biotechnology. His research interests are in the areas of biosensor and diagnostic technologies, and applications to biotechnology, forensic, clinical and environmental chemistry. His research work is exploring the use of luminescent nanoscale materials and microfluidics technologies to build devices for detection of DNA and RNA targets. Krull is an editor for Analytica Chimica Acta and serves on a number of Scientific Advisory Boards for industry.

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    Both authors contributed equally to this work.

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