Quantum dots for Förster Resonance Energy Transfer (FRET)

https://doi.org/10.1016/j.trac.2020.115819Get rights and content

Highlights

  • Quantum dot bioconjugation strategies.

  • FRET theory for quantum dot donors and acceptors.

  • Biosensing using quantum dots and FRET.

  • Quantum dot molecular/spectroscopic rulers.

  • Quantum dot immunoassays, enzyme assays, and nucleic acid assays.

  • Multistep FRET and higher order multiplexing.

  • Imaging using quantum dots and FRET.

Abstract

The analysis of biomolecular interactions using quantum dots (QDs) as both FRET donors and acceptors has become an established technique in the life sciences. This development has been driven by the unique properties of QDs, which include large surfaces for the attachment of biomolecules, high brightness and photostability, strong and spectrally broad absorption, and color-tunability via QD size, shape, and material. Applications include molecular rulers for structural analysis, small-molecule sensors, immunoassays, enzyme assays, nucleic acid assays, fluorescence imaging in-vitro and in-vivo, and molecular logic gates. Here, we will explain the theory of QD-based FRET, review some aspects of QD surface functionalization that are important for FRET, and highlight and discuss the advantages and disadvantages of QDs in FRET-biosensing using both spectroscopy and imaging techniques.

Introduction

Due to their unparalleled properties, since their first application in biological systems [1,2], core-shell semiconductor quantum dot (QD) nanocrystals have become important fluorophores for the biosensing community. Their structure provides them unique photophysical properties, such as high brightness (due to high quantum yields and absorption coefficients), chemo- and photostability, broad absorption and narrow emission spectra, wide spectral coverage from the visible to near-infrared (NIR), and color-tunability by varying their physicochemical characteristics (size, shape, and core-shell composition). Moreover, QDs acquire new properties when coupled with other organic or inorganic materials. In the field of nanophotonics, this highly coveted versatility makes QD probes superior to conventional fluorophores. The aim of this review is to highlight and discuss the ability of QDs to take part in and advance Förster Resonance Energy Transfer (FRET) for analytical applications. QDs have been shown to be both excellent energy donors, for a large variety of organic and inorganic molecules (dyes, fluorescent proteins), polymers, and metal nanoparticles (NPs) [[3], [4], [5]], and acceptors, for lanthanide-based compounds (e.g., chelates, cryptates, nanoparticles), other QDs, and fluorescent polymers [[6], [7], [8]].

Many methods of biomolecular detection, including FRET, continue to use standard fluorescent probes, such as dyes or fluorescent proteins [8,9]. Despite their photophysical drawbacks, including rapid photobleaching, self-quenching at high concentrations, or instability in biological media, these probes are very functional and exist in almost any desired color. Rather than replacing dyes or fluorescent proteins, QDs should be regarded and used as an alternative fluorescent nanoprobe that can provide several advantages over standard fluorophores. In particular, the longer photoluminescence (PL) lifetimes (in the tens to hundreds of nanoseconds), the broader excitability (nearly arbitrary choice of excitation wavelength and one excitation source for different QDs), and the narrower emission bands (significantly better multiplexing capabilities) of QDs present unique benefits for FRET. In this review, we mainly focus on the bioanalytical properties of QDs as versatile FRET platforms. We will discuss different QD bioconjugation methods and explain the basic concept of FRET and the most important FRET parameters (e.g., Förster distance, FRET efficiency, FRET ratio) useful for performing and analyzing FRET experiments. We will also give an overview of how fast QDs revolutionized the field of FRET biosensing and their adaption to various bioanalytical applications ranging from clinical assays to imaging in cells or tissues.

Section snippets

Quantum dot bioconjugation

The use of QDs in FRET-based biosensors requires significant preparation efforts in order to transform them into efficient bioconjugates. A very important point concerns the biocompatibility of the QD material, which is most often accomplished by an appropriate surface coating, which can range from thin capping ligands to thick polymer, lipid, or silica shells. The many surface coating strategies have been described in detail elsewhere [10,11] and here we will restrain ourselves to discussing

General FRET theory

FRET can be defined as an energy transfer process between two molecules, one of which is an energy donor and the other an energy acceptor. The energy transfer does not occur due to donor emission and acceptor absorption but by charge-charge interaction between oscillating donor and acceptor dipoles in close proximity (ca. 1–10 nm) [[50], [51], [52], [53], [54]]. In addition to the proximity condition, the transition dipole moments of donor and acceptor must have favorable orientation with

QD-FRET biosensing

The first applications of QD-FRET were demonstrated by Kagan et al. on QD-QD FRET and date from 1996 [77,78]. They could observe acceptor sensitization of large QD acceptors as well as quenching of small QD donors in a mixed close-packed CdSe solid and showed that the FRET mechanism (dipole-dipole interaction) can be applied to energy transfer between QDs. A few years later, Willard et al. used biotin-streptavidin as biological binding model between QD donors and dye acceptors (vide supra) [65

Conclusions and perspective

QD-based FRET has become a versatile and powerful tool for the analysis of many different biomolecules and biomolecular interactions. Many studies have used QDs as donors and/or acceptors in spectrally and temporally resolved multiplexing for both spectroscopy and imaging in-vitro and in-vivo. The physical and chemical properties of the nanoparticles, as well as their unique photophysics with broad absorption and narrow emission spectra that can be tuned by material composition and size, have

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