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The use of luminescent quantum
dots for optical sensingJose M. Costa-Fernandez, Rosario Pereiro, Alfredo Sanz-MedelSemiconductor nanocrystals, known as quantum dots (QDs), have demon-
strated several remarkable, attractive optoelectronic characteristics espe-
cially suited to analytical applications in the (bio)chemical field. We review
progress in exploiting the attractive luminescent properties of QDs in
designing novel probes for chemical and biochemical optical sensing.
2005 Elsevier Ltd. All rights reserved.
Keywords: (Bio)chemical sensor; Nanostructure; Photoluminescence; Quantum dot
1. Introduction
Quantum dots (QDs) are nanostructured
materials [1], also known as zero-dimen-
sional materials, semiconductor nano-
crystals or nanocrystallites. These colloidal
nanocrystalline semiconductors, compris-
ing elements from the periodic groups
II-VI, III-V or IV-VI, are roughly spherical
and with sizes typically in the range 112
nanometer (nm) in diameter. At such
reduced sizes (close to or smaller than thedimensions of the exciton Bohr radius
within the corresponding bulk material),
these nanoparticles behave differently
from bulk solids due to quantum-
confinement effects [2,3]. Quantum
confinements are responsible for the
remarkable attractive optoelectronic
properties exhibited by QDs, including
their high emission quantum yields, size-
tunable emission profiles and narrow
spectral bands [3,4]. Moreover, their
strong size-dependent properties result in a
tunability emission that leads to new
applications in science and technology.
The past 20 years have seen intense
research activity in the fundamental study
of the synthesis and the photophysical
properties of QDs [58]. Different groups
have studied II-VI semiconductor QDs,
such as CdSe or CdS nanocrystals, in order
to characterize the relationship between
size, shape and electronic properties [2,4].
However, most applications so far have
focused on their use in microelectronics
and opto-electrochemistry (e.g., light-
emitting diodes, solar energy conversion
or quantum cascade lasers) [3,9,10].
The application of luminescent QDs as
biological labels was first reported in 1998
in two breakthrough papers [11,12]. Both
groups simultaneously demonstrated that
highly luminescent QDs can be madewater-soluble and biocompatible by
surface modification and bioconjugation.
They also showed the high potential of
QDs as highly sensitive fluorescent bio-
markers and (bio)chemical probes.
Other key advances enabling the
emerging practical applications of QDs in
biochemistry and medicine included the
synthesis of high-quality colloidal QDs in
large quantities [13] or recent advances
on surface chemistry of QDs by conjuga-
tion with appropriate functional molecules
[14]. The surface modification of QDs can
increase their luminescent quantum yields
[14], improve stability of the nanocrystals
and prevent them from aggregating [15],
and make QDs available for interactions
with target analytes [16], all of crucial
interest for chemical sensor or biosensor
applications.
This article deals with work on the
analytical applications of QDs in develop-
ing novel (bio)chemical sensors, an area of
growing interest in the past few years. We
include a brief discussion on the attractiveoptical properties of QDs and on the
importance of adequate control of the
synthesis and surface modification of
the luminescent QDs, in order to achieve
the desired selectivity and sensitivity for
sensing target analytes.
2. Optical properties
Studies of the physical properties of QDs
have revealed that strong confinement of
Jose M. Costa-Fernandez,
Rosario Pereiro,
Alfredo Sanz-Medel*
Department of Physical and
Analytical Chemistry,
University of Oviedo, c/ Julian
Clavera, 8, E-33006 Oviedo,
Spain
*Corresponding author.
Tel.: +34 985 10 34 74;
Fax: +34 985 10 31 25;
E-mail: [email protected]
Trends in Analytical Chemistry, Vol. 25, No. 3, 2006 Trends
0165-9936/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2005.07.008 2070165-9936/$ - see front matter 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2005.07.008 207
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excited electrons and holes in these nanocrystals exists
at such reduced sizes and led to observations of unique
optical and electronic properties [2,3]. These com-
pounds, which are usually non-fluorescing, develop an
intense, long-lasting luminescent emission when syn-
thesized on an nm scale. Semiconductor QDs are char-
acterized by a band-gap between their valence andconduction electron bands. When a photon having an
excitation energy exceeding the semiconductor band-gap
is absorbed by a QD, electrons are promoted from the
valence band to the high-energy conduction band. The
excited electron may then relax to its ground state by
the emission of another photon with energy equal to the
band-gap [4].
The results of quantum confinement are that the
electron and hole energy states within the nanocrystals
are discrete, but the electron and hole energy levels (and
therefore the band-gap) is a function of the QD diameter
as well as composition [17]. The band-gap of semicon-
ductor nanocrystals increases as their size decreases,resulting in shorter emission wavelengths [18,19]. This
effect is analogous to the quantum mechanical particle
in a box, in which the energy of the particle increases
as the size of the box decreases.
The size-dependent emission is probably the most
striking and the most studied optical property of QDs. As
the emission properties of semiconductor nanocrystals
depend strongly upon the energy and the density of the
electron states, they can be altered by engineering the
size and the shape of these tiny structures. For example,
Fig. 1 shows the fluorescence spectra of CdSe QDs with
different nanoparticle diameter sizes. As can be seen,
differently-sized CdSe nanocrystals can be tuned in the
500700-nm range. Moreover, as each material has
tunability limits, which depend on the physical limita-
tions of the dot size, other materials have been employed
in QD synthesis (see Table 1) (e.g., Zn-based QDs emitbelow 400 nm while Pb-based QDs have an emission in
the near-infrared spectral region).
As a result of their discrete, atom-like electronic
structure, QDs have typically very narrow emission
spectra with full width at half-maximum (FWHM) of the
luminescent emission of around 1540 nm. (QDs with
bandwidths as narrow as 12.716.9 nm FWHM have
been reported [20]). Since the emission lines are com-
paratively much narrower that those of organic dyes,
detection of the QDs suffers much less from cross-talk
that might result from the emission of a different fluo-
rophore bleeding into the detection channel of the fluo-
rophore of interest (analyte).On the other hand QDs typically exhibit higher fluo-
rescence quantum yields than conventional organic
fluorophores, allowing for greater analytical sensitivity.
The quantum yield of a luminophor is a function of the
relative influences of radiative recombination (producing
light) and non-radiative recombination mechanisms.
Non-radiative recombination, which largely occurs at
the nanocrystal surface, is a faster mechanism than
radiative recombination and is greatly influenced by the
surface chemistry. In this context, it has for example
5
0
0.2
0.4
0.6
0.8
1
500 550 600 650 700
Normalizedfluoresce
nce
intensity
Fluorescence
h(=400 nm)
3 nm~ 4 nm~ 7 nm~
155= 155= mnmn 095= 095= mnmn 746= 746= mnmn
Wavelength, nm
Figure 1. Size-tuneable fluorescence spectra of CdSe QDs. The diameter sizes of the nanoparticles are shown over the fluorescence spectrum.
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been demonstrated that capping the nanocrystal with a
shell of an inorganic wide-band semiconductor (e.g.,
ZnS) reduces such non-radiative deactivations and re-
sults in brighter emission [21]. Chan and Nie estimated
that single ZnS-capped CdSe QDs are about 20 times
brighter that single rhodamine 6G molecules [12].There is also evidence that QDs, suitably surface-
derivatized for protection, have also enhanced photolu-
minescent stability as compared to typical fluorescent
organic dyes. Several studies have demonstrated that the
photoluminescence properties of CdSe nanocrystals
(including the quantum yields, peak position and
FWHM) did not show any detectable change upon aging
in air for several months [22]. Moreover, QDs were ob-
served to be 100 times more stable that conventional
organic fluorophors against photobleaching [12].
3. Synthesis and surface chemistry
Progress on the synthesis of high-quality semiconductor
nanocrystals has played and is still playing a critical role
in the progress of QDs applications. Lithography-based
technologies have been widely used for QDs grown onto
adequate substrates [23], but have mainly been re-
stricted to the preparation of optoelectronic devices.
However, colloidal nanocrystals with single crystalline
structure and well-controlled size and size distribution
can be prepared by relatively simple nanocrystal-growth
processes, starting from organometallic precursors in a
mixed solvent [2,3], the latter approach being more
familiar to chemists.
Due to the availability of precursors and the simplicity
of crystallization, CdS and CdSe have been the most well-
studied colloidal QDs. Murray et al. [8] reported the
synthesis of high-quality Cd-chalcogenide nanocrystals
using dimethylcadmium as QD precursor in the presence
of a coordinating solvent at high temperatures. The most
common coordinating solvents used are trioctylphos-
phine oxide, trioctylphosphine and hexadecylamine
(frequently used together). Such solvents, which cap
the nanocrystal and stabilize its surface, determine the
particle solubility in organic media and prevent irre-
versible aggregation of the nanocrystals. However, QDs
capped with these hydrophobic coatings are incompati-
ble with aqueous assay conditions. Consequently, in
order to extend the field of application of the QDs,
hydrophilic capping agents must be introduced.A landmark in the development of wet chemical
routes for Cd-chalcogenide nanocrystals was the use of
thiols as stabilizing agents in aqueous solution [24].
Water-soluble nanoparticles were prepared by synthe-
sizing thiol-capped crystalline nanoparticles in aqueous
solution by using mercapto-alcohols (e.g., 2-mercap-
toethanol or 1-thioglicerol) and mercapto-acids (e.g.,
thioglycolic acid or thiolactic acid) as stabilizers [24].
In an important paper [13], Pengs group reported the
synthesis of high-quality CdTe, CdSe and CdS nano-
crystals using CdO as precursor instead of Cd(CH3)2. This
latter compound is toxic, unstable, explosive andexpensive, rendering QD-synthesis schemes based on its
use unsuitable for large-scale synthesis (due to the need
of critical experimental conditions). The quality of the
QDs synthesized with this new approach [13] was found
to be comparable or superior to the best previously re-
ported. Moreover, the reported synthesis scheme (see
Fig. 2) proved to be reproducible, were based on mild and
simple conditions, and had great potential to be scaled
up for industrial applications.
In recent years, other alternative routes for synthesis of
highly mono-dispersed QDs have been investigated. For
example, the use of stable non-air-sensitive precursors
based on selenocarbamate derivatives of Zn or Cd [25] or
on the air-stable complex Cd imino-bis(diisopropylphos-
phine selenide) [26] have been proposed to synthesize
monodispersed luminescent QDs of comparable quality to
those prepared by more conventional methods.
However, to ensure efficient emission, any traps for
the photogenerated electron and hole should be avoided.
Possible traps in QDs are generally surface atoms that
are missing at least one chemical bond. The surface
atoms must be optimally constructed or reconstructed
and passivated with some ligands to get rid of traps.
Coating nanoparticles with a different semiconducting
Table 1. Nanocrystal materials and range of tunability
QD core materiala Fluorescence-emission range (nm) QD-diameter range (nm)
Zinc sulfide (ZnS) 300410 Zinc selenide (ZnSe) 370430
Cadmium sulfide (CdS) 355490 1.96.7
Cadmium telluride (CdTe) 620710
Lead sulfide (PbS) 700950 2.39Lead selenide (PbSe) 12002340Lead telluride (PbTe) 18002500
aEmission fluorescence of core-shell QDs is also within the range given in the second column.
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material was shown to have a profound impact on the
photophysics of the nanocrystalline core [2,14,21].
Deposition of a semiconductor layer with a large band-
gap (Eg) relative to the core typically results in the
enhancement of the QD emission due to the suppressionof radiationless recombination mediated by surface states
[2,21], while the degree of charge-carrier confinement
does not change. Conversely, an outer layer from a
semiconductor with a small Eg provides an additional
area of delocalization for electron and hole [2,14,21]. Of
course, relaxation of the confinement regime results in a
red shift of the spectral features.
The exciting size-dependent and surface-dependent
properties of nm-sized QDs have stimulated research on
surface modification of QDs, aiming to expand their
practical applications. In this context, the conjugation of
a semiconductor nanoparticle with an organic molecule
[27], able to interact selectively with a target molecule or
(bio)chemical species, extends the area of applications
from the electronic or optical devices to the biological or
chemical systems, such as the preparation of non-
radioactive biological labels [11,12] or chemical opto-
sensors [16].
4. Optical sensing with quantum dots
More than five years have elapsed since QDs were first
proposed as stable luminescent probes in biological
labeling applications. In that pioneer work, Alivisatoss
group [11] reported a link between biomolecules and
CdS or ZnS core-shell CdSe QDs via surface coating with
an additional layer of silica in order to make them bio-
compatible and water soluble, and established the utilityof the nanocrystals for biological staining. Simulta-
neously, Chan and Nie [12] linked biomolecules to
water-soluble and biocompatible QDs surface-modified
with mercaptoacetic acid for ultrasensitive detection at
the single-dot level. They demonstrated that conjuga-
tion of the QDs with appropriate immunomolecules
can be used for recognition of specific antibodies or
antigens by measuring the luminescence emission of the
nanoparticles.
Many authors have stressed the distinct advantages of
QD bioconjugates over conventional organic dyes (such
as rhodamine), namely greater brightness, greater sta-
bility with respect to photobleaching and narrower
spectral line-widths. However, QD biological labeling has
been slow to emerge into common practice, partly due to
the difficulty in producing stable QD-biomolecule com-
plexes. Developments have stressed the importance of
adequate surface modifications in developing lumines-
cent QDs for labeling in bioanalysis and diagnostics, as
tags for protein and DNA immunoassays or as biocom-
patible labels for in vivo imaging studies. Several reviews
have summarized the use of luminescent QDs in such
biochemical applications [2731]. Moreover, the fast
development and improvements in the synthesis of QDs
(a) NANOPARTICLE SYNTHESIS
(b) SURFACE MODIFICATION
-S-CH2-COO(-)
QD
Water-soluble QDs
TOP/TOPOCdSe QDs
(in CH4)
Reflux 12 h.
Thermom
eter syrin
ge
H2HS-C-COOH
Purification
QDs separation(at~ 15,000 rpm)
andre-dispersion in H2O
P
P
P
O
P
OQD
P
O
P TOP
TOPO
TOPO+
CdO+
HPA
TOP-Se
320 C
Thermom
eter syringe
Argon
Nucleation GrowthQD
20 C270 C
Argon
~ 20 min
Purification
QDs separation(at~ 15,000 rpm)
andre-dispersion in CH4
P
P
P
O
P
OQD
Dilution with~ 10 mL CHCl3
Figure 2. Schematic illustration of a typical synthesis process and surface-modification of a luminescent QD based on the use of CdO asprecursor. TOP: trioctylphosphine; TOPO: trioctylphosphine oxide; HPA: Hexylphosphonic acid.
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have uncovered possibilities that analytical chemists
have also started to explore in developing these
nanomaterials for a new generation of optical sensors
based on luminescence.
4.1. Fluorescence-based transduction
As the luminescence of QDs is very sensitive to the sur-face states of the QDs, it is reasonable to expect that the
chemical or physical interactions between a given
chemical species and the surface of the nanoparticles
would result in changes in the efficiency of the core
electron-hole recombination [32]. This has been the
basis of the increase in research activity on the devel-
opment of novel optical sensors based on QD probes.
Following this approach, Cd-based QDs have been re-
ported for optical sensing of small molecules and ions
(Table 2). In a pioneering work, the addition of Cd ions
to a basic aqueous solution containing unpassivated CdS
nanoparticles resulted in important enhancement of the
luminescence quantum yield of the nanoparticles,without detectable changes in particle sizes [7]. This
effect was attributed to the formation of a Cd(OH)2 shell
on the CdS core, which effectively eliminates the non-
radiative recombination of charge carriers.
A similar photoluminescence-activation effect (attrib-
uted to passivation of surface trap sites that are either
being filled or energetically moved closer to the band
edges by this simple chemical process) was also induced
after adding Zn and Mn ions to colloidal solutions of CdS
or ZnS QDs [32,33]. This behavior provided the basis for
optical sensing of such metallic cations with QDs.
Besides the activation effect, QD-based optical sensingquenching strategies (based on the quenching by the
analyte that affects the luminescence emission of the
nanoparticle) have been proposed. Quenching mecha-
nisms to explain how metal ions quench fluorescence
of QDs include inner filter effects, non-radiative recom-
bination pathways, electron-transfer processes and
ion-binding interactions. Measurement of the lumines-
cence-deactivation ratio of peptide-coated CdS QDs has
been proposed for the optical sensing of Cu(II) and Ag(I)
[34]. Similarly, the effect of three different ligands
(L-cysteine, thioglycerol and polyphosphate) was evalu-
ated on the luminescence deactivation of water-soluble
CdS QDs with respect to several cations, including Zn
and Cu ions [35]. This latter work was one of the first
references to the use of luminescent QDs as selective ion
probes in aqueous samples.
Isarov and Chrysochoos [36] observed that the addi-
tion of Cu(II) perchlorate in 2-propanol to CdS nano-
particles led to the binding of copper ions onto the QD
surface, accompanied by rapid reduction of Cu2+ to Cu+.
It was proposed that copper ions bound onto the surface
of the QDs facilitate non-radiative electron/hole (e/h+)
annihilation, thus resulting in a quenching of the
luminescence from the nanoparticles. It was shown thatTable2.
QD-basedfluorescentprobes
forchemicaldeterminationofsmallmoleculesandions
QD
material
QD
coating
Analyte
Matrix
Detectionlimit
Measuringsignal
Ref.
CdS
Cly-His-Leu-Leu-Cys
Cu(II)
Phosphatebuffer
0.5lM
Fluorescencequenching
[34]
Ag(II)
CdS
Polyphosphate
Cu(II)
Water
0.8mMZn(II)
Fluorescencequenching
[35]
L-cysteine
Fe(III)
0.1mMCu(II)
Thioglycerol
Zn(II)
CdSe
2-mercaptoethanesulfonicacid
Cu(II)
Water
3.2nM
Fluorescencequenching
[37]
CdSe-ZnS
Bovineserumalbumin
Cu(II)
Water
10n
M
Fluorescencequenching
[38]
CdSe
Mercaptoaceticacid+bovineserumalbumin
Ag(I)
Water
70n
M
Fluorescencequenching
[39]
CdTe
3-mercaptopropionic
acid
Cu(II)
Water
0.19
ng/mL
Fluorescencequenching
[40]
CdTe
Thioglycolicacid
Zn(II),
Mn(II),
Ni(II),Co(II)
Water
Fluorescencequenching-en
hancement
[41]
CdS
Polyphosphate
I
Methanol
Fluorescencequenching
[42]
CdSe
Tert-butyl-n-(2-mercaptoethyl)-carbamate
CN
Methanol
0.1lM
Fluorescencequenching
[44]
CdSe
2-mercaptoethanesulfonicacid
CN
Water
1.1lM
Fluorescencequenching
[45]
CdS
L-cysteine
Ag
+
Water
5.0nM
Fluorescenceenhancement
[46]
CdSe
Incorporatedinpolym
erfilms
Triethylamine
Gasmedia
Fluorescencequenching-en
hancement
[47]
Benzylamine
CdSe-ZnS
Thioglycolic+organo
phosphoroushydrolase
Paraoxon
Water
10n
M
Fluorescencequenching
[49]
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the quenching could be employed for chemical sensing of
Cu ions in the organic solution.
Water-soluble CdSe QDs with their surface modified
with 2-mercaptoethane sulfonic acid can be used for the
sensitive and selective determination of copper (II) ions
in aqueous solutions, based on fluorescence-quenching
measurements [37].In addition, based on the photoluminescence
quenching of the nanocrystals, CdSe-ZnS QDs modified
with bovine serum albumin (BSA) were investigated for
the determination of copper [38], CdSe QDs modified
with mercaptoacetic acid and BSA were assayed for the
analysis of silver [39] and CdTe nanocrystals modified
with mercaptopropionic acid were proposed for the
determination of Cu(II) ions [40]. It was observed that
the change in the absorption spectra caused by Cu(II)
can be reversed by the addition of EDTA, a good com-
plexing agent for Cu(II) ions. Thus, the authors proposed
that the interaction between Cu(II) ions and the QD
surface should be of the ion-binding type.Li et al. [41] synthesized water-soluble luminescent
thiol-capped CdTe QDs and investigated the effect of
divalent metal ions on their photoluminescence re-
sponses. They found that zinc ions enhanced the lumi-
nescence emission of the QDs. However, other metals
(e.g., calcium, magnesium, manganese, nickel and cad-
mium) quenched luminescence.
Apart from research on QD-based fluorescent sensors
for ion metals, work on other chemical species (e.g., io-
dide [42] or cyanide [43]) has reported quenching the
emission of CdS or CdSe QDs. A polyphosphate-stabilized
CdS QD was evaluated for optical sensing of iodide [42]and found strong decay of luminescence intensity (decay
times 10 ls), brought about by the analyte. Such
quenching effects [42] were attributed to inner filter
effects, non-radiative recombination pathways and
electron-transfer processes.
The strong, reversible adsorption of negatively-
charged CN onto the QD surface, with the consequent
increased location due to compression of the electron-
wave function in the QDs, was used to explain the
quenching effect of cyanide [43].
Following this mechanism, the synthesis of red
photoluminescent CdSe QDs, with their surface modified
with tert-butyl-n-(2-mercaptoethyl)-carbamate, has
been proposed for the selective, sensitive determinationof free cyanide in methanol after a photoactivation of the
QDs [44].
In a further work [45], the authors reported the syn-
thesis of water-soluble luminescent CdSe QDs, surface-
modified with 2-mercaptoethane sulfonate, for the
selective determination of free cyanide in aqueous solu-
tion (see Fig. 3). The addition of surfactant agents to the
measurement aqueous solution was found to further
greatly stabilize the QDs. In this way, the fluorescent
signals observed allowed for high sensitivity (detection
limit 1.1 106 M) and also for great selectivity of the
proposed cyanide detection (over many other anionic
species).As can be seen, most of the methods described so far
rely on the chemical sensing of small molecules and ions
with QDs via analyte-induced deactivation of photolu-
minescence. However, Zhu and Chen [46] proposed a
method for the determination of trace levels of silver ion
based on luminescence enhancement of water-soluble
CdS QDs modified with L-cysteine. The authors showed
detection limits as low as 5.0 109 M. They proposed
that the fluorescence-enhancement effect could be
attributed to the formation of a complex between silver
ions and the RS- groups adsorbed on the surface of the
modified QDs, which resulted in the creation of radiativecenters at the CdS/Ag-SR complex.
The interactions between some reactive gas molecules
and the surface of CdSe QDs have also been exploited in
developing gas-sensing technologies [47]. Nazzal et al.
found that the photoluminescence of CdSe QDs incor-
porated into polymer thin films is reversibly enhanced
or quenched by the presence of certain gases in the
0
100
200
300
450 550 650
Wavelength, nm
IF
0
100
200
300
450 550 650
Wavelength, nm
IF
+ CN-
CdSeCdSeCdSeCdSeCdSe CdSeCdSeCdSeCdSeCdSeC N-
C N-
C N-
Figure 3. Effect of the addition of 0.65 mg/l of cyanide to the luminescence emission spectra of CdSe QDs surface-modified with MES.
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environment. After QD synthesis, photostimulation was
found to be necessary to obtain a stabilized emission
profile and to provide reliable responses to the presence
of the gases. This effect, shown in Fig. 4, was also re-
ported by other groups [37,44,45]. Although the
mechanism(s) explaining this photoactivation is (are)
not clear, it is thought that a reconstruction of the sur-face atoms of the nanoparticle, or an optimization of
surface-ligand passivation, could lead to the observed
enhancement of the measured luminescence [47].
QDs were also proposed for the design of sensing
assemblies for selective detection of paraoxon [48].
Water-soluble CdSe QDs, surface functionalized with
thioglycolic acid, were synthesized and incorporated to-
gether with organophosphorous hydrolase (OPH) in a
thin film prepared by the layer-by-layer technique. The
presence of paraoxon in the sample solution was de-
tected by changes in the photoluminescence emission of
the QDs, attributed to an interaction of the analyte with
the OPH included in the sensing film, changing itsconformation.
Following this approach, the synthesis of (CdSe)ZnS
nanocrystals and their conjugation with organophos-
phorous hydrolase (through electrostatic interaction
between negatively-charged QD surfaces and the posi-
tively-charged protein side chain and -NH2 ending
groups) has been proposed in developing a biosensor to
detect paraoxon, obtaining detection limits as low as
108 M [49]. The photoluminescence intensity of the
OPH/QD bioconjugate was quenched in the presence of
paraoxon, matching very well with the Michaelis-
Menten equation. This result indicated that the quenching
was caused by the conformational change in the en-
zyme, which was confirmed by gas-chromatography
measurements. Although such a strategy of QD-surfacebioconjugation has not yet been exploited frequently for
sensing, it holds great potential for further developments
in optical sensing with QDs.
In recent years, QDs have been used as inorganic,
non-specific, DNA-binding proteins that act as lumines-
cent labels for different applications (e.g., multicolor gene
mapping on the nm scale) [50]. Moreover, fluorescence
quenching of water-soluble CdSe QDs, surface modified
with mercaptoacetic acid, has also been used to develop
a fluorescence probe for rapid, sensitive determination of
DNA in a neutral medium [51]. The mechanism for the
binding of the nucleic acids to the QDs was investigated
and it was concluded that nanoparticles bind to the helixstructure of the DNA in a non-intercalative way,
resulting in the observed deactivation of the lumines-
cence emission of the QDs.
4.2. Fluorescence (or Forster) resonance
energy-transfer-based sensors
Energy-transfer mechanisms have been widely used in
different fields and are the basis of a new generation of
Figure 4. Effect of photoactivation (a) fluorescence spectra from CdSe quantum dots measured after different sunlight time exposures (from ref-erence [44]), (b) Pictures of a methanolic QDs solution (1) freshly prepared and (2) after 3 days exposed to the sunlight.
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luminescent sensors [52]. In this context, the capability
of tailoring (via size) QD-photoemission properties should
allow efficient energy transfer with a number of con-
ventional organic dyes, thus suggesting the use of the
nanoparticles in sensor or chemical assay applications
based on photochemically-induced fluorescence (or
Forster) resonance-energy-transfer (FRET) mechanisms.However, the QD emission spectrum is narrower and
more symmetric than the emission from conventional
organic fluorophores, making it much easier to distin-
guish the emission of the donor from that of the accep-
tor. Moreover, the high quantum yields of QDs make
energy transfer very efficient.
Several studies have already confirmed that QDs are
excellent candidates for use in the design of novel FRET-
based strategies. As an example, specific binding of dif-
ferent proteins was observed via measurements of FRET
between a CdSe-ZnS QD donor, attached to one of the
proteins, and some organic acceptor dyes attached to the
other protein under study. In the presence of specificinteractions between both proteins, strong enhancement
of the acceptor-dye fluorescence was observed [53].
In a more fundamental study, conjugation of BSA
with luminescent CdTe nanoparticles (capped with L-
cysteine) resulted in a significant increase in the CdTe
fluorescent emission, attributed to an efficient reso-
nance-energy transfer from the tryptophan moieties of
the protein units to the CdTe nanoparticles acting as
acceptors [54]. However, despite the demonstrated
favourable properties of luminescent QDs for FRET
experiments, only very few studies on the synthesis of
QD bioconjugates and their applications for QD-FRET-based optical sensors have been published so far.
Luminescent CdSe QDs have been used as energy do-
nors in developing a competitive FRET assay for maltose
[55] (see Fig. 5). Semiconductor nanoparticles biocon-
jugated to different maltose-binding proteins, formed
using a non-covalent self-assembly scheme, act as the
resonance-energy-transfer donors, while non-fluorescent
dyes bound to cyclodextrin serve as the energy-transfer
acceptors. In the absence of maltose, cyclodextrin-dye
complexes occupy the protein binding sites. Energy
transfer from the QDs to the dyes quenches the QD
fluorescence. When maltose is present, it replaces the
cyclodextrin complexes, and the QD fluorescence recov-
ers [55]. This approach has been successfully employed
in developing a prototype QD-based sensor for sensing
maltose in solution [56].
CdSe-ZnS core-shell biocompatible QDs, stabilized by
mercaptopropionic acid modified with a thiolated oligo-
nucleotide, have been proposed as energy donors for
lighting up the dynamics of telomerization or of DNA
replication occurring on the nanoparticles, using FRET
to dye units incorporated into the new synthesized
telomere or DNA replica [57]. After addition of telome-
rase, during the progression of the telomerization, the
fluorescence emission from the QDs at 560 nm decreaseswith the concomitant increase of the 610 nm emission of
the dye (using 400-nm excitation). Emission observed
upon telomerization is attributed by the authors to FRET
from the QDs to the dye molecules incorporated into the
telomeric units by telomerase. The CdSe-ZnS QDs func-
tionalized with M 13~ DNA also enabled the detection of
a viral DNA by following the DNA-replication process by
FRET. Results can be applied to the fast, sensitive
detection of cancer cells [57]. It could be also applied to
the development of chip-based DNA sensors as it func-
tions like logic gates, where FRET readout occurs when
hybridization and replication proceed.
In one application, luminescent ZnS-capped CdSe QDs,
covered with mercaptoacetic acid, have been conjugated
to amine-terminated molecular beacons (MBs) at the 5 0
end for probing DNA sequences [58]. Connected to the 3 0
end of the molecular beacon, there is a quencher mole-
cule [4-(40-dimethylaminophenylazo) benzoic acid,
DABCYL]. In the absence of the target DNA sequence,
MBs form a hairpin structure in which the QDs and
DABCYL are in such close proximity that energy from
the QDs is transferred to the quencher and no fluorescent
signal is observed. After adding the target DNA se-
quence, the MB structure opens. Since QD and quencher
DQ PBM
excitation(350nm)
FRET Quenching
Dye
DC
DQ PBM
excitation(350nm)
maltose+
ecnecseroulF
Dye
DC
a
b
Figure 5. Schematic diagram of the quantum-dot based FRET malt-ose sensor (adapted fromreference [56]). QDs conjugated to around10 maltose-binding proteins function as the FRET donors. Non-fluorescent dyes bound to a cyclodextrin serve as the acceptorsand in the absence of maltose are filling the protein binding sitesresulting in a quenching of the luminescence. Whenmaltose is pres-ent, it removes the cyclodextrin-dye complex and the fluorescenceis recovered. MBP: maltose binding protein, CD: cyclodextrin.
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are then separated from each other, no FRET occurs and
QD emission can be detected. The authors demonstrated
that using QDs in this probe resulted in an improved
lifetime during imaging, as compared to using organic
fluorophores.
The application of water-soluble ZnS nanoparticles,
surface-modified with sodium thioglycolate, as fluores-cence probes has been described for specific determination
of protein content in a serum sample (e.g., human serum
albumin, BSA and gamma globulin) with detection limits
of the order of 10 pg/mL [59]. Energy transfer from sur-
face-adsorbed proteins to the nanoparticles has been
proposed as the mechanism responsible of enhancing the
QD luminescence used for sensing. The methodology was
applied to the analysis of human serum samples, and re-
sults obtained were in good agreement with those given by
alternative, conventional techniques.
The use of luminescent QDs conjugated to appropriate
antibody fragments has been employed to develop solu-
tion-phase, nanoscale, sensing assemblies for detectingthe explosive 2,4,6-trinitrotoluene (TNT) in aqueous
environments based on FRET measurements [60]. The
presence of TNT was detected by displacing the dye-
labeled analogue bonded to the QD surface, resulting in
the elimination of FRET and in the concentration-
dependent recovery of QD photoluminescence.
It should be mentioned that QD-FRET assays can be
designed so that FRET is the dominant energy-transfer
process, but FRET efficiency is still inherently low com-
pared to that of conventional dyes (due to the compar-
atively large size of QDs, it is too difficult to secure close
enough proximity for FRET to occur efficiently). How-ever, several studies have been carried out in order to
gain a better understanding of the process, showing that
enhanced efficiency can be obtained by careful design of
the QD-bioconjugation scheme. Using the FRET scheme
for maltose determination [55], mentioned previously,
the authors found that, by attaching several active dye-
labeled proteins to the QD surface, the overall FRET
signal was improved substantially over a simple one
donor-to-one acceptor FRET pair [61]. Efficiency was
further enhanced by increasing the number of dye
acceptors in the QD bioconjugate, where QDs functioned
as efficient energy donors [61]. Furthermore, the large
size of QD fluorophores, compared to organic dyes,
allowed design of configurations where, for example,
multiple acceptors could coordinate around and interact
with a single QD donor. This strategy, already demon-
strated for multiple detection in immunoassays [62],
suggests the possibility of achieving mutianalyte opto-
sensing using a single QD donor and multiple acceptors
in a FRET-assay format.
4.3. Surface-plasmon-resonance applications
QDs have been also investigated by measuring surface-
plasmon resonance (SPR). Redox transformations
occurring on chemically-modified surfaces may signifi-
cantly alter the refractive index of the interface and thus
induce changes in the plasmon angle of the SPR spectra
[63]. This approach was followed in the design of an SPR
sensor for acetylcholine-esterase inhibitors based on the
photoelectrochemical-charging effect of Au nanoparti-
cles in an Au-nanoparticle/CdS-QD array (coating anAu/glass surface), which was followed by means of SPR
changes upon continuous irradiation of the sample [63].
The fact that other enzymes may be coupled to the Au-
semiconductor-nanoparticle array and so activate
photoelectrochemical functions suggests that using SPR
spectroscopy combined with surface-modified QDs could
provide an alternative tool for new SPR (bio)sensor
probes.
4.4. Phosphorescence transduction
Only fluorescence transduction has so far been employed
for photoluminescence sensing in combination with QDs.
However, investigation of the luminescence properties ofQDs is slowly expanding into phosphorescence, a detec-
tion principle that may provide several advantages for
the design of reliable optical sensors [64,65].
The dopage of sol-gel porous matrices with Tb2S3 QDs
has been found to produce photoluminescent materials
with an emission comprising two well-defined bands,
one at 440 nm (that corresponds to the undoped sol-gel)
and the other at 600 nm that the authors attributed to
the Tb2S3 nanoparticles in the silica xerogel [66]. This
last emission presents characteristics typical of a room-
temperature phosphorescence (RTP) emission, although
the origin of the luminescence and the emission mech-anism is not yet understood [66].
Moore et al. from Mercer University have also reported
phosphorescence emission from aqueous mixed sulfide
QD matrices, QD-CdxZn1-xS, doped with manganese(II)
[67]. The authors evaluated the impact of matrix com-
position on the QD phosphorescence ($590 nm). They
found that the observed RTP intensity for the CdxZn1-
xS:Mn QDs was very sensitive to matrix composition
(e.g., the 590 nm emission increased with the Zn con-
centration of the matrix).
Although very preliminary, those studies seem to open
the door to novel transduction schemes and applications
of QDs for optical sensing.
4.5. Immobilization techniques
Most of the work on QD applications so far has been
restricted to solution-sensing assays. A step further to-
wards developing useful optosensing approaches [68]
consists of immobilizing those QDs in appropriate solid
supports to fabricate active solid phases for working in
flowing solutions [65].
In this context, sol-gel materials have been demon-
strated to be especially suited to the development of
luminescent optical sensors by trapping the indicator
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molecules inside the inorganic structure during the
polymerization process [69]. Several approaches have
been also proposed for synthesis of sol-gel materials
doped with QDs [7072]. Most of the synthetic routes
involve preparing and surface modifying the QDs in
solution followed by sol-gel processing in order to obtain
an inorganic material doped with the luminescentnanocrystals. Considering that QDs are very sensitive to
changes in the environment, the transfer of these
materials into glasses, through sol-gel processes, is not a
simple task. Changes in solvent polarity or QD surface
reactions during sol-gel polymerization would result in
an undesirable quenching of the QD photoluminescence.
In order to overcome such limitations, several ap-
proaches have been investigated, including the use of
alkyl amines as a bifunctional aid in QD-glass synthesis
(amines act as gelation catalysts and stabilizers) [70].
Such QD glasses have demonstrated high stabilities
and resistance to degradation, so they have been mainly
used for optoelectronic applications (e.g., solar concen-trators or as active media in tunable lasers [73]). How-
ever, these sol-gel materials, doped with luminescent
QDs, are also expected to be also for optosensing appli-
cations in the near future.
A related approach is to incorporate QDs into
molecularly imprinted polymers (MIPs) [74], which act
as artificial receptors/antibodies exhibiting tailor-made
selectivity for a given template molecule. Following
this approach, Lin et al. [75] synthesized different
MIPs with several templates incorporating CdSe/ZnS
core-shell QDs, derivatized with 4-vinylpiridine. Adding
the functionalized QDs to the monomers, cross-linkersand template molecules in the precursor mixture
incorporated the nanocrystals into the MIP during
polymerization. Optosensing of the analytes is achieved
by measuring the quenching of the photoluminescent
emission from the QDs included in the polymeric
structure. Such quenching is attributed to fluores-
cence-energy-transfer processes between the QDs and
the template molecules. The approach has been suc-
cessfully tested for caffeine detection, although addi-
tional work needs to be carried out to characterize this
optosensor analytically. It is clear that this approach
also opens up a new avenue for the development of
new QD-based optical sensors.
The advantages and the disadvantages of using the
different optical transduction strategies already at-
tempted in developing chemical sensors based on QDs
can be summarized as follows:
i Methods based on chemical or physical interactions
between target chemical species and the surface of
the nanoparticles are very simple, easy to develop
and have demonstrated very high sensitivity and
selectivity features. However, those methods appear
to be restricted to sensing just a few reactive small
molecules or ions.
ii Quantum dots have been demonstrated to be espe-
cially suited to the development of new chemical
sensors based on energy-transfer phenomena. This
approach will probably be widely used as a general
strategy to develop new QD-based sensor systems
for analytes unsuitable for direct analysis via interac-
tion with QD particles. Of course, those methods arenot as simple as those in i) because many different
parameters need to be carefully controlled (e.g.,
distance of the acceptor/donor dyes to the QD sur-
face, and orientation and number of groups) in order
to achieve an analytically useful energy-transfer
process.
iii RTP methods offer general, exceptional characteristics
in terms of sensitivity and selectivity and some other
advantages over fluorescence methods. However,
work on the development of chemical sensors based
on QDs using phosphorescence transduction is still
at its very early preliminary development stages.
Thus, the practical usefulness of RTP methods hasnot yet been demonstrated.
5. Conclusions and future prospects
The popularity of QDs as photoluminescent probes
for optical sensing is steadily increasing, as research-
ers move to exploit the unique properties of this new
class of luminophores. Optosensing technologies will
probably combine the important advantages of QDs
with flow-analysis techniques and perhaps fibre-opticinstrumentation.
Chemical-sensing developments will benefit from the
continuous advances taking place in the science of
QDs. Thus, future improvements in the nature, range
and quality of prepared nanomaterials can be ex-
pected. Chemical-surface modifications of the QDs
have still to be perfected in order to enhance the
selectivity of the systems and to profit from their
favorable emission features. In this context, the con-
jugation of selective reagents to the surface of lumi-
nescent QDs (a strategy well established for imaging,
immunoassay and labeling applications in biological
science) appears to be a most promising strategy in
further developing bioactive fluorescent probes for
sensing applications.
Moreover, approaches such as the combination of the
nanoparticles with energy-transfer processes, phospho-
rescence detection or inclusion on MIPs are promising
possibilities that are now being investigated.
Last, but not least, QDs should now be integrated into
appropriate solid supports, a process that has only just
begun, in order to develop reliable active phases and
optosensors able to provide useful flow-through optical
sensing or fiber-optic-based sensing applications.
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In brief, the future of QDs for optical sensing looks
bright, as their analytical potential in the field now starts
to be realized.
Acknowledgement
Financial support from the EU Project SWIFT-WFD
(Contract SSPI-CT-2003-502492) and MAT2003-
09074-C02 (Feder Programme and Ministerio de Ciencia
y Tecnologa, Spain) is gratefully acknowledged.
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