Talanta 196 (2019) 456–478

Contents lists available at ScienceDirect

Talanta
journal homepage: www.elsevier.com/locate/talanta

A review on nanostructured carbon quantum dots and their applications in T

biotechnology, sensors, and chemiluminescence
Mohammad Jafar Molaei
Faculty of Chemical and Materials Engineering, Shahrood University of Technology, Shahrood 3619995161, Iran

ARTICLE INFO ABSTRACT

Keywords: Carbon quantum dots (CQDs) are a member of carbon nanostructures family which have received increasing
Carbon quantum dots attention for their photoluminescence (PL), physical and chemical stability and low toxicity. The classical
Biomedical semiconductor quantum dots (QDs) are semiconductor particles that are able to emit fluorescence by excitation.
Bioimaging The CQDs is mainly referred to photoluminescent carbon nanoparticles less than 10 nm, with surface mod-
Drug delivery
ification or functionalization. Contrary to other carbon nanostructures, CQDs can be synthesized and functio-
Sensors
Chemiluminescence
nalized fast and easily. The fluorescence origin of the CQDs is a controversial issue which depends on carbon
source, experimental conditions, and functional groups. However, PL emissions originated from conjugated π-
domains and surface defects have been proposed for the PL emission mechanisms of the CQDs. These nanos-
tructures have been used as nontoxic alternatives to the classical heavy metals containing semiconductor QDs in
some applications such as in-vivo and in-vitro bio-imaging, drug delivery, photosensors, chemiluminescence
(CL), and etc. This paper will introduce CQDs, their structure, and PL characteristics. Recent advances of the
application of CQDs in biotechnology, sensors, and CL is comprehensively discussed.

1. Introduction biocompatibility, high fluorescence emission intensity, resistance to

CQDs have been the focal point of interest of many worldwide re-
searchers in the recent years, due to their unique properties such as
small size (best for some bio-applications), biocompatibility, PL prop-
erties, high-temperature stability, chemically inert structure and the
easy routes of functionalization [1]. CQDs are carbon nanoparticles
which are usually surface passivated and functionalized with organic or
biomolecules. CQDs have a high cross-section for two-photon excitation
and are also nonblinking and water-soluble which besides nontoxicity
makes them superior candidates in bioimaging [2]. The size of these
clusters is usually < 10 nm and still is better to be < 5 nm for some
biological applications.
The semiconductor QDs with the sizes below 10 nm are synthesized
from the groups II–VI or III–V elements of the periodic table. In QDs, all
three dimensions are below a certain critical size that quantum con-
finement effect can occur and the mobility of the internal electrons is
confined in any directions. The conventional QDs are made from almost
heavy metals. Many of the conventional QDs are composed of cadmium
and selenium [3]. Semiconductor QDs as two-photon fluorescence
materials (like CdSe and related core-shell QDs structures) have been
used extensively in different in vivo and in vitro bioimaging experi-
ments [4]. The CQDs have water solubility, acceptable
photobleaching, neglectable cytotoxicity, and are chemically inert.
While the synthesis of semiconductor QDs is costly, the CQDs can be
synthesized on a large scale and inexpensive [3]. The CQDs may have
functional groups such as hydroxyl, carboxyl, carbonyl, and epoxy that
can result in their water solubility. The functional groups on the CQD
surface can bring them the potential for organic, biological or poly-
meric functionalization [5]. Therefore, the CQDs can be considered as
superior alternatives to conventional semiconductor QDs in order to
overcome problems such as expensive synthesis, toxicity, and en-
vironmental problems concerns which are accompanied with semi-
conductor QDs [3].
There are some other almost new carbonaceous materials with
fluorescent properties. The fluorescent carbonaceous materials include
graphene quantum dot (GQD) [6–14], polymer dots (PDs) [15,16],
carbon nanotube dot [17,18], graphene oxide (GO) [19–22], nanodia-
monds (NDs) [23–31] and CQD [4,32–44]. The NDs are composed of
carbon atoms with sp3 hybridization in the core and carbon atoms with
the graphitic structure on the shell [45]. The PDs are dots with bright
fluorescence composed of aggregated polymers or π-conjugated poly-
mers with a typical particle size of less than 100 nm that consist of
discrete discontinuous phase in water or other low molecular-weight
liquids as a continuous medium [46].

E-mail address: m.molaei@shahroodut.ac.ir.

https://doi.org/10.1016/j.talanta.2018.12.042
Received 24 August 2018; Received in revised form 11 December 2018; Accepted 13 December 2018
Available online 15 December 2018
0039-9140/ © 2018 Elsevier B.V. All rights reserved.
M.J. Molaei
Although the CQDs and GQDs are dots that consist of carbon atoms
and the whole QD is covered with functional groups, they differ in
structure, synthesis methods, properties, and applications. Graphene is
a 2D sheet of carbon atoms which has a honeycomb structure with sp2
hybridization. The shape, size, and thickness of graphene sheets can
have a strong influence on its properties. The GQDs have quantum
confinement and edge effects [47]. Graphene can be considered as a
semiconductor which has a zero bandgap and infinite exciton Bohr
diameter. Therefore, it is expected to confinement effects can be ex-
hibited in any fragment of graphene sheet; however, the typical size of
GQDs might be supposed below 20 nm. Electronic transport in all three
dimensions of a GQD is confined. The GQDs with a non-zero bandgap,
show luminescence phenomenon. The bandgap in GQDs can be tuned
through altering the surface chemistry and changing the size of GQDs
fragments. What should be noted is that the PL bandwidth of GQDs is
wider than that of semiconductor QDs. Furthermore, by increasing the
excitation wavelength in GQDs, their PL maximum undergoes a red-
shift and decreases [6]. Similar to graphene, the GQDs have carboxylic
acid moieties on their edges and hence, this makes them water soluble
and helps for an easy functionalizing with organic, inorganic, biolo-
gical, and polymeric species. The GQDs have better surface grafting
through a π-π conjugated network of surface groups [48]. The GQDs
usually have a crystalline structure and also are anisotropic with larger
dimensions in basal plane and smaller dimensions in height.
The CQDs differ from other carbon dots such as GQDs that have
been the focus of several researchers over the past 20 years. The GQDs
have the structure of graphene lattice within the dot while the CQDs
have crystalline or amorphous structure. The GQDs are composed of
one or a few layers of graphene sheets, while the CQDs are quasi-
spherical discrete carbon nanoparticles typically below 10 nm in dia-
meter [49]. The carbon atoms in CQDs and GQDs have sp2 bonding.
Based on the fringes seen via HRTEM, the CQDs have a fringe spacing of
0.34 nm corresponding to the (002) interlayer spacing of graphite. The
fringe spacing for GQDs is 0.24 nm corresponding to the (100) inter-
layer spacing of graphene. Therefore, the GQDs are graphene fragments
(with the thicknesses less than 2 nm) [5].
The GQDs are synthesized through nanolithography or by chemical
breakdown of GO [38]. The CQDs can be synthesized via different top-
down or bottom-up synthesize procedures from organic or inorganic
starting materials. Using organic ingredients such as fruit juice [42]
might result in lower toxicity for the synthesized carbonaceous dots.
CQDs can be used in several applications including photovoltaic cells to
bioimaging (Fig. 1).
In this research we will focus mainly on the CQDs; however, for PL
mechanisms we will discuss GQDs, as well. The fluorescence in CQDs
arises from the defects and in GQDs is caused by defects and/or isolated
π domains of graphene sheet [50].
The carbon-related PL is originated from the passivated surface
defects which act as excitation energy traps or is originated from con-
jugated π-domains. The CQDs can also show two-photon excitation in
NIR [4]. In single- and multi-walled carbon nanotubes (CNTs), fluor-
escence arises from passivated surface defects. The fluorescence in
CNTs occurs in a wide range of excitation wavelengths from UV to NIR.
The CNTs fluorescence inspired the origin of fluorescence in CQDs.
Since CQDs are nanoparticles of carbon with numerous surface defects,
they might also emit fluorescence by surface-passivated defects [50].
This review is intended to survey the recent advances in the fast-
evolving field of CQDs research and aims to update biomedical, sensors
and CL applications of CQDs in order to place emphases on challenges
and future perspectives for their development.
2. Different types of photoluminescence emissions in CQDs
The exact fluorescence mechanism in the CQDs is not clear yet and
has been a controversial issue among scientists. Although there have
been the proposed mechanisms for the origin of the PL in the CQDs,
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Talanta 196 (2019) 456–478
there are not adequate experimental examinations confirming the the-
oretical models. Generally, two models have been proposed for the PL
mechanism in the CQDs. These two models are the CQDs fluorescence
emission originated from conjugated π-domains and/or surface defects
that are discussed below.
2.1. Photoluminescence emissions originated from conjugated π-domains
Size-controlled PL emission of semiconductor nanocrystals is one of
the most attractive properties of these materials [51]. Quantum size
effects [52] results in increasing the band gap of the semiconductor
nanocrystals as their size decreases. For example, for CdSe QDs, the
emission color of PL shifts from red (centered at 650 nm) to blue
(centered at 450 nm) with a decrease in QD size. PL quantum yield (QY)
which is a measure of PL brightness of semiconductor nanocrystals,
strongly depends on the synthesis method and varies from synthesis to
synthesis [53]. Unfortunately, the reproducibility, as well as the sta-
bility of the PL are not predictable [54]. There have been several at-
tempts for surface modification of QDs to enhance their luminescence
efficiency and colloidal stability. Passivation of both anionic and ca-
tionic surface sites using organic ligands is not an easy process.
Therefore, dangling bonds cannot be removed completely. Several in-
organic surface modification methods have been applied in order to
passivate both anionic and cationic surface sites [55]. For example,
CdSe QDs have been covered with CdS [56–58] or ZnS [59] in them the
band gap energy of the core stands within the band gap energy of the
shell and the photogenerated electrons. This core/shell structure of
semiconductor QDs can tolerate chemical degradation or photo-oxida-
tion to some higher extent [55].
GQDs belong to the fluorescence carbon materials such as nano-
diamonds, fluorescence CNTs, and fullerene. Studying the PL me-
chanism of GQDs as a simple model system can help us to understand
the PL mechanism of other fluorescence carbon nanostructures [60].
Similar to semiconductor QDs, the electrons are confined in conjugated
π-domains of graphene sheets. Therefore, we can name them graphene
quantum dots (GQD), knowing that the electron confined π-domains are
not real dots. PL color dependence on the π-domain size of graphene
sheets is manifested to a lesser extent in comparison to semiconductor
QDs. CQDs are photoactive, with the π-plasmon absorption covering
UV/Vis and NIR spectral regions [61].
Graphene sheet has an extended π-network which can be considered
as a large planar aromatic molecule. Graphene, however, has different
electronic transitions in comparison with aromatic molecules. The π-
domains are isolated as sp2 hybrid islands which are rich in π-electrons
and are created through reduction of graphene oxide (reduced gra-
phene oxide (rGO)). Graphene oxide is obtained by harsh oxidizing
conditions applied on graphite flakes (Hummers method) and this
condition exfoliates the graphite into single-layer sheets of GO. There is
no connection between sp2 islands of graphene sheets. In fact, if there
are any π-connections between sp2 islands of graphene sheets, interis-
land quenching of fluorescence emission occurs [33,62]. Bandgap
fluorescence requires preserving a single-layer configuration after par-
tial conversion to rGO or applying other methods for inducing isolated
sp2 islands. In an effort [63] with the aim of fluorescence emission,
oxygen plasma etching was applied to treat graphene sheet. However,
in spite that single layer sheets emitted fluorescence, multiple layers did
not emit due to the quenching.
GQDs with a single layer of carbon and functional groups on the
surface and edges have a chemically similar structure to GO which
includes oxygen-based functional groups on the graphene plane or its
edges. Therefore, sp2 domains in GO are between C–O sp3 domains of
epoxy and hydroxyl groups [64]. It has been reported that in GO thin
films deposited via exfoliated suspensions, the isolated sp2 clusters
within the carbon-oxygen sp3 matrix results in electron-hole pairs lo-
calization and radiative recombination of small clusters. The optoe-
lectronic properties of carbon materials including sp2 and sp3 bondings
M.J. Molaei
Fig. 1. Different applications of CQDs.
are dictated by π states of sp2 sites. The π and π* electronic levels of sp2
clusters is lying localized between σ and σ* states bandgap of the sp3
matrix. These sp2 domains act as luminescence centers as a result of
recombination of electron-hole pairs. The bandgap is affected by the
fraction of sp2 domains, their size, and shape. Based on calculations, in
chemically derived GO, the sp2 clusters of conjugated repeating units
lead to a bandgap corresponding to blue emission [19]. The PL spec-
trum of GO varies from visible to NIR. This wide emission spectrum of
GO is due to the wide size distribution of sp2 domains that have dif-
ferent band gaps [64].
The PL spectrum of GQDs can be considered the transition from the
lowest unoccupied molecular orbital (LUMO) to the highest occupied
molecular orbital (HOMO). The bandgap of HOMO-LUMO depends on
the GQDs size and decreases as the GQDs size increases. Therefore,
different mixtures of GQDs with different sizes, have different PL
spectra [48]. Kwon et al. [65] synthesized GQDs through the amidative
cutting of tattered graphite in the range of 2–10 nm, easily with chan-
ging the amine concentration. They observed that by increasing the size
of the synthesized GQDs the energy gap decreases and the PL changes
from blue to brown. Tan et al. [66] used electrochemical exfoliation of
graphite in K2S2O8 and showed that red fluorescence in GQDs are due
to the isolated sp2 domains with the size of 3 nm. The domains were
generated by SO4− radicals as scissors to cut graphene to isolated sp2
domains.
Synthesize of CQDs with different size and nitrogen content resulted
in CQDs which generate RGB luminescence with a stable and bright
emission [67]. However, most of the times the PL color of CQDs can be
tuned via surface groups rather than size. Therefore, it is not efficient to
control the PL color in CQDs by controlling their size [64]. On the other
hand, the PL is not exclusively affected by the CQDs size; but is affected
by functional groups, edge, and size in a synergic manner [60].
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Talanta 196 (2019) 456–478
2.2. Photoluminescence emissions originated from surface defects
Many distinctive fluorescences in graphene materials cannot be
explicated via emission caused by sp2 islands. Functionalized surface
defect sites in GQDs can facilitate strong blue emission and high up-
converted PL. Surface passivation in GQDs results in higher fluores-
cence performance and upconversion properties [68]. It has been re-
ported that surface defects formed by surface oxidation would be as
capturing spots of excitons and this, in turn, results in the surface-state-
related fluorescence. More defects on the surface of CQDs forms by a
higher degree of surface oxidation. This leads to narrowing energy le-
vels and red-shift [69]. The surface defects can be any site that has not a
perfect sp2 domain and acts as an energy trap. The functionalized sur-
face defects as well the sp2 and sp3 carbons that exist in the CQDs could
contribute to multi-color emission [33].
Functional groups on the CQDs could have different levels of energy
that results in different emissive traps. By illuminating the CQD with a
certain excitation wavelength, the emission is dominated by surface
state emissive traps. If the surface oxidation degree is higher or if some
modifications are made, more surface defects form which result in red-
shift emission [64].
Wang et al. reported that in CQDs and GQDs the common origin of
green luminescence emission centers is assigned to the edge states that
are composed of carbon atoms on the edges of carbon backbone and
functional groups that include (C=O) like carbonyl and carboxyl
groups. They suggested that the competition between emission centers
(edge states) and traps can conquer the optical properties of these
structures [70].
Furthermore, it has been claimed that quasi-molecular fluorescence
of GO arises by carboxylic acid groups coupled electronically by the
adjacent atoms of the graphene sheet which forms quasi-molecular
M.J. Molaei Talanta 196 (2019) 456–478

fluorophores similar to polycyclic aromatic compounds [71]. Strong

and spatially uniform PL across the flakes can be induced in single-layer
graphene sheet using an oxygen plasma treatment. The PL is connected
to elastic scattering spectra distinctly different from those of gapless
pristine graphene [63]. The mentioned quasi-molecular fluorescence
and graphene PL after plasma treatment are non-bandgap PL which are
attributed to the defect size in the graphene sheets. As discussed in the
previous section, being a single sheet is required for occurring PL in
bandgap related emissions of graphene in order to suppress substantial
interlayer quenching. However, being a single sheet is not required for
PL occurred via defect-derived origin ones [62].
Some defects on the graphene sheets and on the CQDs are similar.
Therefore, it expected that these two carbon structures have common
PL mechanism. The emission mechanism of CQD which is adopted in
recent years is a radiative recombination of electron-hole pairs that are
confined on the surface. The electron-hole pairs are generated by photo-
induced charge separations in CQDs. Passivation of the dot surface by
organic or inorganic compounds creates more stable surface sites for
the effective radiative recombination [62]. Surface passivation of CQDs
has a strong effect on PL performance. Passivation of CQD using oli-
gomeric poly(ethylene glycol) diamine (PEG1500N) molecules, results in
green fluorescence emissions with QY near to 20% which with further
processing with the aim of better surface passivation the QY reaches to
50% [2]. Passivation of CQD by a combination of doping with na-
noscale semiconductors and organic functionalization, coupled with gel
column fractionation to harvest the most fluorescent carbon dots,
showed a high QY of 78% (Fig. 2) [43].
Changing of surface chemistry in GQDs can alter or suppress the
emission from surface defects. The surface chemistry of GQDs can be
altered through reduction or modification and as a result, the green
luminescent emission of the GQDs would change to the blue. During the
reduction of GQDs, the epoxy, carbonyl, and amide groups change to
–OH groups. In fact, the chemical structure changes by reduction or
modification via replacing of -COOH and epoxy groups which induce
non-radiative recombination of localized electron-hole pairs. This sup-
presses non-radiative recombination and enhances the integrity of
surface π electron network. Therefore, in reduced GQDs the intrinsic
state emission dominates the defect state emission [72].
In another work on the effect of functional groups of CQDs on their
fluorescence, samples of CQDs with similar size distribution and gra-
phite structure and with different surface state and different degree of Fig. 2. Photographs of CQDs coated with ZnS (CZnS) and CQDs coated with TiO2
oxidation showed red-shift in emission from 440 to 625 nm. The red- (CTiO2) solutions compared with fluorescein in ethanol (fluorescence QY is
shift in these samples was attributed to the gradual reduction in about 80%) under sunlight (upper) and under the monochromated light, xenon
arc source, (lower). Reprinted with permission from [43]. Copyright 2011
bandgaps by increasing of oxygen species in the structure of the CQDs
Royal Society of Chemistry.
surfaces. Their work showed that the energy bands depend mainly on
the surface structure and functional groups, not on the CQDs size [73].
The PL tuning via amino functional groups is also has been reported
[10,74,75]. Dong et al. which synthesized CQDs in the range of the The PL in GQDs can also be tuned by changing the pH. The PL shift
4–10 nm and functionalized with branched-polyethylenimine (BPEI) as a result of changing in pH could be due to the protonation/depro-
found that the fluorescence emission of the synthesized CQDs is ex- tonation of functional groups. Experiments and calculations based on
citation wavelength independent. Since the surface state of the syn- density functional theory (DFT) confirm that electron-donating and
thesized CQDs was similar and the CQDs sizes were different, therefore, electron-withdrawing of the functional groups applied on the GQDs can
the fluorescence emission could be mainly due to the surface state CQDs tune the bandgap which this, in turn, causes a PL peak shift [75]. Yuan
[76]. et al. synthesized GQDs which have different colors of fluorescence in
The PL shift of GQDs can occur as a result of charge transfer be- different pH values from 1 to 14 [77]. The fluorescence of the CQDs
tween GQDs functional groups. For example, Jin et al. showed that the which their surfaces were capped with BPEI was dependent on the pH.
GQDs band gap and hence, PL can be tuned by changing electron The fluorescence activity of the BPEI-capped CQDs decreases by in-
density in GQDs which occurs via applying functional groups on them creasing pH more than 9.0. This pH dependence has been attributed to
[75]. the protonization of the amino groups on the capped CQDs surfaces.
Functionalizing of GQDs does not always give result in direct Below the pH of 9.0, the BPEI is charged positively and hence, the
bandgap changes, but can form energy levels within the bandgap. First- stability and fluorescent activity of the CQDs increases by decreasing
principles calculations on amino-functionalized GQDs showed that pH due to their electrostatic repulsion. The fluorescent activity again
amine edge termination (NH2) forms an interband within the bandgap decreases in the acidic media (pH < 4) that is probably because of the
of GQDs which is responsible for tunable PL emission. The additional high positive charges carried by the BPEI which might inhibit the ex-
interband within the bandgap is due to the hybridization of p orbital of citation process of CQDs [76].
C–N atoms at the edge sites [74].

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M.J. Molaei Talanta 196 (2019) 456–478

3. Applications of CQDs
Reference

[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
[91]
[92]
CQDs have been the subject of numerous researches in several fields
such as biomonitoring, sensors, photocatalysis, drug and gene delivery,
solar energy conversion and LEDs. However, still more researches are
CQDs as imaging probe, RGD peptide as active targeting ligand, and cisplatin(IV) as prodrug
needed in order to lead to their development in these applications.
Some of the CQDs applications will be discussed in the following sec-
tions. Table 1 summarizes examples of the CQDs applications in bioi-
Delivery of phototrigger conjugated anticancer drug, bonded to the surface of CQDs

maging, drug delivery, gene delivery, sensor, CL, and their synthesis
methods and achieved quantum yields.

3.1. Biomonitoring
Transfection experiments with plasmid TGF-β1/CQDs complexes

Real-time dynamic observation of bio-molecules in live cells can

elucidate many hazy phenomena in cell biologies such as molecules
translocation, interaction with partners, and response to environmental
Dihydronicotinamide adenine dinucleotide detection

cues [93]. Single particle tracking (SPT) is a technique which is enabled

Delivering plasmid DNA or small interfering RNA

to track single bio-molecules with high resolution [93,94]. By using

brighter probes, like semiconductor QDs in SPT, actual molecular dy-
namics can be monitored. Photo-physical properties of semiconductor
CL of luminol with CQDs as the catalyst

QDs depends on chemical composition, shape, size and surface mod-

Drug delivery of doxorubicin (DOX)
Incubation of HeLa and other cells

ifications. Semiconductor QDs advantages such as wide absorption

Gene expression of plasmid DNA

Screening of O-states in CQDs

spectra, narrow emission band and being orders of magnitude more

photo-stable than organic dyes have made them as superior candidates
Incubation of MCF-7 cells
Incubation of HeLa cells

in live cells biomonitoring for long tracking trajectories [93]. Apart

Details of application

Hg2+ ions detection

Cu2+ ions detection

from the conventional semiconductor QDs which suffer from toxicity

Detection of Fe3+

due to the presence of the elements such as Cd and Pb in their structure,

Examples of the CQDs applications, precursors for synthesis, synthesis method, optical properties and details of the applications.

other nanostructures such as CQDs capable of showing bright and col-

orful fluorescence emission have been recently introduced for biomo-
nitoring [50]. CQDs have potential bioimaging applications in several
fields which are described in the following sections.
Quantum yield

3.1.1. Cell imaging in vitro

The CQDs have some advantages such as physicochemical stability,
20–30%
5–60%

2–11%

non-blinking, biocompatibility and aqueous solubility that makes them

46.4%

25.5%
14.0%

12.7%

31.8%
46.2%
4.84%

42.5%
4.3%

54%

suitable for bioimaging. CQDs can be readily taken by cells and enable
–

cell imaging via both one and multiple photon excitations [50]. Sun
et al. synthesized CQDs with the possibility of using them for cell
Chemical carbonization
Chemical carbonization

Pyrolysis (microwave)

Pyrolysis (microwave)

Pyrolysis (microwave)

Microwave treatment

imaging and beyond. The CQDs synthesized with laser ablation of a

Chemical oxidation
Synthesis method

carbon target (baked and cured graphite powder and cement mixture)
Acid treatment
Hydrothermal

Hydrothermal

Hydrothermal

Hydrothermal
Hydrothermal

in the presence of water vapor by using a carrier gas. The non-emissive

CQDs showed PL after acid treatment and passivation by attaching
Pyrolysis

Pyrolysis

organic species such as PEG1500N to the surface of the dots (Fig. 3).
The PL was also observed using confocal microscopy after incubation of
E. coli ATCC 25922 cells with the treated CQDs [95].
Bhunia et al. [78] reported the application of chemically synthe-
Carbohydrate, octadecylamine, octadecene

sized CQDs for biological labeling and imaging. Fig. 4 shows the TAT
peptide- or folate-functionalized CQDs which were mixed with cell
Diammonium hydrogen citrate, urea

Sodium alginate, hydrogen peroxide

Microalgae powder, formaldehyde

culture medium, and after incubation for several hours were imaged
Citric acid, diethylenetriamine

with a fluorescence microscope. The CQDs had controlled emissions in

Glycerol, phosphate solution

colors such as blue, green, yellow and red. The QY for the synthesized
Alanine, ethylenediamine

CQDs was in the range of 6–30% [78].

The intensity of the CQD PL is dependent on the doped nitrogen
Activated carbon
Waste polyolefin
Citric acid, BPEI

Citric acid, BPEI

Citric acid, urea

Citric acid, urea

content. Nitrogen doping can be used for improving emission char-

acteristics. For example, nitrogen-doped CQDs with a core-shell struc-
Precursors

Chitosan

ture of a carbon core and the oxygen-containing shell were used for cell
Milk

imaging. After 2 h of incubation of the nitrogen-doped CQDs with HeLa

and HepG2 cells, the cells illuminated with multicolor emissions when
excited with 405, 488, and 543 nm laser pulses. It was observed that
Chemiluminescence (CL)

nitrogen-doped CQDs were concentrated in the cytoplasm and in-

filtrating into the cell nuclei was not remarkable [96]. In another re-
search, cell imaging using nitrogen-doped CQDs which were prepared
Gene delivery
Drug delivery

by Bombyx mori silk and via hydrothermal procedure was investigated

Application

Bioimaging

on human lung cancer (A549) cell lines through CKK-8 assay. It was
Table 1

Sensor

observed that the major part of the CQDs reaches into the cell nucleus
and illuminate the whole cell. The experiment showed that PL intensity

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M.J. Molaei Talanta 196 (2019) 456–478

Fig. 3. The aqueous solution containing CQDs which are surface passivated by PEG1500N; a) excited at 400 nm and photographed using different wavelengths band-
pass filters (indicated on image) and b) excited at the indicated wavelengths and photographed without a filter. Reprinted with permission from [95]. Copyright 2006
American Chemical Society.

does not reduce even after excitation for a long time. In fact, it has been
suggested that the synthesized CQDs are alternative candidates for or-
ganic dyes (which are easy to photo-bleach) and semiconductor QDs
(which have bio-toxicity concerns) [97]. Fluorescence microscopy of
MCF-7 cells which were incubated with nitrogen-doped CQDs (with QY
of 46.2%) for 24 h, resulted in colorful PL with no substantial change in
shape and viability of the cells [88]. Ray et al. synthesized CQDs with a
diameter of 2–6 nm and QY of about ∼3% through oxidation of carbon
soot with nitric acid. It is claimed that the CQDs have graphitic struc-
ture and nitric acid oxidation incorporates nitrogen and oxygen atoms
into the CQDs which results in water solubility. In order to study cell
labeling of CQDs, Ehrlich ascites carcinoma cells (EAC) collected from
the peritoneal cavity of adult female mice after 7 days of inoculation
and the suspension was mixed with CQDs solution incubating for

Fig. 4. CQDs used as fluorescent cell label. CQDs are incubated 3–6 h with HeLa cells. Images are prepared under bright field (BF) and fluorescence (FL) mode of a
confocal or Apotome microscope. Reprinted with permission from [78]. Licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported
License, http://creativecommons.org/licenses/by-nc-nd/3.0/.

461
M.J. Molaei
30 min. Imaging under UV blue excitation resulted in illuminated cells
with bright blue-green and imaging under blue excitation resulted in
illumination in yellow. Control samples with no CQDs were colorless
under UV excitation [37].
Surface passivation of CQDs makes them strongly photoluminescent
in solid state or in a solution. In this case, the spectral features of CQDs
would be similar to surface-oxidized silicon nanocrystals [95]. In fact,
the emission is due to the trapped surface energy on the CQDs surface.
As an example, surface passivated CQDs were used as wavelength-
tunable optical nanoprobe to target HeLa cell line cancer cells. Passi-
vation was done with polyethylene glycol (PEG) chains, poly-
ethylenimide-co-polyethylene glycol-co-polyethylenimide copolymer,
and 4-armed PEG molecules and the CQDs conjugated with transferrin.
It is assumed that surface passivation leads to more absorbing centers
on the CQDs [98]. PEG1500N-capped surface passivated CQDs with an
average diameter of 1.5–2.5 nm were applied as bioimaging agents for
labeling of E. coli cells. These cells were covered thoroughly with the
CQDs and the dots could emit PL using excitations from a broad range
of wavelengths. The CQDs internalized in murine P19 progenitor cells
as well. Photo-stability of the used CQDs was high and accompanied by
low photo-bleaching and no blinking [99].
In most of the reported cell imaging using CQDs, it has been ob-
served that CQDs are internalized by the cell through endocytosis,
while remarkable infiltration to the cell nucleus is not observed [33].
Zhang et al. synthesized CQDs via one-pot hydrothermal oxidation of
nanodiamond and used them for cell imaging. Cell internalized CQDs
excited by 405 and 458 nm wavelengths, emitted green and green-
yellow fluorescent emissions. The images confirmed that CQDs could
uptake by the cells and accumulate in them. In the confocal laser
scanning microscopy (CLSM) images, numerous dark areas were seen
that might be cell nucleus. In fact, CQDs could translocate into the cells
and locate at cytoplasm [100]. In another attempt for cell imaging, it
was seen that CQDs with an average diameter of 5 ± 2 nm, synthesized
from coffee grounds were localized in the cell membrane as well cy-
toplasm of LLC-PK1 cells [101]. Ehrlich ascites carcinoma cells (EAC)
were incubated with an aqueous solution of CQDs for 30 min. It was
seen that CQDs enter into the cells which as a label can be detected
using a fluorescence microscope [37]. CQDs exhibited a uniform dis-
tribution in the cytoplasm when MCF-7 cells were incubated with
3–4 nm hydrothermally synthesized CQDs for 24 h. Outstanding lumi-
nescence of the CQDs in the cells was observed with excitation at a
wavelength of 405 nm [102]. Cell membrane and cytoplasm and areas
surrounding cell nucleus had the most emission in an in vitro cell
imaging of CQDs incubated with HeLa cells [103]. The cellular uptake
assessments of the synthesized CQDs from the carbon source of sodium
alginate via hydrothermal carbonization method showed that both ca-
veolae- and clathrin-mediated endocytosis pathways are included in the
cellular uptake of CQDs/plasmid DNA (pDNA) complexes. The pDNA
finally enters the cell nucleus while the CQDs remains outside the cell
nucleus [104]. CQDs and Cy5-labeled DNA (DNA-Cy5) were incubated
with A549 cells and were observed at different time intervals. NR12S
was used for labeling cell membrane (Fig. 5). It was observed that the
blue color of CQDs fluorescence could be detected after 1 h incubating
and the fluorescence intensity increases with increasing incubation
time. The red fluorescence is almost restricted to the outside of the cells.
On the other hand, it can be concluded that CQDs/DNA-Cy5 complexes
disassembled in the cells and released DNA molecules have weak
fluorescence which cannot be detected [105].
The reported fluorescent carbon nanoparticles for using in cell
imaging is not confined to the CQDs. Larger hollow carbon nano-
particles can also show fluorescence properties and can be used for
bioimaging. Fang et al. [106] used cross-linked hollow fluorescent
carbon nanoparticles (HFCNs) without the modifier/surface passivation
agent as a bioimaging material. They reported that no remarkable de-
crease in the fluorescent intensity observed (> 95% normalized in-
tensity in 5000 s) that means the HFCNs have suitable photo-stability.
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Comparison of cellular imaging photo-stability of the HFCNs, CdTe QDs
and the organic dye (fluorescein isothiocyanate (FITC), Hoechst)) elu-
cidated that the cells containing HFCNs were detectable after 25 min,
while those labeled with CdTe QDs, FITC, and Hoechst almost were not
detectable with the same conditions. Extended laser exposure up to
100 min resulted in almost no change in the green fluorescent emission
of HFCNs [106].
One of the advantages of the CQDs for bioimaging is their photo-
stability and resistance to photobleaching. For example, The CQDs that
were synthesized from pyrolysis of the waste plastic residue were em-
ployed for fluorescence imaging of MDA-MB 468 cells. The CQDs had
high photostability. The CQDs showed low photobleaching and the
fluorescence intensity observed from the cells was stable for 1 h after
constant excitation [89].
The CQDs can also be used in multifunctional fluorescence imaging/
magnetic resonance imaging (MRI) drug delivery systems. For example,
Fe3O4@CQDs coated CNTs were used for photodynamic and photo-
thermal therapy (PTT) with the aid of 808 nm laser irradiation. The
synthesized platform was also loaded with doxorubicin (DOX) to be
used in drug delivery. The platform was conjugated with a sgc8c ap-
tamer. The resulted nanovehicle was used for targeted fluorescence
imaging/MRI. When the nanovehicle was incubated with lung cancer
cells and was irradiated with a laser, was able to kill most of the cancer
cells. This phenomenon was attributed to the generation of OH· and ·O2
and simultaneous DOX release and heat generation [107]. Dual-modal
fluorescence imaging and MRI has been also reported by using Gd(III)-
doped CQDs synthesized through hydrothermal method. Incorporation
of Gd into the solid matrices results in tumbling of the Gd complex.
Therefore, the r1 relaxivity will be augmented [108]. Other multi-
functional therapy and/or diagnosis systems based on the CQDs such as
CQDs doped with Gd, Mn and Eu for fluorescence imaging and MRI
[109], gold/Gd-doped CQDs for simultaneous MRI and photothermal
ablation (PTA) therapy [110], FeN@CQDs conjugated with folic acid
and riboflavin for simultaneous photodynamic therapy (PDT) and PTT
[111], gadolinium oxide–iron oxide core with mesoporous silica sell
gated with CQDs for drug delivery, fluorescence imaging, and MRI
[112] have also been used.
Food, fruit juices and natural precursors can be used for the
synthesis of CQDs. Using natural precursors may result in lower toxicity
for the synthesized CQDs which is beneficial for bioimaging and other
biomedical applications. As an example, Citrus sinensis and Citrus
limon peels were used to synthesize CQDs through carbonization route.
The CQDs were used for in vitro imaging. The cell viability for the cell
lines that were incubated for 48 h with 400 μg/mL of the synthesized
CQDs was above 90% [113]. The CQDs that were synthesized from
carbonized walnut shells as a natural precursor did not show toxicity on
MC3T3 cells in an MTT assay with an exposure time of 72 h and a
concentration of 100 μg/mL [114].
3.1.2. Cell imaging in vivo
The fluorescent nanomaterials have been used as contrast agents in
bioimaging in vivo. The main requirements for application of nano-
materials for in vivo bioimaging are high fluorescence intensity, bio-
compatibility and nontoxicity. The fluorescent nanomaterials should
also resist photobleaching for in vivo bioimaging. The application of
QDs instead of conventional organic dyes for in vivo bioimaging has
been proposed in the literature. CQDs can be used for in vivo cell
imaging due to the excellent fluorescence properties and null cyto-
toxicity [115].
Yang et al. first reported using of CQDs for optical imaging in vivo.
The results revealed that CQDs could act as a brightly fluorescent
contrast agent in live mice. CQDs and ZnS-doped CQDs which were
passivated by PEG diamine were used for in vivo imaging. The injected
CQDs diffused relatively slowly and the emission faded at ∼24 h post-
injection. ZnS-doped CQDs had brighter green fluorescence and were
used to track the migration through lymph vessels. QDs like CdSe/ZnS
M.J. Molaei
Fig. 5. Confocal laser scanning fluorescence microscopy from CQDs/DNA-Cy5 complexes incubated with A549 cells at different time intervals (1, 4, and 24 h); a)
Excitation wavelength = 488 nm (NR12S); b) Excitation wavelength = 405 nm (CQDs); c) Excitation wavelength = 635 nm (DNA-Cy5); d) merged images, (all scale
bars: 10 μm). Reprinted with permission from µm). [105]. Copyright 2015 Elsevier Ltd.
migrate to axillary lymph nodes in minutes. However, the CQDs mi-
gration was slow due to the small sizes (< 5 nm) and due to functio-
nalization with PEG chains which protein resistance characteristics
might reduce interactions of the CQDs with lymph cells [115]. In a
tissue imaging experiment, it was observed that the CQDs can be up-
taken by the stomach and reach to liver and kidney by blood circulation
and be used for imaging of liver and kidney [116].
The in vivo imaging is preferred to be done at longer wavelengths
due to the better photon tissue penetration. For example, the CQDs
have been synthesized by harsh oxidation of MWNTs and were injected
subcutaneously into a nude mouse at three different locations. By using
blue, green, yellow, orange, red, deep red, and NIR light excitations in
vivo imaging performed. The signal-to-background separation was
better for the images taken under longer-wavelength excitation
(595 nm and beyond). As it is evident in Fig. 6, at longer wavelengths
the fluorescence emission of CQDs is weaker. However, at longer wa-
velengths excitations (red and NIR) signal-to-noise increases due to the
decrease in the tissue auto-fluorescence background. In fact, due to the
photon tissue penetration as well as decreased background auto-fluor-
escence, in vivo imaging is preferred to be performed at longer wave-
lengths (NIR region) [117].
The pH in physiological conditions is an important parameter for
controlling and diagnosis of different diseases. If the pH deviates by
0.10–0.20 pH units from a normal pH of 7.40, can result in cardio-
pulmonary and neurological problems such as Alzheimer. Conventional
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down-conversion fluorescent materials that absorb a higher-energy
excitation photon and emit one lower-energy fluorescence photon (such
as semiconductor QDs and organic dyes) are not preferred for pH
evaluation in living cells since the application of high energy photons
can cause problems such as auto-fluorescence of biological samples and
in some cases introducing damages to the cells. CQDs can be used as pH
probes in the living cells. CQDs based two-photon fluorescent probe
with high photo-stability and low cytotoxicity were used for two-
photon imaging and biosensing of pH gradients in tissues and living
cells. Through this approach, real-time imaging and biosensing of pH
have been executed in living human lung cancer A549 cells, mouse LLC-
MK2 cells, and tumor tissues generated by implanting tumor cells
[118].
The CQDs can be used for nucleus imaging as well. The nucleolus is
the site for ribosomal RNA (rRNA) production and ribosome factory of
the cell. It was shown that the CQDs can be used for fixed cell nucleolus
imaging and also tracking of the nucleolus-related behaviors of the
living cells. The CQDs after cellular internalization have a rapid
movement toward the nucleus within 5 min of incubation while are
kept localized at nucleoli even after 24 h. This indicates that CQDs can
be used as dyes for nucleus fluorescence imaging. The mechanism of
nucleolus-targeting is selectively binding of the CQDs to RNA (instead
of DNA) after nucleus entrance. The conjugation of the CQDs with
protoporphyrin IX (PpIX) photosensitizer and application for in vivo
experiments showed effective tumor accumulation and retention which
M.J. Molaei Talanta 196 (2019) 456–478

Fig. 6. a) In vivo fluorescence images of a CQDs injected mouse; the excitation wavelengths are 455–704 nm indicated on the image. Fluorescent signals of CQDs and
the tissue auto-fluorescence are red and green, respectively; b) Signal-to-background separation of the image (excitation wavelength: 704 nm) which confirms that
the signal (fluorescence from CQDs) is well distinguished from the background (tissue auto-fluorescence). Reprinted with permission from [117]. Copyright 2012
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

might be due to the extended blood circulation due to the negative
charge, small size, augmented cellular uptake and good targeting for
nucleus [119].
3.2. Drug delivery systems
Recent advances in nanomedicine have resulted in drug delivery
systems that are capable of targeting and delivery of the drug to the
specific parts of the body. The drug delivery systems are sometimes
conjugated with fluorescent nanomaterials for imaging. The QDs with
small sizes, various surface chemistry, and at the same time fluores-
cence properties have been used in therapeutic applications as an ef-
fective drug delivery vehicle. The nanovehicle localization can be done
in vitro or in vivo using methods such as high-performance liquid
chromatography (HPLC) and by the aid of fluorescence emission
properties of some of the drugs which are time-consuming methods
[120]. QDs have been used for developing numerous drug delivery
systems in recent years [121–126]. The CQDs which are mainly com-
posed of C, N, O and H atoms are excellent candidates for drug delivery
systems as well. The CQDs with small sizes less than 10 nm have at-
tracted attention for drug delivery systems due to their superior prop-
erties such as fluorescence emission, facile preparation, easy functio-
nalization, biocompatibility, aqueous solubility, no toxicity, and
chemical inertness [127].
The DOX is one of the most used model anticancer drugs in drug
delivery systems. The DOX has also been loaded on CQDs for drug
delivery. The possible mechanism for DOX loading on the CQDs is
functional groups that make bonding between the CQDs and DOX. On
the other hand, the electrostatic interaction between positively-charged
DOX and negatively-charged CQDs as well as hydrophilicity of the
CQDs which promotes hydrogen bonding between DOX and CQDs are
the main proposed mechanisms for observed enhanced drug loading on
the CQDs [83]. Different steps of the drug delivery of CQDs-DOX in-
clude a) CQDs-DOX entry into the cells (through endocytosis) and
forming vesicles, b) transporting CQDs-DOX vesicles into the lysosomes
and c) release of the protonated DOX (in lysosomes acidic environment)
and entry into the cell nuclei [128]. By the aid of electrostatic inter-
actions, DOX was loaded on CQDs that were anchored onto the heparin
(an auxiliary medicine) to make a CQDs-heparin-DOX pH sensitive
nanovehicle for drug delivery [129]. Mitomycin drug can also be
loaded on CQDs via hydrogen bonding and then could be released
through the breaking of this bond in the acidic environment of the
tumor [130].
Monitoring of the CQDs fluorescence in the delivery systems and
checking the location of emission (regarding the cell nucleus) can de-
termine living and apoptotic cancer cells. CQDs were incorporated into

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hydrogels (with/without 5-Fluorouracil, an anticancer drug) to be up-
take by A549 cells. Fluorescence microscopy observations revealed
green emission from CQDs and blue emission from cell staining dye
Hoechst 33342 using an excitation wavelength of 360 nm. The green
emission from CQDs was concentration dependent and increased with
increasing CQDs concentration in the gel. Living cells could be char-
acterized by nucleus which is deprived of fluorescence. However, it was
observed that cell size reduction shifts the location of the fluorescence
from cytoplasm to nucleus [131].
The application of CQDs in drug delivery systems could result in a
more localized drug-loaded CQDs in tumor cells compared to the using
drug alone. CQDs that were synthesized hydrothermally from milk were
used for DOX delivery to cancer cells. It was observed that DOX-loaded
CQDs were more toxic to the adenoid cystic carcinoma cell line (ACC-2)
compared to the mouse fibroblast cell line (L929). The fluorescence
imaging showed that compared to the DOX alone, the drug delivery
system of DOX-loaded CQDs was more localized in the tumor cells
nuclei with a faster rate of apoptosis in the ACC-2 cells [83]. In another
in vivo test, cancer cell growth inhibition of DOX conjugated CQDs
showed a better progress compared to the free DOX injection. In order
to verify the DOX conjugated CQDs activity in the body, these delivery
systems were incubated with HepG2 and MCF-7 cells to investigate
their pharmaceutical and imaging characteristics. The MTT cell pro-
liferation assay revealed that the cytotoxicity of DOX conjugated CQDs
in cancer cells (HepG2 and MCF-7) is more than their cytotoxicity in
normal cells (CHO-K1 and COS-7). The DOX conjugated CQDs were
Fig. 7. Fluorescence images that were taken by confocal microscopy of HepG2 cells incubated for 24 h with a) bare CQDs (G-tag) and b) DOX conjugated CQDs (T-
tag) via excitation with a wavelength of 380 nm, and schematic showing location for c) bare CQDs and d) DOX conjugated CQDs in nucleus and cytosol of cancer
cells, respectively. Reprinted with permission from [132]. Licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. http://
creativecommons.org/licenses/by-nc-sa/3.0/.
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excited with a wavelength of 380 nm via a two-photon laser scanning
confocal microscope (Fig. 7). Almost no background fluorescence was
seen for HepG2 cells. By 24 h incubation with HepG2 cells, the fluor-
escence of DOX conjugated CQDs was detected in the cytoplasm, while
the free CQDs translocated into the nuclei. This has been attributed to
the smaller size of the free CQDs compared to those which are DOX
conjugated. The bare CQDs had superior photo-stability even after
240 h (aqueous conditions) as well as low cytotoxicity (2 mg mL−1)
[132].
Deng et al. developed a multifunctional Nitric oxide (NO)-delivery
platform with target directing, light-controlled NO delivery and fluor-
escence tracking. In this platform, ruthenium nitrosyl and folic acid
molecules were bonded covalently on CQDs. The platform can re-
cognize certain cancer cells via FA–folate receptor binding and the
fluorescence emission of CQDs makes this platform trackable in the
cellular environment [133].
In another research, the nanogel network as a functionalizable non-
fouling matrix was used for drug loading and CQDs were responsible for
the fluorescence signals in real-time imaging. The labeled dextran,
encapsulated in nanogels could release in a controlled manner. The
studies on this vehicle demonstrated that the folic acid-conjugated
nanogel via the folate receptor could be internalized into the cancer
cells, missing normal tissue cells. This makes the vehicle as a superior
targeted delivery system with the ability to be monitored via the CQDs
emission [134].
Hollow CQDs have been also used for drug delivery systems that
M.J. Molaei
take advantage of rapid uptake by the cells. The hollow CQDs does not
affect drug activity and can be used for the pH-controlled release of the
drug. In an attempt, hollow CQDs with a diameter of 6.8 nm and QY of
7% that were synthesized via solvothermal reaction of bovine serum
albumin, were used as a delivery system for DOX. The DOX loads and
get physisorbed on hollow CQDs through interactions such as van der
Waals, π-π stacking and hydrophobic. DOX was loaded up to 6 wt% on
the hollow CQDs. The CQDs-DOX solution did not aggregate, was stable
for several weeks, and was able to emit red fluorescence under UV. In
vitro experiments determined that about 4% and 70% of DOX releases
at pH 7.4 and pH 5.0, respectively. The conditions of pH 7.4 and pH 5.0
is a simulation of the extracellular environment and intracellular ly-
sosomes, respectively. Incubation for 24 h resulted in CQDs-DOX sys-
tems to reach to the cell cytoplasm and to surround the nuclei. On the
other hand, CQDs-DOX were able to be internalized by A549 cells and
localize in the cytoplasm. The fluorescence of DOX showed that the
drug could reach to the cell nuclei [128].
CQDs can be used in polymer-based nanovehicles. The polymer
dendrimers with three-dimensional architecture and numerous func-
tional groups on the outer side of the dendrimer can be used as a sui-
table platform for drug delivery to them CQDs as fluorescence agents
can be attached. CQDs with anionic terminus noncovalently combined
via self-assembly to cationic acetylated G5 Poly(amidoamine) den-
drimers and encapsulating chemo-drug epirubicin (EPI) inside the
dendrimer branches were used as a therapeutic vehicle for cancer
treatment. CQDs fluorescence improves in the vicinity of amine groups
of the dendrimers and is used for tracking the distribution and cytotoxic
effects of the drug. Apoptosis-inducing ability of the mentioned com-
plex in breast cancer (MCF-7) cells was confirmed [135].
CQDs have been used for delivery of neurological diseases drugs as
well. Dopamine hydrochloride (DA), the inotropic vasopressor agent in
neurological diseases was conjugated with CQDs for controlled release
in vitro. The DA/CQDs was biocompatible against Neuro 2 A cells. The
conjugate can easily penetrate into the blood capillaries because of its
small size. The increased penetration of the conjugate results in the
enhanced permeability of the drug. The conjugate does not show toxic
effects on the weight of mice during the observations for 45 days [136].
3.3. Gene delivery
Gene delivery i.e. introducing of foreign DNA into the cells has been
developed using fluorescent nanomaterials. Gene delivery vehicles
might be viral or non-viral vectors. Viral vectors have enhanced
transfection efficiency, however, high likelihood of mutagenesis or
carcinogenesis results in some limitations for their applications. The
non-viral vectors (e.g. cationic polymers, cationic liposomes, and in-
organic nanoparticles) have the benefit of being safer, accompanied by
high transfection efficiency. Multifunctional vectors with low toxicity,
enhanced transfection efficiency, and simultaneous imaging can result
in a more trusted gene delivery treatment while non-viral vectors miss
possessing the ability of self-tracking [137].
CQDs are promising candidates for multifunctional vectors with the
ability of fluorescence imaging in gene delivery. The transfection stu-
dies of the CQDs/pDNA complexes illustrated that the transfection ef-
ficiency analogous to the Lipofectamine2000 (positive control) effi-
ciency and much better than other positive controls (like semiconductor
QDs) could be achieved. Due to lower toxicity, the CQDs were also
preferred for gene delivery over cationic transfection reagent, PEI,
25 kDa. Condensation effects on pDNA suppress pDNA enzymolysis
during transport which increases the transfection efficiency of the
synthesized CQDs [104]. Cationic CQDs were synthesized from citric
acid and PEI via microwave pyrolysis and were used for delivering
plasmid DNA or small interfering RNA (siRNA) to different cell lines.
The transfection efficiency and cytotoxicity for the CQDs were analo-
gues to those of the PEI, the raw material which the CQDs were syn-
thesized from. The CQDs were efficient for siRNA delivery to the cells. A
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55% specific gene silencing for CQDs/siRNA weight ratio of 12 and
85% gene knockdown for weight ratios of 50–100 was achieved [105].
The cationic CQDs/gene plasmid SOX9 (pSOX9) nanoparticles showed
better transfection efficiency than the PEI-CQDs/pDNA complexes
while the PEI as a polymer gene carrier attaches to the cells easily and
possess high transfection efficiency. The pDNA attachment to the cell
membrane could be improved by the aid of the CQDs with fine particle
size and no cytotoxicity [137].
RNA interference (RNAi) technology by siRNA or double-stranded
RNA (dsRNA) triggered post-transcriptional gene silencing is an en-
vironment-friendly approach for insects control. Das et al. compared
CQDs, chitosan and silica nanoparticles in conjugate with dsRNA in
order to target mosquito genes (SNF7 and SRC) with the aim of con-
trolling Aedes aegypti larvae. The investigations shed light that com-
pared to chitosan and silica nanoparticles, CQDs were a more efficient
carrier for dsRNA retention, delivery and hence, gene silencing and
mortality in Ae. aegypti [138].
CQDs as the fluorescent nanoparticle in conjugate with quencher
nanoparticles can be used for monitoring the complexation and dis-
sociation of polyplex in the cytoplasm. Kim et al. used CQDs for mon-
itoring of association/dissociation of polymeric carrier/pDNA complex
during transfection. The delivery complex was synthesized as follow:
CQDs and gold nanoparticles were modified with a cationic polymer,
PEI and then were treated with pDNA. The fluorescence of CQD-PEI
quenches through dynamic quenching of Au-PEI. Finally, the fluores-
cence quenches statically when CQD-PEI and Au-PEI completely form
complexes with pDNA. It can be assumed that pDNA as a glue keeps the
CQD-PEI and Au-PEI in an intimate contact. Dissociation of the complex
might restore fluorescence emission of CQD-PEI. For fluorescence re-
covery, the charge interaction should be decreased. Using a high con-
centration of salt (NaCl) for destabilizing the charge interaction leads to
the dissociation of the complex. This, in turn, results in fluorescence
recovery which has been attributed to the increase of the distance be-
tween CQD-PEI and Au-PEI on the complex [139].
The PEI molecule can passivate the surface of the CQDs and at the
same time could play as a polyelectrolyte to condense DNA. CQD-PEI
exhibited bright multicolor fluorescence and showed superior photo-
stability. CQD-PEI mediated gene transfection in COS-7 and HepG2
cells with high efficiency [86]. In order to visualize gene expression, Hu
et al. [102] used branched PEI-based CQDs (PCD) with QY of 54.3% for
gene delivery. The DNA/PCD complexes with different DNA/PCD
weight ratios prepared through mixing. As the DNA/PCD weight ratio
decreased, the fluorescence intensity increased. It was concluded that
the PCD fluorescence can be used as a proper labeling agent for gene
delivery. However, some of the PCDs fluorescence does not super-
impose with the reporter gene of EGFP (enhanced green fluorescent
protein) fluorescence. This phenomenon occurs since broken PEI chains
on the CQDs miss the capability of acting as a gene carrier [102].
3.4. Optical sensors for metal ions
The CQDs can be used in sensors and biosensors due to their PL
characteristics, low cytotoxicity, cell internalization (useful for bio-
sensors), chemically inertness, fast and easy synthesis and functionali-
zation. The fluorescence emission quenches in the presence of metal
ions (e.g. Hg2+) because of the charge transfer process. Fig. 8 is the
schematic illustration of the heavy metal ions detection mechanism in
which the CQD fluorescence quenches in the presence of the Hg2+ ions.
The CQDs show fluorescence in an aqueous solution. If certain ions are
added to the solution, then the fluorescence might be quenched because
of the charge transfer. The fluorescence in the CQDs is due to the ra-
diative recombination of excitons (similar to other semiconductor QDs).
The metal ions (such as Hg2+) can cause non-radiative electron-hole
pair recombination annihilation because of effective electron transfer
process [140]. The fluorescence emission of the CQD is affected by its
surface state; i.e. the change in the environment and surface state would
M.J. Molaei
Fig. 8. Schematic illustration of the heavy metal ions detection mechanism via CQD fluorescence quenching in a) absence and b) presence of Hg2+ ions. Reprinted
with permission from [140]. Copyright 2013 Elsevier Ltd.
result in the change in the fluorescence emission [141].
Heavy metals, which are metallic elements with much higher den-
sity compared to water, have arisen globally ecological concerns on
environment pollution due to increasing application of these elements
in different industries and agricultural field. The environmental pollu-
tion in the vicinity of mines, foundry factories, smelters and etc. is the
main concern of these production plants [142]. The QDs fluorescence
has been used for detection of heavy metal ions, extensively. However,
the conventional semiconductor QDs are expensive to be synthesized
and are toxic to the environment in some cases which suppress their
usage in a detector system. The CQDs can be used instead of conven-
tional semiconductor QDs since with superior PL properties are water
soluble and can be synthesized easily and inexpensively while are not
toxic. For example, Yu et al. [143] synthesized CQDs from a plant
(Jinhua bergamot) as a carbon source. The CQDs were water-soluble
with a QY of 50.78%. The PL of the hydrothermally synthesized CQDs
quenched by using Tris–HCl buffer solution for Fe3+ and HAC–NaAC
solution for Hg2+. Using the CQDs, the detection limits of 0.075 μmol
L−1 for Fe3+ and 5.5 nmol L−1 for Hg2+ were achieved.
The detection limit of heavy metals measurements in aqueous so-
lutions can be decreased to less than μmol L−1 and nmol L−1 ranges, by
application of CQDs fluorescence in the detection systems. The best-
reported detection limit for the CQDs synthesized through reflux
method of poly(ethylene glycol) (PEG), applied for detection of Hg2+
ions in the samples from the lake, river, and tap water was 1 fmol L−1
[140]. The detection limit among 15 different metal ions including
Hg2+ was 2 μM. Between the investigated ions, only the detection of
Fe3+ had interference with Hg2+. The low toxicity of the synthesized
CQDs showed that they can be used for probing of Hg2+ in the living
cells as well [144]. The detection limit for Hg2+ using the CQDs sensor
synthesized through the hydrothermal method of apple juice was 2.3
nmol L−1[145]. Amino-functionalized CQDs synthesized from anhy-
drous citric acid (carbon source), sodium borohydride (reducing agent)
and ammonia (surface passivation agent) could be quantitatively
quenched in the presence of Hg2+ in an aqueous environment. The
detection limit of this sensor reaches to 20 nmol L−1 [146].
The sensor systems of CQDs and heavy elements ions can be en-
gineered to be used with an on-off molecular switch. In these types of
sensors, one ion quenches the fluorescence of the CQDs, while the other
recovers it. As an example, the on-off sensor for detection of Hg2+ and
I− has been developed. The fluorescence of CQDs quenches if Hg2+
exists in the environment and addition of I− to the CQDs/Hg2+ dis-
persion, results in fluorescence recovery. The detection limit for Hg2+ is
0.201 μmol L−1 and that of I− is 0.234 μmol L−1 [147]. CQDs/Hg2+
system sensor has also been applied for cysteine, glutathione, and his-
tidine which works based on the fluorescence recovery of CQDs/Hg2+
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suspension [148].
The cysteine has been used in conjugate with Hg2+ for on-off sen-
sors in some of the research experiments. For example, the magnesium
and nitrogen co-doped CQDs were used for the detection of Hg2+ and
cysteine. The Hg2+ ion quenches the CQDs fluorescence and cysteine
recovers it. The recovery is because of the stronger affinity of Hg2+ to
cysteine than to CQDs. This system can be used for detection of both
Hg2+ and cysteine [149]. In another attempt, an on-off CQDs sensor
was developed for detection of Hg2+ ions with a detection limit of
0.017 μM. L-cysteine used to recover the fluorescence of CQDs after
quenching by Hg2+ ions [150]. Nitrogen-doped CQDs with a QY of
35.4% which are quenched in the presence of Hg2+, completely recover
with the addition of L-cysteine to the solution. The detection limit for
this on-off sensor can be in the order of 1.48 nmol L−1 with a linear
range of 0–10 μmol L−1. The complex can also be used as an on-off
sensor of L-cysteine with a detection limit of 0.79 nmol L−1 and a wide
linear range of 0–50 μmol L−1 [151].
Detection of other elements such as Cu2+, Pb2+, Pt4+, As3+, and
etc. is also possible with the aid of CQDs fluorescence. Wang et al. used
CQDs for detection of Cu2+ which the quenching effect could be re-
covered with the addition of ethylene diamine tetraacetic acid. The
CQDs probes can reach a detection limit of 0.0295 μmol L−1 and a
response time of 3 s for Cu2+ ions. The probe works in the range of
0.25–10 μmol L−1 [152]. The detection limit for detecting Cu2+ ions by
CQDs synthesized from prawn shells is 5 nmol L−1 [153]. By using
CQDs which were synthesized from chocolate by a hydrothermal
method, a sensor for detection of lead ion (Pb2+) in the water was
developed. The quenching in this sensor is due to special chelation
between the lead ion and the hydroxyl group of the CQD surface. The
detection limit of the CQD sensor for lead ion reaches 12.7 nmol L−1
[154]. CQDs which are functionalized with poly(amidoamine)
(PAMAM-NH2) dendrimer were used as a chemosensor for detection of
Pt (IV) ion in water. The detection limit for Pt (IV) ion sensor was 657
nmol L−1 and had a sensitivity of 78 nmol L−1 in the range of 6–96
μmol L−1 of the dissolved platinum ions [155]. A Cu2+ ion detection
sensor which applied BPEI functionalized CQDs had a detection limit of
6 nmol L−1 and a dynamic range of 10–1100 nmol L−1. By capturing
the Cu2+ via amino groups of the BPEI, the CQDs fluorescence quen-
ches [156]. CQDs have been used for a colorimetric dual mode sensor of
As3+ and glutathione with the naked eye. The detection limit for As3+
reaches the low value of 32 pmol L−1. The synthesized CQDs can detect
glutathione among other biothiols like homo-cysteine and cysteine. The
detection limit can reach to 43 nmol L−1, even in blood plasma [157].
CQDs based sensors can recognize a certain ion in a solution con-
taining several ions. CQDs optical sensor could recognize Fe3+ among
other ions such as Na+, Ni2+, Co2+, Ag+, Mn2+, Cd2+, Pb2+, Hg2+,
M.J. Molaei
K+, Zn2+, Al3+, Cu2+, and Fe2+ with a linear relationship of emission
intensity versus the concentration in the range of 0–20 μmol L−1 [158].
As another example of detection of a certain ion among several ions,
CQDs synthesized via laser ablation of carbon targets immersed in
water and functionalized with NH2–polyethylene-glycol (PEG200) and
N-acetyl-L-cysteine, experience fluorescence quenching upon presence
of Hg2+ or Cu2+ in the environment; while no fluorescence quenching
observes in the presence of Cd2+, Ni2+, Zn2+ and Ca2+ ions. For Hg2+,
25% decrease and for Cu2+, 13% decrease in fluorescence emission
observes via the addition of 2.69 × 10−6 mol L−1 metal ions [159]. In
another research for detecting several metal ions, it was revealed that
most of the added metal ions of Cu(II), Cr(II), Co(II), Ni(II), Al(III), Ca
(II), Pb(II), Zn(II), Sn(II) and Hg(II) have quenching effect on CQDs
based sensor. While Zn(II), Hg (II) and Ca(II) ions showed the lowest
quenching effect, that of Cu(II) and Pb(II) ions were significant [160].
The optical sensors which work with the aid of CQDs can be de-
signed by application of optical fiber to make their usage easy. It is
important to immobilize the CQDs in a permeable matrix to be able to
interact with the surrounding environment, while must prevent
leaching. CQDs immobilized in a sol-gel matrix at an optical fiber tip
and functionalized with PEG200 and N-acetyl-L-cysteine can reach a
detection limit of submicron molar concentrations for Hg2+ in aqueous
solutions [161].
Other researchers have used CQDs for detection of Hg2+ [162–178],
3+
Fe [172,178–196], Fe3+ ions in human blood, urine and water
samples [113], Fe2+ [197], Ag+ [198–201], Au3+ [202,203], Al3+
[204], Cr6+ [205–208], Cr3+ [172], Co2+ [209], Cr2O72− [210], Pb2+
[172,178,211,212], Zn2+ [211], Cd2+ [213], Mo6+ [214], Pt2+ [203]
Eu3+ [172], Cu2+ [172,175,215–220], Cu2+ in rat brain [221], sele-
nite (SeO32–) [222], and Li+ in water samples [223].
3.5. Optical sensors for other molecules
Fluorescence is one of the most used methods in biosensing of
biomolecules. Organic dye and protein-based fluorophores which are
used for this purpose have disadvantages such as narrow absorption
window, photobleaching, self-quenching at high concentrations and
short excited state lifetime. Therefore, various fluorophores have been
synthesized to overcome these drawbacks. Colloidal luminescent
semiconductor QDs have been considered as alternatives to the organic
and protein-based fluorophores [224]. However, the semiconductor
QDs have some drawbacks such as complexity of production procedure
and application prohibition due to toxicity concerns [225]. CQDs with
appropriate resistance to photobleaching and null toxicity might be
preferred to organic dye and protein-based fluorophores and semi-
conductor QDs.
Fluorescence resonance energy transfer (FRET) is a phenomenon
occurs between two chromophores which one is a donor and another
one is an acceptor. For occurring FRET, donor emission and acceptor
absorption spectrums should overlap. The donor chromophore could
transfer energy to the acceptor one, through a non-radiative interaction.
This phenomenon is extremely distance-dependent and is used for
probing complex intermolecular interactions. CQDs can play the role of
a chromophore in this mechanism and can be used for sensors with
superior detection limit. Kundu et al. used CQDs for detection of ribo-
flavin (RF, known as vitamin B2) in aqueous solutions. The absorption
spectrum of RF and emission spectrum of the used CQDs have an
overlap which indicates the possibility of a FRET interaction that can
occur from the CQDs (as the donor) to the RF (as the acceptor). By
increasing the RF concentration, the fluorescence emission intensity of
CQDs decreases with a blue shift, and that of RF increases. The hydroxyl
and carboxyl groups found on the surface of the functionalized CQDs
strongly attract > C=O and –NH groups of the RF, resulting in hy-
drogen bonds formation which leads to fluorescence quenching. The
detection limit for vitamin B2 by the CQDs sensor is 1.2 nmol L−1
[226]. CQDs were used for a sensor of 2,4,6-trinitrotoluene (TNT)
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explosives residues in water that works based on the FRET mechanism.
The fluorescence of the CQDs can be selectively quenched in the pre-
sence of TNT via FRET mechanism. The detection limit is as low as
0.213 μmol L−1 [227].
FRET mechanism was also applied for detecting glutathione by
CQDs. Glutathione has a strong effect on cellular functions and ab-
normal levels of this protein molecule cause different clinical diseases.
Therefore, detection of glutathione with an excellent detection limit is
critically important. For detecting glutathione, a nanocomposite of
MnO2 nanosheets/CQDs was synthesized through an in-situ method by
Cai et al. [228]. The CQDs in the as-synthesized nanocomposite are
quenched because of the FRET. If the glutathione is present in the en-
vironment, MnO2 nanosheets will be reduced to Mn2+ ions which re-
sults in releasing of CQDs and sufficient recovery of its fluorescence.
The detection limit for glutathione through this approach would be
down to 300 nmol L−1 and this sensor has a sensitive response in
analyzing human serum samples [228]. Another sensor for glutathione
has also established based on the degree of the surface passivation of
the CQDs [229].
Gold nanoparticles can be used as a quencher for the sensors that
use CQDs and performs based on the FRET mechanism. The gold na-
noparticles have a larger extinction coefficient and broader absorption
spectrum that has an overlap with the emission spectrum of the CQDs.
In an experiment, it was observed that the fluorescence quenching of
the CQDs via gold nanoparticles, based on the FRET mechanism, can be
recovered by the aid of thiocholine (produced from acetylthiocholine
via hydrolysis of butyrylcholinesterase (BChE)) that cause the
gold nanoparticles to aggregate due to the Au–SH interaction.
Organophosphorus pesticides can inhibit the catalytic activity of BChE
and therefore, the recovery process will be diminished. The variations
in the fluorescence intensity can be used as a measure for organopho-
sphorus pesticides determination [230]. Gold nanoparticles have also
been used as fluorescence quencher and colorimetric reporter of a
mixture of CQDs and gold nanoparticles that have been used as a
sensor. Protamine can induce gold nanoparticles to aggregate and
therefore, the fluorescence emission of the CQDs no longer coincides
with the absorption spectrum of the aggregated gold nanoparticles and
would not be quenched. Aggregation of gold nanoparticles results in a
color change from red to blue that can be used as a colorimetric re-
porter. The FRET mechanism has been used for a protamine sensor with
a detection limit of 1.2 ng mL−1 [231]. The FRET, based on the amino-
functionalized CQDs and gold nanoparticles was also applied for de-
tecting of melamine in milk samples. If melamine is added to the gold
nanoparticles solution and then the CQDs are introduced into the so-
lution, the amino groups of the melamine molecules bind covalently to
the gold nanoparticles and hence, this prevents the CQDs interactions
with the gold nanoparticles On the other hand, by addition of melamine
to the gold nanoparticles solution, fewer CQDs have the possibility of
absorption onto the gold nanoparticles surfaces. Therefore, the FRET
effect hinders and fluorescence intensity increases. The FRET-based
mechanism of the melamine detection is shown in Fig. 9 [225].
The quenching mechanism of hydrogen bonding seen in the work of
Kundu et al. [226] was observed in the detection of carboxylated
multiwalled carbon nanotubes (c-MWCNTs) in water by a CQDs sensor.
The detection limit for sensing c-MWCNTs was 0.37 mL−1. By the ad-
dition of other carbogenic nanoparticles in the water, it was concluded
that the interaction of the CQDs sensor with other carbogenic species is
almost absent, especially, nonoxidized nanoparticles. This, in turn,
suggested that CQDs may interact with c-MWCNTs by hydrogen bonds
and not the π-electronic surface [232].
CQDs can be used for monitoring certain drugs in the body. For
example, 6-Mercaptopurine (6-MP) as an anti-cancer drug can be
monitored in the human serum by application of CQDs based sensor.
Carboxyfluorescein-DNA macro-molecules through π–π stacking were
conjugated on the CQDs. The resulted complex could be used as a
sensor for 6-mercaptopurine. An enhanced emission can be detected
M.J. Molaei
Fig. 9. The FRET-based mechanism for melamine detection; a) The CQDs fluorescence quenches in the presence of gold nanoparticles, b) the CQDs fluorescence
enhances if melamine is incubated with gold nanoparticles before addition of CQDs. Reprinted with permission from [225]. Copyright 2014 Elsevier B.V.
from carboxyfluorescein. Moreover, the interaction between Hg2+ and
DNA forms T-Hg2+-T (T: thymine base) complex which destroys the
conjugate system of CQDs, DNA and 6-mercaptopurine and results in
fluorescence quenching. The detection limit for Hg2+ in this sensor
reaches to 1.26 nmol L−1 through this mechanism [233].
The inner filter effect (IFE) which occurs by overlapping of the
absorption spectrum of the quencher with fluorescence excitation/
emission spectra of the donor and is accompanied by a decrease in the
fluorescence intensity [234] has been used in some CQDs-based sensors.
For example, the IFE between CQDs and hematin (in human red cells)
that occurs due to the fluorescence quenching as a result of absorption
of the excitation and emission spectrum of the CQDs by hematin has
been used for developing a hematin sensor. The CQDs quenching is
influenced by the hematin concentration and hence, this linear de-
pendence has resulted in developing a sensor with superior detection
limit of 0.25 μmol L−1 [235]. CQDs have also been used in a nanosensor
which works based on the IFE for imaging of the apoptosis. Fluores-
cence imaging by the aid of CQDs has been used for detection of cy-
tochrome c (Cyt c) which acts as a biomarker in the early stage of
apoptosis. The nanosensor has been utilized for in situ visualization of
Cyt c release in the living zebrafish. Fluorescence quenching due to the
IFE was suggested as the main quenching mechanism of the CQDs
fluorescence by the Cyt c [236]. The IFE has also been the mechanism
for the CQDs-based fluorescence sensor for detection of methotrexate
[237].
The CQDs could act as oxidizing or reducing agents in the sensors
since they are great electron donors and electron acceptors. The func-
tional groups on the CQDs surface such as carboxy and hydroxy groups
have a key role in the CQDs ability for reduction which can make them
as nucleation centers for metallic nanoparticles growth. In a sensor for
detection of arginine based on CQDs, when arginine is mixed with
HAuCl4 solution, the formation of Au/CQDs composite is restricted
before addition of CQDs. The CQDs act as reducing agents and stabilizer
to result in Au/CQDs composite via carboxy and hydroxy groups on the
surface of CQDs. The designed sensor has a detection limit of 450 nmol
L−1 through fluorescence spectroscopy [238].
CQDs have also been applied for detection of iodide (I–)
[169,174,239], K+ [240], F– [241], phytic acid [242], ascorbic acid
[195,207,243–245], ascorbic acid in rat brain [246], uric acid [247],
boric acid and hydroxylamine hydrochloride [248], hyaluronic acid
and hyaluronidase [249], picric acid [250], HClO [251], biothiols
[200,252–254], proteins in phosphate buffered saline [255], adenosine
triphosphate [188], β-galactosidase [256], α-glucosidase [257,258],
2,4,6-trinitrophenol [259], trinitrotoluene (TNT) in water [260], pyr-
ophosphate anions and alkaline phosphatase [261], polypeptides and
Deoxyribonuclease I [262], hydrogen peroxide [263–265], double
strand DNA detection [266], miRNA detection [267], proteins [268],
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tuberculosis [269], folic acid in human serum [270], neurotoxin qui-
nolinic acid in human serum [271], cholesterol [272], pollutants such
as 2,4-dinitrophenol and 2-amino-3,4,8-trimethyl-3H-imidazo[4,5-f]
quinoxaline [273], nitrobenzene [265], sinapine [274], promethazine
hydrochloride [275], hematin in human red cells [235], selenite in
water [276], amoxicillin (the drug) [277], tiopronin [177], flumioxazin
[278], phenolic carbofuran [279], dopamine [179,247,280], DNA
[281], hypochlorite (ClO−) [282], histidine [283], cysteine [199,284],
L-cysteine [187], hydrazine [192], arsenite [285], tetracycline
[265,286,287], prilocaine [288], aflatoxin B1 [289], vitamin B12 [290],
NO2– in water [291,292], nitric oxide (NO) [293], phosphate anions
[294], alkaline phosphatase [295], and organophosphorus pesticides
[296].
3.6. Chemiluminescence
Chemiluminescence (CL) is the light emission due to relaxation of
electronically excited intermediate or product state to the ground state
in which the excited state is caused by a chemical reaction between
reagents. The CL has application in analytical chemistry because of high
sensitivity and simple instrumentation. Luminol as well as potassium
permanganate, lucigenin and peroxalate are frequently used and stu-
died CL reagents in analytical chemistry due to their acceptable CL
intensity. However, the used reagents are expensive and poisonous and
suffer from excellent selectivity. Therefore, developing other CL sys-
tems with strong emission intensity and green approaches is essential
[297].
CQDs can enhance the CL effect through several routes. CQDs can
act as reaction catalyst or can concentrate the excited CL emitter and
enhance the emission. The CQDs can also impart in CL reaction and the
CL emission occurs by the annihilation of the hole-injected and elec-
tron-injected CQDs [298].
The reaction between potassium permanganate (KMnO4) and CQDs
and reduced state CQDs (r-CQDs) in an acidic environment can result in
CL. In the CQDs-KMnO4 system, the KMnO4 has the role of hole injec-
tion into the CQDs and by the interaction with electrons of CQDs, high
energy state electrons are produced which makes excited CQDs*. The
CQDs* relaxation leads to the emission. Furthermore, r-CQDs reduces
KMnO4 and produces excited state of Mn (II)* which relaxes with CL
emission [299].
The CL of the CQDs can be applied for detection of analytes with a
high sensitivity. The CL has the potential to be used as a tool for rapid
spectroscopic technique in characterization techniques as well [91]. For
example, Lin et al. [298] showed that CQDs enhance the CL in Na-
NO2–H2O2–Na2CO3 system. (CO2)2* is an energy donor to the CQD that
converts it to an excited state (CQD*) which returns to the ground state
via CL emission. The annihilation of hole-injected and electron-injected
M.J. Molaei
CQDs also result in CL emission. This method was used for sensing ni-
trite in tap water with proper accuracy. Although, the CL can be used
for determining the oxygen states (O-states) of the CQDs. The O-states
of the CQDs have an influence on their optical properties. It has been
reported that the C–O group-related O-states of the CQDs have influ-
ence on the CL intensity of the CQDs in presence of peroxynitrite
(ONOO−) that this can be used as a probe for characterization of O-
states of the CQDs [91]. CL has been used for DNA detection on the
paper analytical device. CQDs dotted nanoporous gold was employed as
signal amplification label. The detection limit of 8.56 × 10−19 mol L−1
has been achieved for the target DNA [300]. The CQDs were also used
as a fluorescence component in chemically initiated electron exchange
luminescence. The CQDs-based peroxyoxalate CL results in a linear
dependence between hydrogen peroxide (H2O2) concentration and PL
intensity that can act as a probe for H2O2 determination in the range of
10–1000 μmol L−1 [301]. The CQDs have been used in CL systems for
detection of adenosine [302], ranitidine [303], thiourea or tannic acid
[304], bromate [305], gallic acid in food samples [306], Mn2+ [307],
m-phenylenediamine [308], and metronidazole [309].
Zhao et al. [310] discovered that CL can be generated by the only
injection of a strongly alkaline solution into the CQDs, while no CL
reagent of oxidants or CL system is used. Using a high concentration of
NaOH solution with CQDs resulted in a prompt CL response. The sug-
gested mechanism for this phenomenon was “chemical reduction” of
CQDs in high concentration alkaline solution. The single orbital de-
tected by electron paramagnetic resonance (EPR), acts as electron traps.
Thermally excited generated holes annihilate with the electrons which
are injected by chemical reduction and the energy releases in the form
of CL.
CL is observed in CQDs functionalized with BPEI as well. The
mentioned CL obtained from CQDs as a probe in alkaline solution can
be applied for detection of iron(III) ions. The proposed mechanism for
CL says that iron(III) is selectively captured by the surface groups of
BPEI and injects holes into the BPEI functionalized CQDs as the oxidant,
and as a consequence, CL emission is generated. Fig. 10 is a schematic
illustration of the CL and fluorescence emissions in BPEI functionalized
CQDs/NaOH/Fe(III) system [92].
By the aid of polymer-surfactant interaction on the surface of CQDs,
a selective CL probe was designed for Co(II). The system can determine
Co(II) in HepG2 cells [311].
Fig. 10. Schematic illustration of the CL and fluorescence emissions in BPEI functionalized CQDs/NaOH/Fe(III) system. Reprinted with permission from [92].
Copyright 2014 The Royal Society of Chemistry.
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The CL of luminol can take place by using CQDs acting as catalyst,
without adding oxidant to the system. The π-rich electronic structure of
the CQDs cause formation of the activated complex [CQDs…luminol]
via charge transfer between luminol (donor) and CQDs (acceptor). It
was observed that by application of 3-aminophthalate as the lumino-
phore, the CQDs in the system accelerate the electron transfer processes
and catalyze the decomposition of the dissolved oxygen and this leads
to the generation of superoxide radical anion in the luminol solution.
The CL emission occurs as a result of the reaction of superoxide radical
anion with luminol. The catalytic activity of CQDs is influenced almost
by surface states, while CQDs size misses a considerable effect on it.
Therefore, by engineering the functional groups, one can tune the
catalytic activity of CQDs [90].
3.7. Electrochemiluminescence
Electrochemiluminescence (ECL) or electrogenerated chemilumi-
nescence is a process in which species generated at electrodes experi-
ence high-energy electron-transfer reactions and therefore excited
states form and light emits. Generally, luminescent processes include
photoluminescence (PL), bioluminescence (BL), electroluminescence
(EL), radiochemiluminescence, sonoluminescence (SL), CL and ECL. In
both ECL and CL, species undergo high energetic electron-transfer re-
actions and light emission. Mixing of necessary reagents and controlling
of fluid flow can initiate and control luminescence in CL. However, in
ECL, change in electrode potential can initiate and control the lumi-
nescence [312].
In recent years several QDs such as CdSe, CdTe and CdSe/ZnSe have
been used in ECL investigations. However, especially for biological
applications, the metal-based QDs have raised cytotoxicity concerns.
CQDs with much lower cytotoxicity have received researchers’ atten-
tion [313].
The ECL of the oxidized CQDs is mostly affected by surface state, not
like other QDs by particle size. The ECL can be obtained in CQDs
without surface passivation. Oxidized CQDs without surface passivation
were used as ECL luminophores in pH 7 of phosphate buffer solution
(PBS). The ECL signal of the CQDs was observed both in negative and in
positive potential regions. Without CQDs, ECL signal was not detected
in the system. In the absence of co-reactants, both cationic radical CQD
(R•+) and anionic radical CQD (R•−) should cooperate for ECL signal.
M.J. Molaei
ECL of CQDs occurs by the annihilation of (R•+) and (R•−) radicals. The
(R•+) and (R•−) radicals transfer charge at colliding and form the ex-
cited state CQD* [314].
The wavelength of the maximum ECL emission shows a red-shift
from the wavelength of the maximum PL. This has been attributed to
the smaller energy separations of the CQDs surface states (for ECL)
compared to the CQDs band gap in PL [313].
The CQDs can be used in ECL immunosensors for detection of tumor
markers. The detection of trace changes in the tumor markers is es-
sential for cancer diagnosis and treatment since, a small change in their
concentration can be correlated to the cancer occurrence, development,
and palindromia. For the synthesis of a nanomaterial designed as a
tumor marker ECL immunosensor, graphene was used as nanocarrier
and perylenetetracarboxylic acid and CQDs as luminophores. The re-
sulted immunosensor with a detection limit of 0.00026 fg mL−1 can be
applied for versatile cancers’ sample detection [315].
The K2S2O8 is used as the co-reactant in most of the CQDs cathodic
ECLs. The ECL mechanism by the K2S2O8 as the co-reactant is as follow:
electro-generation of CQDs•− radicals is accelerated through functional
groups of CQDs; SO4•− radicals are produced by S2O82− electro-
chemical reduction; resulted SO4•− radicals react with CQDs•− radicals
through electron-transfer annihilation and excited-state of CQDs
(CQDs*) forms for light emission (ECL) [316]. It has been reported that
when K2S2O8 (10 mmol L−1, as an oxidative reactant and a hole donor)
is added to the ECL system of N-doped CQDs/K2S2O8, the ECL emission
is strong, while no ECL emission is observed when K2S2O8 is used
without CQDs. It can be concluded that K2S2O8 acts as coreactant (or a
hole donor) and the N-doped CQDs are ECL luminophores in this system
[317].
In spite of that S2O82− is the mostly used co-reactant in CQDs ECL,
sulfite (SO32−) has also been suggested for this purpose. For cathodic
ECL signal of the CQDs, by potential cycling, SO32− oxidizes electro-
chemically and SO3• − radical in the anodic polarization process forms.
The electro-generated SO3•− in the presence of dissolved oxygen pro-
duces sulfate radical SO4•−. CQDs electrochemically reduces through
cathodic polarization process and negatively charged CQDs•− forms
which react with SO4•− and results in an excited state of CQDs (CQDs*).
The excited CQDs then returns to its ground state by emitting light
[318].
CQDs can be used for enhancing ECL of the semiconductor QDs. It
has been reported that CQDs have improved the ECL of CdSe QDs with
co-reactant of dissolved O2. The low electron-transfer resistance and
surface states of the CQDs facilitate the formation of electron-injected
QDs which results in an increase in ECL emission. The QDs were as-
sembled on poly(diallyldimethylammonium chloride)-functionalized
carbon nanospheres (PFCNSs) and the complex was used for detection
of oxidase substrates. The biosensor was designed by immobilizing the
enzyme on the QDs/PFCNSs complex. The detection limit for hypox-
anthine was 5 nmol L−1 [319].
Ru(bpy)+3 2 is a classic metal-organic which generate ECL emission by
application of analytes as co-reactants. This complex has the capability
of covalent bonding to other co-reactants and forms self-enhanced ECL
complexes which show high luminous efficiency. For example, PEI
capped N-doped CQDs were used as co-reactant of Ru(bpy)+3 2 na-
nosheets as the luminophore. Furthermore, reduced graphene oxide
introduced into the complex for the benefit of electron transferring and
ECL signal amplifying. The resulted complex on glass carbon electrode
showed nearly 69 fold better ECL signal intensity in comparison with
just Ru(bpy)+3 2 nanosheets on glass carbon electrode. The produced
sensor had a detection limit of 10 nmol L−1 with a linear range of
0.01–50 μmol L−1 for sensing of dopamine [320]. In another work, N-
doped CQDs were used as co-reactant and for enhancement of a
Ru(bpy)+3 2 ECL sensor signal. The sensor was able to detect bisphenol A
(BPA) via quenching effect of Ru(bpy)3+2/CQDs with the linear re-
lationship in the range of 0.03–1.0 μmol L−1 and detection limit of 10
nmol L−1. In this sensor, CQDs react with electro-generated Ru(bpy)+3 3
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and produce an excited state of Ru(bpy)+3 2 * which shows the ECL signal.
Addition of BPA results in quenching and inhibition of ECL. The elec-
tron transfer from the excited state of Ru(bpy)+3 2 * to BPA oxidation
product may be responsible for inhibition mechanism [321]. Ru(bpy)+3 2
as a donor and amorphous carbon nanoparticles (ACNPs) as an acceptor
in a Ru(bpy)+3 2 -labeled antibody and ACNP-antigen conjugate resulted
in ECL quenching of Ru(bpy)+3 2 . The target antigen (when is present)
competes with ACNP-antigen for Ru(bpy)+3 2 -labeled antibody and
hence, ECL quenching decreases. The system can detect mouse IgG with
a detection limit of 0.35 ng mL−1 [322]. Ru(bpy)32+/CQDs/polyvinyl
alcohol system was also applied in an ECL sensing platform for detec-
tion of sophoridine [323].
ECL resonance energy transfer (ERET) can be used for the produc-
tion of highly sensitive immunosensors. Nitrogen-doped CQDs as ECL
luminophores and aminated graphene (NH2-G) as quenching labels of
secondary antibody were incorporated in an ECL immunosensor. The
NH2-G have the ability to quench the ECL of CQDs on electrodes due to
the ERET. A detection limit of 3.3 pg mL−1 with the linear relationship
in the range of 0.01–100 ng mL−1 was achieved, using alpha-fetopro-
tein as a model for analytical performance assessment [324].
CQDs were also used in ECL based sensors for selective detection of
MCF-7 cancer cells [325], selective detection of cancer cells via func-
tionalized CQDs and graphene nanosheets (as signal amplification
agents) [326], aptasensor for thrombin based on CQDs-capped gold
nanoflowers [327], a probe for the evaluation of CD44 expression on
breast cancer cells [328], detection of microRNAs based on a DNA
functionalized CQDs [329], carcinoembryonic antigen immunosensor
[315,330], detection of squamous cell carcinoma antigen [331], de-
tection of 8-hydroxy-2′-deoxyguanosine using CQDs coated Au/SiO2
core-shell nanoparticles [332], detection of chlorinated phenols by
CQDs immobilized on graphene [333], detection of human IgG using
nitrogen-doped CQDs as luminophore and K2S2O8 as co-reactant [334],
and detection of Cu2+ with oxidized CQDs and K2S2O8 system [335].
4. Challenges and prospective
In this review, we introduced the CQDs and different properties and
applications of these nanostructures were discussed. Different types of
PL emissions in CQDs were explained and their mechanisms were
clarified. The versatile applications of CQDs in drug delivery, gene
delivery, in-vivo and in-vitro bioimaging, optical sensors, chemilumi-
nescence, and electrochemiluminescence illustrated.
The increasing need for QDs with tunable band gap has resulted in
extensive researches on different kinds of semiconductor QDs. The
classical semiconductor QDs have mostly complex production methods
and the disadvantages such as expensive raw materials and toxicity
confine their use in certain fields such as biomedical applications.
However, the CQDs with suitable fluorescence properties have eco-
nomical and easy production methods with minor toxicity. Several top-
down and bottom-up methods have been applied to produce CQDs with
the sizes below 10 nm. Surface passivation and doping have great in-
fluence on fluorescence properties of these structures.
There are still some obstacles that need to be conquered by further
researches before the development of the CQDs in the aforementioned
fields. For fluorescent QDs, the need for high QY and intensive
brightness is vital in bioimaging applications. Furthermore, the QDs
should have uniform size and hence, uniform emission properties. For
CL reactions, low QY and weak intensity of the emitted light of the most
used reagents are obstacles to the development of high-performance CL
sensors. Furthermore, poor selectivity is another drawback that hinders
the application of these sensors for some species. Except for some
limited cases that high QY of the synthesized CQDs has been achieved;
other synthesized CQDs suffer from low QY. Therefore, further re-
searches must be accomplished in order to overcome low QY, low in-
tensity and non-uniform optical properties of the CQDs. Still, more re-
search should be done to increase fluorescence intensity in the NIR
M.J. Molaei
region which is essential in certain biomedical applications. Since the
surface chemistry and impurities doping of the CQDs play important
roles in their optical properties, studies should focus on the effect of
these factors on the PL of the CQDs.
It seems that if these obstacles are passed within a few next years,
CQDs can be used commercially in various areas and compete with
traditional semiconductor QDs. The minor toxicity and low price can
lead to substitution of CQDs instead of semiconductor QDs in the bio-
medical application in the near future.
Acknowledgment
The author would like to appreciate Shahrood University of
Technology and Iran Nanotechnology Initiative Council for financial
support of this project.
Conflicts of interest
There are no conflicts of interest to declare.
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