(2023) 2:37
Al Ragib et al. Carbon Research
https://doi.org/10.1007/s44246-023-00069-x
Open Access
REVIEW
Multifunctional carbon dots in nanomaterial
surface modification: a descriptive review
Abdullah Al Ragib1,2†, Ahmed Al Amin1†, Yousef Mohammed Alanazi2*, Tapos Kormoker3, Minhaz Uddin3,
Md. Abu Bakar Siddique4* and Hasi Rani Barai5
Abstract
The surface properties of nanomaterials are an important consideration in most scientific and technological applications. Several methodologies can maneuver these properties while surface modification is the most common
technique. Carbon Dots (CDs) are viable competitive materials for their pacific environment, chemical inertness,
tunable photoluminescence, low cost, eco-friendliness, biocompatibility, schematic surface functionalization,
and sophisticated utilization in nanomaterial’s surface modification. The nanoparticle surface attribute is modified
for a specific purpose to use in several applications by dint of the tunable properties of CDs. Multifunctional CDs have
a great potential to replace traditionally toxic and costly quantum dots through surface modification. This review
presents how multifunctional CDs conjugated with other nanoparticles take an active part in medicine and biomedical fields with chemical and physical collaborations. Moreover, the basics of conjugate formation by different chemical
and physical interactions of functional molecules are appraised from multiple perspectives. This article also describes
different modification mechanisms followed by properties of the modified nano-conjugates. The surface modification
affects fluorescence quantum yields, complexation potential, fluorescent coloring, and quenching capabilities. Resultant-modified nanoconjugates are powerful surfaces for drug delivery, biosensing, bioimaging, analysis, and therapeutic methods. Finally, the most fruitful current challenges and further possibilities are discussed in the conclusion
section.
Highlights
• Classified the modifications of carbon dots (CDs) surface.
• Elaborated on the exceptional and recognized features of CDs.
• Summarized the implementations of CDs for emerging applications.
• Disclosed ongoing research, gaps, challenges, and potential scope of future work.
Keywords Nanoconjugates, Molecular surface, Photoluminescence, Biocompatibility, Cytotoxicity, Xenograft
†
Abdullah Al Ragib and Ahmed Al Amin contributed equally to this work.
Handling Editor: Hailong Wang.
*Correspondence:
Yousef Mohammed Alanazi
yalanazi1@ksu.edu.sa
Md. Abu Bakar Siddique
sagor.bcsir@gmail.com
Full list of author information is available at the end of the article
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or
other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/.
Al Ragib et al. Carbon Research
(2023) 2:37
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Graphical Abstract
1 Introduction
Carbon nanodots commonly known as Carbon Dots
(CDs) with sizes in the microscopic region (normally
10 mm or less) possess several optical qualities with
handsome biocompatibility and many such properties under development or soon to be revealed (Zhou
et al. 2017; Hao et al. 2016; Simões et al. 2016). Impressively, steady photoluminescence at the visible range
of wavelength in the aqueous solution is noticed when
the light is emitted on the excitation wavelength of the
CDs. For purposes like visualization, biosensing, bioimaging, drug delivery studies, analytical purposes,
therapeutic methods, and photocatalysis as well as in
terms of chemical inertness (Zhang et al. 2012), high
solubility (Baker and Baker 2010), easy modification
(Ray et al. 2009), and high resistance to photobleaching (Li et al. 2011a), CDs are promising aspirants in
comparison to covalent organic dies, regular nanoparticles, and semiconductor quantum dots (Li et al. 2015,
2017a; Das et al. 2014a; Anjana et al. 2018). Lately,
much development has been successfully crowned
in the process of preparation, exploration of chemical properties, and application of carbon-based quantum dots in therapeutic medicine (Li et al. 2012). Soon
after the invention of CDs, they became the hot topic
of discussion for their above-mentioned properties
and applications in all possible sectors straight from
the beginning. The preparation process is no longer a
very tough and expensive one and can be easily dealt
with for its very inert nature. Nevertheless, pristine
CDs that have drawbacks in the procedure of detecting
particles due to the presence of interference out of the
absence of a specific recognition group for the analytes
on CDs surface and low quantum yields in bioimaging generally cannot be conducted smoothly. They also
have drawbacks of showing biological functionality as
a biological system is poorly interacted (Xia et al. 2017;
Zu et al. 2017). As a result, the CDs distort the nanomaterial surface integrated via covalent modification
(amide coupling reactions, silylation, and other reactions including esterification, sulfonylation, and copolymerization), noncovalent modification (interactions,
complexation/chelation, and electrostatic interactions),
and sol–gel coordination (Mao et al. 2012). As a result,
the modified CDs thus formed are significantly used
in targeting and extracting several analytes and most
importantly in drug release. These surface modifications extraordinarily enhance the internal and external properties such as fluorescence quantum yields,
complexation capacity, the color of fluorescence, and
their quenching capability in a qualitative manner (Yan
et al. 2018). Ultimately, the features of Carbon Quantum Dots (CQDs) must be regularly revised and regulated by the precursors used during synthesis, surface
Al Ragib et al. Carbon Research
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passivation, and functionalization as acknowledged.
For the accuracy in luminescence properties and development in novel applications, assumingly the most
important aspect to be taken care of is modification/
manipulation of the surface of CDs other than only
integrating and partially substituting or synthesizing
CDs with new precursors. In this review article, we are
going to discuss the different procedures to reorientate
the nanomaterial’s surface properties and utilize them
accordingly for multiple functions in biological systems
such as bio-imaging, bio-sensing, optical properties as
photocatalysis, detection of metals, and many more.
Farshbaf et al. (2018) noticed that the synthesis and
analysis of CDs are normally easy and handy processes
that employ handy and accessible materials. Moreover, ordinary chemical reactions are required for the
modification of CDs. Researchers are attracted by the
various size-dependent optical properties of CDs and
employ these nanoparticles for extensive application in
medicine and biomedical sectors (Farshbaf et al. 2018).
Particularly, this nanomaterial has had no abundancy in medical or technological applications till now
with large-scale production facilities due to a miniature
understanding of its structure-performance relationship,
controllable luminescence (fluoro and photo–luminescence) properties, and characteristic relationships when
coincides with a wide variety of chemicals trending now.
So, this outlook will provide the functional modification
processes that have been used in vivo or in vitro so far,
opening a door to future application scaling with further research initiatives. The major surface modification
processes that can replace the prior performances are
explained with extensions. Endowing to the idiosyncratic
features of CDs, the modified surfaces gain potentiality in
photoluminescence, catalytic surfaces, cytotoxicity, biotoxicity, surface prevention, and many more properties
to be used in medical science. Maturity in the modification and applications of CDs with other nanoconjugates
reveal the effect of their vast sneaking properties for
technological/medicine/chemical/mechanical/ hardware
industries. There has been a plethora of research works
on the conjugation of CDs and other nanomaterials making them viable for instrumenting biosensors, bioimaging, drug delivery processes, and anatomical analysis
or screening. In summary, we accumulated most of the
current research on different modifications of CDs, pathways of modified CD utilizations, and their future potentiality in health, technology, and science sectors from the
year 2008 to 2021. This article is designed and compiled
to learn how CDs can alter the functionality of any biochemical/chemical/technological determinants when
their surface is modified with nanoconjugates.
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2 Modification of CDs surface
2.1 Covalent modification
Among many chemical reaction-based modifications,
the covalent modification of CDs is the result of a reaction between functional molecules and reducing groups
on the surface of CDs. The chemistry behind the synthetic process is often used to control the size, passivation, and physical properties of CDs, which can aid in
the light generation traps that split radiation when stimulated. On the other hand, non-covalent modification of
CDs and modified nano agents that are established on
π interaction or the van der Waals force have comparatively less negative impact than that of covalent modification, thus providing easily tunable photoluminescence
and interfacial properties. The biocompatibility and optical properties are seen to be increased remarkably after
the modification as we can see high quantum yield (QY)
and tunable photoluminescence (PL) of CDs with amino
groups (-NH2) for π orbital and delocalized molecular orbitals of aromatic rings (Lim et al. 2015). Furthermore, the PL property is also enhanced for the virtue of
surface energy traps and electron–hole recombination of
the oxygenated functional groups on the CD’s outer layer.
This feature, however, can be enhanced by controlling
the degree of oxidation on the surface of CDs. In addition, this tunable PL of CDs is useful in detecting and targeting a specific molecule, which is possible when drugs
are altered in conjunction with the standard CD surface.
It can, therefore, specify the sites of disease and release
drugs in the drug delivery site which make CDs a significant carrier in drug delivery applications (Yan et al.
2016; Wang et al. 2011a; Fu et al. 2017). Surface modification can be classified into various types based on chemical reactions between distinct functional groups such as
amide coupling, sialylation, esterification, sulfonylation,
and copolymerization reaction.
2.1.1 Via amide coupling reaction
Typically, CDs are prepared by using oxidizing agents
to treat organic intermediates that have a lot of carboxyl
groups on the surface, which gives them exceptional
water solubility, selectivity, and the ability to be modified.
However, numerous carboxylic groups on the surface of
CDs recombine electron–hole pairs, and emissive traps
form as a result, affecting the fluorescence properties of
CDs dramatically (Wang et al. 2016a; ChandanH et al.
2018; Huifang et al. 2017).
Condensation of carboxyl groups with amino compounds is commonly utilized as a surface modification
technique to improve intrinsic fluorescence emission,
according to Dong et al. (2015) who used a conventional EDC/NHS (N-ethyl-N-(3-(dimethylamino)propyl)
Al Ragib et al. Carbon Research
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carbodiimide/N-hydroxysuccinimide)-catalyzed
reaction. Using glucose as a carbon source, it generated ethylenediamine (EDA) modified CDs-COOH via an EDC
coupling mechanism. Due to the property of well-passivized strong linkage of CDs-COOH improved QY from
1.3 to 3.0% was obtained (Fig. 1). Since free amino groups
were bounded with the surfaces of CDs, these modified
CDs showed magnificent optical properties along with
biological compatibility, hence it is signed in for microscopic imaging and biolabeling of human gastric carcinoma cells (Dong et al. 2015).
D’Angelis do E. S. Barbosa et al. (2015), on the other
hand, synthesized CDs-COOH by chemical oxidation
from cow manure (Fig. 2). Under nitric acid activation
conditions, modified CDs surfaces were yielded through
aggregation with EDA. The QY was found to be as high
as 65% from the previous study of Dong’s group; the
modified CDs with EDA have good biocompatibility
that can be used to label the nuclei of breast cancer cells
MCF-7 with precision. Subsequently, they were used as
a subcellular-specific live-cell fluorescence-imaging assay
(D’Angelis do E. S. Barbosa et al. 2015).
Dopamine can participate in the amide coupling reaction to manipulate CDs-COOH and the phenolic moiety
can be catalyzed to quinone compounds in the presence
of the matching oxidant that can suppress the fluorescence of CDs after an alteration of CDs-COOH through
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the amide coupling process. Taking advantage of it,
Chai et al. (2015) have taken activated carbon dust as a
raw material to temper CDs-COOH and then changed
dopamine via an amide coupling reaction to create new
CDs that are used to monitor tyrosinase (TYR) activity
(Fig. 3). Hence, under the particular catalysis of TYR, the
dopamine molecule in CDs was oxidized to a dopaquinone derivative. Amid CDs and the dopaquinone moiety,
there was an intraparticle photo-induced electron transfer (PET) mechanism, followed by the quenching of fluorescence of the newly modified CDs. Later on, for TYR/
pH-associated medical diagnosis and disease monitoring,
this fluorescence assay was employed. Moreover, the catalytic activities of CDs can be enhanced by using β-CD
as the dopamine receptor unit even after the competitive
host–guest interaction between β-CDs conjugated target
analytes and stain molecules.
Amino acid combining supramolecular compounds
can also be connected covalently with CDs-COOH
through an amide coupling mechanism. Cyclodextrin
(β-CD) has been used as a host molecule for a unique
molecular microstructure comprising a hydrophilic
external surface and a hydrophobic internal cavity. Previous study designed fluorescence probes in which they
used 6-aminoethyl amino-β-cyclodextrin to modify CDs
with CDs-COOH via the EDC/NHS coupling mechanism (Sun et al. 2017). The structure thus formed can
Fig. 1 Modification of CDs nanostructure via amide coupling (Dong et al. 2015)
Fig. 2 Synthesis of modified CDs by amide coupling (D’Angelis do E. S. Barbosa et al. 2015)
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Fig. 3 Molecular surface modification with CDs for determination of TYR via amide coupling (Chai et al. 2015)
generate host–guest inclusion complexes combining with
the guest molecules P-nitrophenol to quench the fluorescence of CDs and host molecule cholesterol to remove
p-nitrophenol to initiate the fluorescence power output.
This technique is very popular in distinguishing cholesterol from the blood serum sample with high efficiency in
medical pathology (Fig. 4).
A very popular glycopeptide microbicidal, vancomycin
(van) is sometimes used as a wide-ranging antibiotic. CDs
can also be associated with the vancomycin group antibiotics to combat dangerous germs like Staphylococcus
Aureus and Methicillin-resistant Staphylococcus Aureus
(MRSA) for gram-positive staph infection treatment. The
amide coupling reaction was employed by Zhong et al.
(2015) to modify CDs by the combination of citric acid
and carbon from urea along with the modifying agent
van (Zhong et al. 2015). It is easy for these nano surface
modified CDS to preserve CD properties, i.e., CDs conjugated with a van cannot cause a noticeable change in
the fluorescence spectra of CDs. Identification of Staphylococcus aureus is led by the ligand-receptor interaction
of van and the cell wall by the application of this modified
nanoparticle (Fig. S1). Van can also lead to fluorescence
quenching by forming a hydrogen bond with the surface
of the gram-positive bacterium and the peptide D-Ala-DAla. It has been verified that there is a noticeable linear
relation between the fluorescence intensity and the concentrations of S. aureus. Detection of gram-positive bacteria in a practicable initiative following this assay is in
practice (Zhong et al. 2015).
A common bio probe that achieved high appreciation
and attention in medicine and nanotechnology is fluorescence immunoassay because it possesses the particular benefit of high sensitivity fluorescence technique and
Fig. 4 Synthesis of the modified CDs and method of determining Cholesterol (Sun et al. 2017)
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high selective immunoassay. The traditional fluorophores
such as Fluorescein amidites (FAM) and Texas red on the
other hand are not so reliable and reasonable for longterm detection owing to their photobleaching effect.
Mohammadi and coworkers showed the development
of a selective Förster resonance energy transfer (FRET)immunoassay in order to detect sensitively CA 15–3
tumor marker (Fig. 5) (Mohammadi et al. 2018). Though
this assay is a sandwich-type immunoassay, consisting of
CDs-COOH and CA 15–3 antibody (by EDC/NHS coupling reaction)—as a fluorescence generator and gold
nanoparticles (AuNPs) labeled poly-amidoamine dendrimer (PAMAM) aptamer as the suppressor. The rigid
complex interaction of CA 15–3 antigen aptamer can
be produced with the conjugation of AuNPs-PAMAMaptamer, which can result in adjacent CDs and AuNPs.
The fluorescence intensity of CDs reduces when the
FRET across CDs and AuNPs approach closer. However,
further advantages of the assay include simple operation,
rapid detection, low cost, the requirement of normal and
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affordable equipment, and be extended to determine biomarkers of various types.
Another study shows that nano-hydroxyapatite (HAP)
or its analogs can be prudent multifunctional bio-nanoplatforms or efficient in building biocompatible scaffolds
proving its successful biomedical application. Zhao et al.
(2015a) using a hydrothermal route, employed monodisperse F-substituted hydroxyapatite (FHAP) nanorods and
phosphoethanolamine (PEA) to make amino-terminated
fluorine-substituted hydroxyapatite. Taking ethylenediamine carbon source and ClCH2COONa as modifying
regent, CDs-COOH was prepared with citric acid. Then
these modified CD nanomaterial surfaces were acquired
through an amide coupling reaction by interfusing CDsCOOH and FHAP. They have been effectively used as
bio-nanoplatforms to image MCF-7 breast cancer cells
in vitro (Fig. 6).
Semiconductor nanoparticles CQDs with a radius in
the range of exciton Bohr radium are mostly CdTe QDs,
CdSe QDs, and CdS QDs. The surface modification
Fig. 5 Procedure of CDs modification of nanomaterial surface and formation of immunoassay (Mohammadi et al. 2018)
Fig. 6 Modification pathway of CDs via amide coupling (Zhao et al. 2015a)
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allows them to link other fluorophores or biomolecules,
which might be useful in chemical engineering and biomedicine. Xu et al. (2017) developed a silica shell encapsulating amino-passivated cadmium telluride (CdTe)
CDs to strengthen the optical and molecular stabilities
and minimize the toxic effects of CdTe QD. Through an
EDC/NHS coupling process, CDs-COOH were mounted
with CdTe QDs-NH2 to generate nanosurface-modified
CDs and these modified CDs were used for the detection
of Hg2+. A filter paper-based assay was applied, which
was non-toxic and made the identification of Hg2+ quite
fast and reliable (Fig. 7).
2.1.2 Via silylation reaction
Silane is a biocompatible non-toxic material that functions as a silica shell that encases two types of fluorescent components to create colorful, harmless fluorescent
probes for the two types of functional groups. Silylation is
the word used to describe the interaction between silane
and functional hydrogen on the exterior of CDs. This
strategy aims to enhance the CD solubility in water, selectivity, and lower the level of cytotoxicity while increasing
the surface area to ensure excellent dispersion. It is very
popular in ion detection and temperature sensing.
CDs-NH2 was developed by undergoing a hydrothermal method taking acetic acid as the source of carbon by
Rao et al. (2016) in the year 2016. Then through the silylation reaction, they managed to encapsulate CDs-NH2 in a
silica shell operating with tetraethyl orthosilicate (TEOS)
and 3-aminopropyl triethoxysilane (APTES). A healthy
mix of inactive and active functional groups, minimization of conglomeration, and indifferent bindings are the
primary advantages of this modification method. Plenty
of room for amino groups is noticed on the nanomaterial-modified CDs surface that can undergo EDC/NHS
coupling reaction to get covalently associated with thioglycolic acid-modified CdTe QDs and thus associates
with the neighboring carboxyl and CdTe QDs surface
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hydroxyl groups. This is how Cu2+ ions can be detected
(Fig. S2).
CDs@CdTe QDs progressively collaborate with families in the hybrid spheres system, causing the CdTe QDs’
fluorescence to fade. CDs’ fluorescence is unaltered even
by the addition of Cu2+ in the range of 0.1–1.0 M with
such a LOD of 0.096 M, but CdTe QDs’ fluorescence is
quenched. This technology is widely used in the detection of Cu2+ in several fruits and spiked vegetables.
Amino passivated CDs were developed by Liu et al.
(2014) taking raw material N-(β-aminoethyl)-γ aminopropyl methyl-dimethoxy silane (AEAPMS) and through
a silylation operation, they were converted into Rhodamine B-doped silica nanoparticles, yielding CDs@SiO2.
Since the main raw material (AEAPMS) that is used,
contained methoxy group, saline groups, and the remaining ethylenediamine groups on CDs exterior, they could
serve as Cu2+ recognization sites, so these were used for
the detection of Cu2+. Furthermore, in real-life, Cu2+ in
MCF-7 cells and actual tap water may be measured with
this fluorescent probe.
2.1.3 Via esterification reaction
Synthesizing of CDs requires organic precursors that usually carry an ample amount of the hydroxyl group on their
exterior. The esterification reaction can manipulate them
in several routes effectively by interacting with different
functional components and the nanomaterial’s surface
is modified accordingly. The modified CD surfaces have
qualities such as good selectivity, reversibility towards
targets, and good imaging, which derives an implication
in the detection and cell imaging fields. Moreover, this
strategy helps to change the CD’s hydrophobic and oleophilic properties to lipophilic hydrophobicity.
A group of researchers prepared CDs-OH (Algarra
et al. 2014) by taking lactose as a carbon source at a relatively low temperature and the quantum yield jumped
to 46% directly (Fig. 8). These CDs were prepared using
Fig. 7 The modification method of CDs via amide coupling reaction and the detection pathway for Hg2+ (Xu et al. 2017)
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Fig. 8 Modification of CDs by esterification reaction and detection of Ag+ (Algarra et al. 2014)
mercaptosuccinic acid (MSA) nucleophilic addition–
elimination process with the help of hydroxyl groups on
the CD’s surface. The MSA’s thiol groups were potentially
combined with Ag+ to generate a ground-state complex;
adding 0–30 μM of Ag+ resulted in fluorescence quenching via static quenching. CDs-OH was used for the static
quenching technique Ag+ detection and further in the
dissolution of silver nanoparticles. It could efficiently
quantify Ag+ ion.
A solid-state synthesis procedure of CD modification
was developed by Lai et al. (2016) taking carbon from
ammonium citrate along with the identification ligand
folic acid (Fig. 9). The modified CD surface was generated
by the dry heating method, where the folic acid microstructure was anchored with CD surfaces via a simple
dehydration reaction. These CDs were therefore served
in the labeling of tumor cell selectivity, because they have
the property of high labeling efficiency and bright fluorescence for their selected targets. These modified nanosurfaces with CDs have wide applications in tumor tissue
targeting and imaging that are confirmed by the selectivity level of HeLa cells. Soon after that, the research
team demonstrated another probe of CD modified with
Mannose in terms of general E. coli acknowledgment to
mannose. Various nanomaterial component preparations such as carbon nanodiamonds, carbon nanotubes,
graphene oxide nanosheets, and fullerene nanoparticles
are some inspirations from this modification method as
well as other kinds of biolabeling exercise with selective
therapies.
2.1.4 Via sulfonylation reaction
Nevertheless, CDs that contain amino groups can be
rearranged remarkably by surface modification employing sulfonylation reaction agglomerating with several
sulfonyl chloride complexes. Upon adding sulfur atoms
on the surface, the energy trap site develops, for photoexcited electron capture, the emissive trap states rise,
and the modification range of the electronic composition of CDs is enhanced. Sulphonyl bonds are always
Fig. 9 The modification mechanism of CDs via esterification reaction and the application of biolabeling (Lai et al. 2016)
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a water-soluble phenomenon that takes place in buffer
condition of alkali solution significantly optimizing the
variety in pristine CD’s application and performance.
Lin et al. (2018) employed the host–guest recognition
principle undergoing a two-step sulfonylation reaction
to develop the β-CD modified CDs-NH2. Generally, contingent on the unique molecular formation CDs-NH2 is
often employed in the determination of analyses of catechol (CC) and hydroquinone (HQ). Depending on the
hydrophilic external surface and hydrophobic internal
cavity, a rigid host–guest complex generates upon the
entry of analytes into cavities of β-CD ensuring intensive fluorescence quenching. Furthermore, the CDs-NH2
modified surface has an elevated water solubility level
and reveals strong fluorescence. Therefore, CC and HQ
in real water samples can be detected.
Besides, DNS-modified CDs-NH2 has been prepared
via sulfonylation reaction by Wang et al. (2015) (Fig.
S3). In this process a precursor, phenylenediamines was
employed to prepare CDs-NH2. The newly modified CDs
produced afterward exhibited non-fluorescent behavior
useful for the identification of selenocysteine (SEC). With
the help of the nucleophilic substitution process, the DNs
moiety of the modified CDs surface was readily cleaved
by selenolate after a period of incubation in an aqueous
solution at room temperature using SEC. This procedure increased the fluorescence properties dramatically
owing to a modified compound Y-G-CDs. These modified CDs with the surface of nanomaterials are capable of
high-level selectivity towards SEC compared with other
bio thiols and other bio-species along with enhanced sensitivity. Therefore, this can efficiently help in L929 cells
exogenous SEC imaging.
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2.1.5 Via copolymerization reaction
CDs normally contain functional groups as active hydrogen and hence are modified by copolymerization reaction
in cooperation with cyclic or double bond compounds.
Bulky CD nanomaterials can be generated by this
method. Li et al. (2017b) managed to prepare CDs-OH
by taking carbon from cyclodextrin (Fig. 10). Then the
nanomaterial surface modifications of CDs were performed by glycidol anionic ring-opening polymerization
taking the hydroxyl group as an initiator. The outstanding
solubility, biocompatible property, and extended circulation half-time in vivo made this dedicated hyperbranched
polyglycerol (HPG) a highly acceptable compound for
copolymerization modification. The HPG layer lessened
the CD’s energy traps, causing the declined QY of the
modified CDs (1.2%) compared to that of pristine (1.5%).
The emission peak of modified CDs showed mild cytotoxicity, strong water dispersibility, strong blue fluorescence, and improved hemocompatibility for which it is
generally used for A549 cell imaging.
Yuan et al. (2014) managed to prepare CDs-NH2 by
pyrolyzing the mixture of 4, 7, 10-trioxa-1, 13 tridecanediamine, and citric acid in glycerol (Fig. 11). To make
fluorescence probe CDs, carbon disulfide was added to
the amine groups on the surface of the CDs, then Cu2+
and ammonium N-(dithicarbaxy) sarcosine (DTCS) were
coordinated. The application of this modified CD
was appropriate for the detection of Hg2+ because of
the strong fluorescence quenching by CuDTC2 via the
process of energy transfer and electron transfer. The
chelating ability of Hg2+ was seemingly higher than Cu2+
to dithiocarbamates, so an extra Hg2+ (of 0.04–1.0 μM)
could develop stability in the molecular surface bond
Fig. 10 Modification procedure of CDs via co-polymerization reaction (Li et al. 2017b)
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Fig. 11 Modification mechanism of CDs nanostructure and determination of Hg2+ (Yuan et al. 2014)
stiffness of CuDTC2 complex enhancing the fluorescence. Hg2+ from real samples was identified by a whole
complex fluorescence assay which is often reliable. The
drawbacks of different covalent modification reactions
associated with CD surface modification are enlisted in
this study (Table 1).
2.2 Interaction reaction modification
When new functional groups association is necessary
or the provision of new functional groups is evident, π
interactions or electrostatic interactions between CDs
and modified molecules help in targeting a different nanoparticle or molecule interfacial properties to provide an
effective bridge at the junction of nanoparticle and biological systems interaction (Luo et al. 2013). The main
advantage of this kind of modification is structural integrity that can be generated depending on the structure
characters of different functional groups.
2.2.1 Via π interaction
An extended π system is located at some parts of CDs
and when aromatic molecules are encountered, the surface can be modified with CDs through π interaction.
These modified nanomaterials have high homogeneous
fluorescence probes possessed by extended conjugation
domain due to modification through π interaction. They
have enhanced QY, photostability, and biocompatibility.
With the help of the microwave-assisted method, Jiang
et al. (2016a) prepared Si-doped CDs (Si-CDs) employing glycerol and APTES as the initiating compound
(Fig. 12). The π interactions among Si-CDs and dopamine
on a one-to-one basis were practiced for the production
of these modified surfaces. These modified CDs had a QY
of 12.4% that was utilized for the determination of Ag+
ion, due to the ultra-bright fluorescence emissive properties. In this media, Ag+ can be reduced to nanoparticles
of silver in contact with dopamine. Further applications
of these modified nano-dots were exposed in assaying
intracellular Ag+ and HeLa cells for their salt stability,
photostability, and lower cytotoxicity.
According to Li et al. (2011b), π interactions of CDs
with DNA may be strategically employed as a binding
scheme to detect any specific nucleic acid. As they have
proposed so far, via π interactions fluorescence from dyelabeled single-stranded DNA probes can be quenched
right after their absorption into the outer layer of CD to
form double-stranded DNA by the target DNA and dyelabeled DNA accumulation. They highly enhance fluorescence recovery by falling off the CD’s surface. This unique
strategy is employed for the safe detection of metal ions
Table 1 Drawbacks of different covalent modification reactions associated with CDs surface modification (Shi et al. 2015)
Amide coupling
Esterification
Sulfonylation
Silylation
Copolymerization
i) Carboxyl group pH = (4–6).
ii) Amide bond pH = 7.5.
iii) pH adjustment necessary.
iv) Cumbersome operation.
i) Reversible reaction.
ii) Nucleophility of water
and hydroxyl/ester group are
the same.
iii) It is difficult to modify
with an ordinary reagent
system.
i) Difficult to directly sulfonate CDs-NH2 with sulfonic acid.
ii) Necessary to react
sulfonic acid compound
into sulfonyl chloride.
iii) Increases difficulty
in modification.
i) Common but unstable.
ii) Granting conditions.
iii) Disproportionation reaction necessary.
i) The reaction is uncontrollable.
ii) The surface of the modified CDs is usually contaminated.
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Fig. 12 Modification principles of CDs nanomaterials by π interaction and detection of Ag+ (Jiang et al. 2016a)
(Hg2+ amid T-Hg2+-T base pair and Ag+ amid C–Ag+-C
base pair) (Li et al. 2011c).
2.2.2 Via electrostatic interaction
Due to the functional groups such as carboxyl, amino,
and hydroxyl on the surface of CDs, they usually inherit
either a negative or positive charge. The fun fact here is
that by the electrostatic interaction method, the charges
of CDs can be interchanged. This kind of modified nanodots generate some targeting molecules and fluorophores
that result in highly efficient implementation in several
therapeutic/theranostic methods and bio-targeting.
By using carbon from natural carrot Jin et al. (2017)
synthesized negatively charged CDs and then modified
them with the help of opposite potential Nile Blue (NB)
and polyethyleneimine (PEI) via electrostatic interaction
to generate CD@TPF two-photon fluorescence nanocomposite. In the conjugated nanomaterial CD’s aqueous solubility was enhanced by PEI. These modified CDs
are employed in S2− detection. In addition, these CDs
are found to be highly sensitive and selective towards
S2− (Fig. 13).
In addition, electrostatically modified CD nanomaterials generally have specific targeting and binding
Fig. 13 Modification CDs nanoparticles via electrostatic interaction and detection mechanism of S2− (Jin et al. 2017)
Al Ragib et al. Carbon Research
(2023) 2:37
properties of molecules, making it a potential candidate
to be used in drug delivery systems. Recent findings by
Sarkar et al. (2017) prove the control of cell proliferation in cancer cells for the binding capacity of estrogen
receptors to 17β-Estradiol. They generated estradiol
hemisuccinate (E2) out of 17β-estradiol which is a negatively charged compound. Side by side, using betaine
hydrochloride and tris(hydroxymethyl) aminomethane
the positively surface-charged blue-emitting CDs had
been generated. Ultimately, a modified surface of CDs
prepared through electronic interaction of noncovalently
coupled blue emitted Cationic Carbon Dots (CCDs) with
negatively charged estradiol hemisuccinate (E2). These
CDs’ functionality has been extended to include precise
cell-based marks of estrogen receptor-rich (ER-positive)
MCF-7 cells atop estrogen receptor-negative (ER-negative) MDA-MB-231 cells with non-cancerous Chinese
Hamster Ovary Cells CHO cells. Indulging these CDs to
the mammalian cell in vivo exhibited outstanding stability in the biological milieu. Therefore, minimal biological
compatibility issues made it a useful drug carrier in vivo.
Taking CDs loaded with the anticancer drug doxorubicin
(dox) (modified by Sarkar and follow researchers) and
following the delayed apoptotic pathway selective killing of (ER-positive) MCF7 cells is possible. It shows the
efficacy of 2 folds more in comparison with (ER-negative)
MDA-MB-231 cells and no-carcinogenic Chinese Hamster Ovary Cells or (CHO) cells. Furthermore, for cancertargeting theranostic agents, these surface-modified CDs
are treated as research candidates of great potential.
2.3 Chemical complexation reaction modification
Complexation here refers to the conjugation of CDs and
metal ions on the surface of the nanomaterials that sometimes take place for some definite outcome in a specific
condition through a coordination bond. On the surface
of CDs, molecules such as hydroxyl, amino, or carboxyl
groups are present that take part in complexation with
metal ions. When the hydrophobic part increases the stability of CDs in organic solvents, the amphiphilic part/
molecule gets attached to the surface of CDs through
complexation and thus modulates the external and internal behavior of the CDs that are most advantageous in
practical utilizations.
Unique ratiometric fluorescent nanoprobe CDs were
generated by Chen et al. (2015), where they used ethylenediaminetetraacetic acid (EDTA) as the generation
source of CDs and carried out complexation reaction of
terbium in association with amino and carboxyl groups
on the CDs surface (Fig. S4). CDs were successfully
organized to work as podiums along with the retaliation
unit of Dipicolinic Acid (DPA) as the fluorescence reference unit Tb3+.
Page 12 of 30
This kind of nanomaterial-modified CD surface is used
normally for the detection of DPA. In the presence of two
carboxyl groups and a pyridine group, the DPA can maintain very strong interactions with lanthanide ions via
ion-pairing interactions and metal–ligand chelate coordination. DPA has a very low energy level in triplet conditions which makes it a suitable candidate to detect Tb3+
by accurate energy transformation to the central metal
ion from the ligand. Hence, the selectivity of this modified CD can be too much inclined to the DPA. Moreover,
these modified CD surfaces are known to have quick and
functional detection properties of several other bacterial
spores and biomolecules. In addition, Wang et al. (2020)
used EDTA as the generation source of CDs and carried
out a complexation reaction of europium in association
with amino and carboxyl groups on the CDs surface for
successfully applying it as a biomarker for quantitative
and qualitative (visual) assay of DPA in river water (Wang
et al. 2020).
Another research shows the activity of nanoprobes
generated by CD modified with a lanthanide, which is
used for expansion in the application of bioimaging and
other biomolecular identification. Shi et al. (2015) managed to modify and form a different kind of CDs-modified surface (CDs-NH2) for magnetic resonance imaging
(MRI) nanoprobe or dual model fluorescence imaging
in the presence of PEI through low-temperature pyrolysis, Modification was continued through carbodiimide
chemistry with cyclic Diethylenetriamine pentaacetate
(DTPA) dianhydride and then gradually complexed with
harmonious addition of Gd3+ to obtain dual-modal fluorescence/MR imaging nanoprobe CDs (Fig. 14). As the
Gd3+ ions were only chelated onto the outer surfaces
of nanoprobes the modified CDs possessed negligible
cytotoxicity and enhanced longitudinal. These CDs were
successfully applied in the imaging of HeLa showing
improved sensitivity and upgraded MRI resolution with
indications of future practical application in bioimaging
and medical translation.
2.4 Sol–gel modification
A very useful method of modifying the surface of CDs
is the sol–gel strategy. In the process, organosilane is
employed as a coordinating solvent to create amorphous
CDs that are extremely luminous (QY = 47%) in just one
minute as illustrated in Fig. 15. The process is preceded
for a complete minute at 240 ℃ through pyrolysis of
anhydrous citric acid in N-(b-aminoethyl)-c-aminopropyl methyl dimethoxy silane (AEAPMS). The modified
nanodot thus generated (with a diameter of 0.9 nm) was
marked up with the methoxysilyl group. Moreover, when
these CDs are simply heated (80 ℃ for 24 h.), they get
converted into pure fluorescent films, popularly known
Al Ragib et al. Carbon Research
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Page 13 of 30
Fig. 14 Modification mechanism of nanomaterial surface of CDs via complexation (Shi et al. 2015)
Fig. 15 Schematic diagram for the preparation of photoluminescent CDs, flexible CD film, and CDs/silica particles (Wang et al. 2011a)
as monoliths. Furthermore, CDs with hydrophilic silica
encapsulation (CDs/Silica) can be generated from hydrophobic CDs that are biologically compatible and do not
bear any sign of toxicity in the selected cell lines (Wang
et al. 2011a). A molecular perception item CDs@MIP
(molecularly imprinted polymer) was used in the same
study to structure the dopamine (DA) Fluoroluminescence (FL) Opto sensor in the beginning. Then taking
AEAPMS as an organosilane precursor undergoing a
single-step hydrothermal reaction highly luminescent
CDs were shaped. After that, the CDs@MIP composite
could be easily separated from the anchored MIP matrix.
The obtained combination of CDs and MIP revealed high
template selectivity and photo-stability in DA detection
via the sample’s FL intensity module.
3 Features
3.1 Photoluminescence
A fascinating property of CDs is photoluminescence (PL),
also termed size-dependent optical absorption bearing
a classic sign of quantum confinement. Further analysis
and elucidation about the exact modus operandi of PL
are necessary owing to the inconsistent and controversial findings in the existing literature (Zhao et al. 2008).
Emission wavelength and intensity is the key feature for
the behavior of the PL to be taken for granted on account
Al Ragib et al. Carbon Research
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of diverse emissive traps in CDs outer layer and most
importantly nanoparticle size. It was asserted by Zhao
et al. (2008) that compared with nanoparticles having a
similar size and particle characteristics, the influence of
CDs PL on the wavelength of excitation range was tailoring more emissive trap sites. Moreover, the optical
behavior of these CDs/CQDs is determined by the dispersion of the diverse emissive sites. As Liu et al. (2009)
stated that the emission of surface energy passivation due
to the presence of energy traps on the surface, is an attribution to enhancing the CD’s photoluminescence. They
further assumed that emissive energy traps have a quantum confinement effect, which is present on the surface
and is accountable for a powerful exhibition of PL when
the surface is passivized. To achieve strong PL emission
on modification of the nanosurface, the CDs generated
by the supported approach required surface passivation
(Liu et al. 2009). This report showed that colorful PL was
emitted from CDs due to surface energy traps which
eventually emitted strongly in action for the dispersion of
emissive trap sites (Fig. S5).
Again, Zhu et al. (2018) structured CD/PVP (polyvinyl pyrrolidone) composite films that made white lights
quite visible with photoluminescence Quantum Yields
of 15.3%. Then it was confirmed that the blue/green/red
emissions originally came from three different emitting
states namely the intrinsic state, C = O- and C = N-related
surface states, respectively.
3.2 Up‑conversion photoluminescence (UCPL)
Until the last couple of years, the UCPL of CDs has not
yet been yet a much noticeable discovery but recently due
to the application of up-conversion fluorescence matter
in bioimaging, it became a frontline research topic. The
property of CDs that is considered the main reason for
UPCL is simply the multi-photon activation process that
is at its best level after being conjugated with other nanodots. When two or more photons are absorbed at the
same time, they emit light with a wavelength shorter than
the excitation light, allowing two-photon luminescence
microscopy to be used for cell imaging. Excitation by a
femtosecond pulsed laser for two-photon excitation
within the N-IR region (800-840nm) or by an argon-ion
laser results in significant emission in the visible area
(Cao et al. 2007). The representative two-photon luminescence spectrum in such CDs has been used to demonstrate their UCPL features (Fig. S6).
A recent investigation shows that the electrochemical module aided by alkali excels in exhibiting UCPL
features. However, on differently modified CDs and raw
CDs prepared from different processes, it is confirmed
from the Fluoroluminescence (FL) spectrophotometer
that CDs did not exhibit observable UCPL. According to
Page 14 of 30
these findings, normal FL is the derivative of UCPL, since
it is triggered by a leaky component from the second diffraction in the monochromator of the FL spectrophotometer. By installing a long-press filter in the excitation
lane, the leaking component and subsequent UCPL can
be eliminated from the FL spectrophotometer. Coupled
with some other findings, it is assumed that rather than
many photon pathways, UCPL is pure fluorescence with
a linear response. A very critical step in this detection of
up-conversion FL is to eliminate the normal fluorescence
(Wen et al. 2014).
3.3 Cytotoxicity
In the last few years, a wide range of studies have been
conducted place regarding the production of CDs-based
bio-probes with high stability, owing to the deep necessity of their application and functionalization in live tissues, cells, and animals in biocompatibility. Recently,
both functionalized CDs and pristine CDs have been
assessed systematically for their cytotoxic effects, and
the results often disgruntled researchers. Yang et al.
(2009) prepared CDs by arc discharge of graphite rods
that afterward were outflowed with HNO3 for half a day.
Evidence of safe unmodified dose of CDs was found to
be only up to a level of 0.4 mg/mL. In another output, it
came out that CDs did not show any effective mark on
cell viability when a human kidney cell line was employed
for the evaluation of electrochemically prepared CDs.
A very improved soot-based method was employed
by Ray et al. (2009) for the preparation of CQDs with a
diameter of 26nm that had insufficient cytotoxicity at
desired concentrations of Fluoroluminescence bioimaging. The CDs were examined after being modified with
functional groups such as PAA (polyacrylic acid), BPEI
(branched poly ethylenimine), PEI, and Polyethylene
Glycol (PEG) (Yang et al. 2009; Wang et al. 2011b). The
PEG-modified CDs with all available sizes were found to
be safe and biocompatible at any concentration necessary for utilization in every sector including cell imaging.
In addition, the PEG1500N–modified CDs were tested
in mice in vivo and the result exhibited no substantial
harmful effect up to 28 days (Qi et al. 2009). Furthermore,
under relatively high concentrations, CDs functionalized
with
poly-propionylethyleneimine-co-ethyleneimine
(PPEI-EI) were significantly nontoxic toward cells. CDs
changed with Polyethyleneimine (PEI) were more hazardous than PPEI-EI-modified CDs leading to excessive ethylenimine (EI) units in the PEI. Moreover, when
administered at low doses, both pure PAA and PAAfunctionalized CDs proved toxic to cells, at only 50mg/
mL, as per the experiment result. Functional groups with
high cytotoxicity as Bi-Propionlylethyleimine (BPEI) can
be applied to functionalize CDs even in extreme cases
Al Ragib et al. Carbon Research
(2023) 2:37
like small concentrations or in a short incubation period,
which would be extremely dangerous.
Notwithstanding their photoactivity, it is unknown if
cytotoxic effects are valid for photo-induced degradation
or if the degradation of CDs happens when illuminated.
According to the findings of Yue-Yue et al. normal (HEK293) and malignant (HeLa and HepG2), human cells are
both hazardous to CDs treated with light that degrade
into molecules. They tested different concentrations (0,
10, 30, 100, and 300 mg carbon/L) of CDs that had been
irradiated with white fluorescent light (60 mol photons/
m2/s) for 0.5 (i0.5-CD), 1 (i1-CD), 4 (i4-CD), and 8 (i8CD) days on three different cell lines (HeLa, HepG2, and
HEK-293). Coincidently, CDs that had not been irradiated (N-CDs) came out to be viable the most. The cell
viability is seen to increase in HEK-293 cells as the concentration of CDs increased. When HeLa, HepG2, and
HEK-293 cells were subjected to the greatest concentration (300 mg carbon/L) of i8- CDs, their survivability
dropped to 91, 49, and 90%, respectively. It was assumed
that during the irradiation, cytotoxic photolyzed particles
may emit or that reactive oxygen species may be produced on CDs surface that leading to light-induced cytotoxicity of CDs (Liu et al. 2021).
3.4 Electrochemical luminescence (ECL)
A parameter that is normally used for the measurement purpose of fluorescence emission of semiconductor nanocrystals is Electrochemiluminescence (ECL)
(Qi et al. 2009). Coincidentally, the ECL behavior of
CDs and QDs (CdSe) is similar. The ECL procedure of
CDs is as follows: firstly, CDs can be produced in two
states, oxidized (R+) and reduced (R−). Secondly, after
the elimination of two oppositely charged carriers (R+
and R−) by electron transport, an energized state (R*) is
formed. Finally, through emitting a photon by a radiative pathway, the CDs in the R* condition (excited) have
returned to ground level. The R+ was found to be more
stable than R− owing to a lower cathodic ECL response
than the anodic one. Moreover, over time, ECL response
has acquired much stability and got employed in several
research fields. Strong ECL emission was recorded from
CDs produced by electrochemical oxidation of graphite,
during cyclic potential between + 1.8 and -1.5 V (Zheng
et al. 2009). Research reports unveil the potential use of
ECL emission in CDs. Surface states were termed to be
the core point of most ECL exhibited in semiconductor nanomaterials and subsequently found to be redshifted in comparison to the peak of photoluminescence.
Because ECL is mostly connected with nanoparticle surface state transitions, it is mostly used to study the surface traps that could be implemented in the comparison
of PL and ECL before or after the surface modification.
Page 15 of 30
3.5 Electrochemical performance and electrolytes used
for CDs
When it comes to the electrochemical application and
performance of CDs, a number of their good qualities can
be underlined, including electrical conductivity, a variety of electrochemically active sites, an extensive surface
area, compatibility with different materials, strong plasticity, and environmental durability (Hoang et al. 2019).
For instance, Niu et al. (2018) employed one of the CDs
as nano conductive agents called graphene quantum
dots (GQDs) instead of regular carbon black (CB) which
showed great potential for the creation of an efficient conductive network to increase the specific capacitances of
super capacitors. It is possible to build different shapes
of electrodes and reduce the transmission paths of ions
due to the nanoscale diameters of CDs. Different functional groups (hydroxyl, carboxyl, amine, etc.) on CDs
can provide greater capacities, allowing them to be used
with various electrode production techniques (inkjet
printing) (Zhang et al. 2019). Furthermore, by expediting intermolecular electroconductivity, these large functional groups can provide a significant number of sites for
surface modification to improve electrocatalytic activity
(Tian et al. 2021). Oxygen reduction reaction (ORR), alcohol oxidation reaction (AOR), oxygen evolution reaction
(OER), and hydrogen evolution reaction (HER) are some
examples of electrochemical processes in which CDs can
significantly improve electrocatalysis (Jana et al. 2020).
Table 2 compiles information obtained from a comprehensive body of literature on the electrochemical performance of CDs and their derivatives for supercapacitors.
4 Implementations
4.1 In drug delivery
According to many researchers, AuNPs are found to be
the most studied nanoparticles in drug delivery systems
(DDSs). However, owing to their less ideal biocompatibility and cytotoxicity, their pathological applications
are bounded. CDs on the other hand, having high aqueous degradability, praiseworthy biocompatibility, and
flexible modification properties in and out of cells, are
a superlative competitor in replacing AuNPs for drug
delivery purposes. Carbon nanodots have gained much
appreciation because of their capacity to serve as a foundation for attaching to several drugs and ligands. In cancer research, CDs are widely used for exposing receptors
in imaging and drug delivery for specific cells. CDs are
found to inhibit human insulin fibrillation because of
their non-toxic nature. It has been found that CDs can
resist HepG2 (a liver cancer), MCF-7, and MDA-MB-231
cancer cells (breast cancer) growth in several cases happening as a result of a large number of reactive oxygen
species (ROS) generated (Yang et al. 2016a).
Al Ragib et al. Carbon Research
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Table 2 Some information about the electrochemical performance of CDs and their derivatives for supercapacitors
Electrode materials
Specific capacitance
Rate capability
Graphene Quantum Dots (GQDs)
70 mF·cm−2 at 50 mV·s−1
−1
−1
Electrolyte
Voltage window (V)
References
50–500 mV·s−1
1 M H2SO4
0 to 0.8
(Tjandra et al. 2019)
1 M H2SO4
− 0.2 to 0.8
(Wang et al. 2017)
N-Carbon Quantum Dots (N-CQDs)/Polyaniline (PANI)
498 F·g at 1 A·g
498–348 F·g−1 at 1–10 A·g−1
Carbon Quantum Dots (CQDs)/Bi2O3
343 C·g−1 at 0.5 A·g−1
343–61 C·g−1 at 0.5–1.6 A·g−1
3 M KOH
0 to 0.8
(Prasath et al. 2019)
–
1 M LiPF6
− 2.5 to 2.5
(Alas et al. 2019)
−1
Mn/PANI/N-CDs
595 F·g
Carbon Nanotubes (CNT)/Bi2O3/GO/CDs
1.90 mAh·cm−2 at 1 mA·cm−2
1.57 mAh·cm−2 at 200 mA·cm−2
6 M KOH
− 1.05 to 0
(Wang et al. 2019a)
CDs/MoS2/ZnS
2899.5 F·g at 5–20 A·g
2899.5–1400 F·g−1 at 5–20 A·g−1
6 M KOH
0 to 0.5
(Zheng et al. 2019)
Graphene Nanoplatelets (GNP)/CDs/Polypyrrole (PPy)
173.8 mF·cm−2 at 0.1 mA·cm−2
–
H3PO4/PVA
0 to 0.8
(Lima and Oliveira
2020)
−1
−1
Page 16 of 30
Al Ragib et al. Carbon Research
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CDs-Dox (Doxorubicin) complexes functionally persuade apoptosis in adenocarcinoma cells of human lungs
as found by Yang et al. (2016b). Dox on the other hand
is normally taken for lymphomas, sarcomas, and leukemia. When they investigated the efficiency of both Dox
and CDs-Dox, the in vivo efficiency was found to be way
higher in the case of CDs-Dox. Further studies proved
the ideal drug release profile of CDs and Dox following the first-order release kinetics at slightly acidic pH.
Moreover, in normal cells, the toxic effect declined due
to receptor-mediated delivery (Wang et al. 2016b). Wang
and his colleagues found that the fluorescence of Dox
and CDs was put off in a conjugated form, which was put
back when they separated within the tumor cell. This can
be observed under a confocal microscope (Fig. 16), which
directs to the fact that the most dependable measure to
release the attached conjugate system is pH-dependent release. Paclitaxel and hyaluronan conjugated CDs
expectedly showed the tumor cell dispatching capability; the CDs in the study were imaged and progressed by
using near-infrared light, and subsequently, paclitaxel
was released in a pH-dependent manner.
CDs-Dox-transferrins conjugation is used to indicate
tumor cell death for pediatric patients compared to the
free drug alone along with bypassing the blood–brain
barrier. In addition, for bioimaging purposes transferrin
is quite remunerative owing to its natural capacity to shift
Page 17 of 30
iron, which results in a cleaner tumor outline in MRI
reports, aiding in surgical resection, particularly when
magnetic CDs are conjugated together (Łubgan et al.
2009). Folic Acid (FA) exposes higher potential in detecting cancerous cells while CDs are functionalized with FA
devolving endocytosis at a greater frequency compared
to ordinary cells. FA readily conjugates with carboxylrich CDs due to having amines attached to aromatic
rings along with several carboxyl groups. The mechanism
uses 1-ethyl-3-(-3-dimethyl aminopropyl) carbodiimide hydrochloride/(N-hydroxysuccinimide) (EDC/NHS)
chemistry. Hyaluron-conjugated CDs are often equally
functionalized for drug and gene carriers. The toxicity
in CDs is surprisingly decreased and characteristics are
maintained greatly by the conjugation.
Another research on gemcitabine (Gem) conjugated
CDs showed positive outcomes. Patients with mesotheliomas, pancreatic malignancies, cervical cancers, ovarian cancer, lung cancer, or other complicated situations
are usually administered (Gem). CDs impede the growth
of tumors as well as exhibit prevention of metastasis after
successfully being conjugated with Gem making a complete full-proof drug delivery vehicle (Yang et al. 2011).
Chung et al. (2020) created a carbon dots/hydroxyapatite (CD-HAP) nanoparticle as an acetaminophen drug
carrier (mild pain killer). CDs were made here using
the hydrothermal approach from a bio-waste precursor,
Fig. 16 Confocal microscopy demonstrates that Doxorubicin is released from CDs-Dox conjugate at 6 h post-treatment inside the cell, wherein,
the conjugate regains the fluorescent capacity; the scale bar is 20 µm (Wang et al. 2016b)
Al Ragib et al. Carbon Research
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sugarcane bagasse char. In recent years, scholars have
focused their attention on the combined application
of CDs and HAP. The HAP-decorated CDs (CD-HAP)
exhibit good biocompatibility and solubility, as well as
an enhanced luminous characteristic. Because of their
qualities such as controlled drug release, beneficial trackable drug release, and excellent targeting ability, they are
commonly used in the pharmaceutical industry as quality drug delivery vehicles (Chung et al. 2020). The surface
area of the sample mainly had a large impact on drug
loading capacity. The acetaminophen loading is easier
and has higher adsorption capacity when the surface
area is bigger. Hence, CD-HAP-40 implies the best loading performance as it has the highest surface area. The
loading of acetaminophen onto the CD-HAP happens
through physical surface adsorption (Fig S7).
Zheng et al. (2014) reported the production of CDOxaylation (CD-Oxa) by fabricating fluorescent CDs
with oxaliplatin, an anticancer drug where the carboxyl
groups of oxaliplatin derivatives combine together in a
condensation process along with amino molecules on the
CDs surface enhancing its effectiveness to cancer resistance. In the reducing environment (hepatic cancer cells),
the drug is released as demonstrated in the case of assynthesized CD-Oxa. Moreover, it is proved that CDs are
biocompatible with ordinary fibroblast cells; on the other
hand, CD-Oxa has issues with hepatic cancer cells for the
cytotoxic effect. For both in vivo and in vitro operations,
the research team utilized CD-Oxaylation as an imageguided delivery of drugs. They observed that CD-Oxa
injected intratumorally successfully killed tumor cells in
the hepatic tumor cell of xenograft tumor mice models
that assisted in diminishing tumor size without altering
the surrounding environment. Using data on the distribution of the CDs-Oxa by monitoring the FL signal of the
CDs, the proper dosage and timing of medicine can be
perfectly traced.
On consequent practice, Feng et al. (2016) fabricated
image-guided drug delivery centered on the precursor’s
molecules (citric acid and diethylenetriamine) using
cisplatin (IV) pro-drug-loaded charge convertible CDs
[CDs-Pt(IV)@PEG-(PAH/DMMA)]. Further functionalizing of CDs with PEG-poly-(allylamine) and polydimethyl maleic acid (PEG-(PAH/DMMA)) resulted in
the generation of charge convertible CDs. The demonstration in vitro signified the high therapeutic capability
of charge-adaptable nano-carriers in comparison with
normal physiological conditions. Their reports also suggested that for the xenograft mice model, intravenous
administration of the nanoformulations showed higher
tumor cell suppression capabilities with less systemic
toxicity.
Page 18 of 30
Thakur et al. (2014) reported CDs with antibiotics and
Gum Arabic (GA) as a prelude via a microwave-assisted
method, which was used as a theranostic agent for controlled drug release, enhanced antimicrobial activity, and
clear bioimaging. In their study, a wide-spectrum medication, ciprofloxacin hydrochloride was delivered to
patients via CDs (Cipro@CDs), a synthetic CD that was
affixed to the surface. In comparison to (1.2 mM) unconfined ciprofloxacin, Cipro@CDs showed good biocompatibility in that physiological conditions controlled the
ciprofloxacin released from CDs. This conjugation of
Cipro@CDs was also used to observe units of yeast live
with the fluorescent microscope as it showed much precious antimicrobial effect opposing both gram-positive
and gram-negative microorganisms.
Later, Liang et al. (2020) eventually came up with a pH
serial dual sensitive drug delivery system that was contrasted by three different nanoparticles, such as chitosan
(CS), CDs, and hyaluronic acid (HA). Finally, mesoporous
silica nanoparticles (MSNs) were prepared. The outcome of their experiment indicated that the doxorubicin
(DOX) (the model drug selected for their study) could
be discharged from MSNs when glutathione (GSH) and
pH are serially boosted. Low toxicity and high drug loading efficiency were found when the conjugation of MSNCS@HA-CDs NPs was utilized (up to 32.5%). This nano
platform proved fetal for the liver cancer cells along with
high target ability. This research successfully initiated the
era of a desirable anticancer drug delivery System.
4.2 Biosensors
CDs are a very promising candidate for biosensor agents
due to their high photostability, excitation-dependent
multicolor emission, good biocompatibility, good water
solubility, superior cell permeability, and finally flexible
surface modification capability. This property of CDs
could be utilized widely in the monitoring metals and
ions in biomedical sectors like the presence of iron, and
copper along with the detection of several nucleic acids
and their pH levels. Through π- π interactions of CDs as
fluorescent quenchers based on adsorption of the fluorescent single-stranded DNA (ssDNA) probe, nucleic
acid biosensing can contribute to biosensing science. A
target DNA can be detected by this mechanism. For that,
a double-strand DNA (dsDNA) is synthesized from the
hybridized ssDNA with its target. From the surface of
CDs, fluorescence is emitted with the desorption of replicated dsDNA which is the key factor for the sensing of
target DNA (Li et al. 2011d).
For sensing and imaging mitochondrial H2O2, a powerful and versatile Fluorescence resonance energy transfer (FRET) probe based on CDs was used. CDs served
Al Ragib et al. Carbon Research
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as both the carrier and source of energy for the detecting mechanism. The further experiment ended up in the
fabrication of a nanoprobe by a mitochondrion binding
site ligand triphenylphosphonium (TPP) and a pharmaceutical formulation intermediate structure and PFI, a
versatile H2O2 identifying segment, which was covalently
linked with the probe into CDs (Fig. 17). Then PFI moieties on CDs transformed space in presence of H2O2, a
FRET-based ratiometric probe for H2O2 was generated as
a nano-platform (Du et al. 2014).
Qian et al. (2014) discovered the use of hydroquinone
and SiCl4-derived CDs as Fe3+, H2O2, and melamine
sensors. Between Si-doped CDs and H2O2, the electron
transport mechanism immensely helped in the determination of H2O2. On the contrary, Fe3+ was determined
to undertake the operation of both electron and energy
transfer principles. Following melamine addiction, the
stabilization of adducts between H2O2 and melamine
regained the fluorescence and so served as a sensitive
detector for melamine. Dong et al. (2012) successfully
Page 19 of 30
demonstrated a novel system for the determination of
Cu2+ ion centered on CDs modified with BPEI or simply (BPEI@CDs). Surface amino groups of BPEI-CDs
would capture the Cu2+ ion from the complex, which
results in CD fluorescence quenching by the inner filter
effect. The intricate structure was found reliable, fast, and
of high selectivity for Cu2+ ion recognition as low as 6
nM of concentration, and eventually at an effective range
of 10 to 1100 nM. These CD-based new strategies made
pathologists not only rely on the use of QDs and organic
dyes. They are now capable of applying meteoric, to-thepoint, cheap, and eco-friendly strategies.
4.3 Bioimaging
The qualities of its aqueous solubility, superior photobleaching resistance, lower toxicity, and distinctive
luminescent nature make CDs a promising candidate for
bioimaging applications. Yang et al. (2018) managed to
synthesize F-doped CDs from the combination of sodium
fluoride, urea, and citric acid. They experimented with
Fig. 17 FRET-based ratio metric sensing of mitochondrial H2O2 in living cell by the nano-probe (Du et al. 2014)
Al Ragib et al. Carbon Research
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imaging in both in vivo and in vitro conditions. CDs fluoresced red when the cytoplasmic glioma C6 cell line was
stimulated at 530 nm. The group of researchers took a
nude mouse-bearing xenograft tumor for in vivo assessment and observed the 530 nm excitation and 600 nm
emission wavelengths for whole-body fluorescence. Due
to the EPR effect, the CDs were most likely to accumulate
within the tumor region.
Yang et al. (2009) manufactured PEGylated CDs for
in vivo imaging systems of various organs, such as
the liver, kidney, and bladder. Significant contrast was
observed in the image of PEGylated CDs, which were
subsequently injected into the mice model. A strong fluorescent image of the injected CDs was formed in vivo
that later concerning their biocompatibility, would offer
a wide application range in bioimaging and pathological
studies (Fig. S8).
The thermal degradation of ultrafine water-dispersible Gd(III)-doped CDs with a dual MRI/FL feature was
recently revealed by a group of scientists who made a
revolutionary change in bioimaging with MRI (Bourlinos
et al. 2012). When compared to commercial Gadovist,
the produced nanoconjugate showed brilliant fluorescence in the visible spectrum and T1-weighted MRI contrasted dramatically with negligible cytotoxicity. As a
result, the Gd-doped CDs could be used in biomedicine
for multifunctional image analysis. In addition, MRI and
Fluorescence modalities can be used in tandem to facilitate picture analysis.
Another investigation used the pyrolysis of complex
organic molecules as a starting substrate to make (Srivastava et al. 2012) iron oxide doped CDs (IO-CDs) in the
presence of microscopic Fe3O4 nanoparticles for MR/
FL multi-imaging. FL signals in spleen slide samples and
contrast-enhanced MRI images were observed using both
T1 and T2 mice models after intramuscular infusion of
IO@CDs. The nano-composite, on the other hand, was
biocompatible and showed no signs of cytotoxicity.
Qian et al. (2014) created 20% QY silicon-doped
CDs (SiCDs) and utilized them in imaging HeLa cells.
Excitation-dependent fluorescent behavior, superior
photobleaching resistance, and negligible cytotoxicity
towards HeLa cells were all exhibited in the SiCDs. The
cell proliferation was shown to be greater than 80% at
concentrations of up to 100 g/mL of SiCDs. The cytoplasmic portion of HeLa cells was tagged with SiCDs.
The segregated sp2 carbon clumps and defective phases
well within the crystallographic core were the sources of
CDs’ fluorescence. Due to the creation of a greater interface region and more discrete sp2 carbon clumps inside
the graphitic core, Si doping increased the fluorescence
nature of CDs. Jiang et al. (2016b) investigated the use of
Page 20 of 30
Si-doped CDs coupled with dopamine (Si-CDs@DA) for
imaging HeLa cells and assessing intracellular Ag+. Most
importantly, up to a concentration of 100 g/mL, Si-CDs@
DA was reported to be nontoxic to HeLa cells (Jiang et al.
2016b).
4.4 Analysis
Several suggestions have been offered, but scientists in
pathology investigations are still struggling to identify
the actual mechanism for CDs’ chemo-sensing of diverse
substances. It is promising that after the practice of modification of CDs for –CvO –OH, –COOH, –NH2, etc.
enriched surface CDs can build coordination complexes
with electron-deficient entities by donating their lone
pair of electrons.
Complexation is mainly responsible for the change in
color and aggregation. With the addition of Fe3+, colorless banana peel-derived N-doped CDs became yellow
which was described by Atchudan et al. (2020). They
proposed that due to the development of a complex
between surface constituents, such as –COOH, –OH, –
NH2, this color change is evident (Fig. 18). The complexation is proved by the Fourier transform infrared (FT-IR)
analysis that displays the shift of –COOH, –NH2, and –
OH bands towards higher wave numbers when reacted
with Fe3+ ion.
The movement of an electron from the LUMO (lowest
unoccupied molecular orbital) of CDs to the reagent is
frequently alluded to as electron transfer-oriented sensing/analysis by CDs (Omer et al. 2019). In addition to the
ferric ion solution, N-doped aminophenol-based CDs
in a colorless solution appeared purple. The attribution
of this color shift to the transfer of an electron from the
LUMO of CDs to the d-orbital of the Fe3+ ion (Fig. S9)
has been developed by electrochemical investigations
based on cyclic voltammetric measurements.
Oxidation–reduction processes are used in the colorimetric detection of numerous chemical and biological
entities. Zhao et al. (2015b), for example, described the
fading of the yellowish asparagine-based silver nanoparticles (AgNPs) topped CDs due to a redox reaction
amongst AgNPs and S2− in the aqueous phase premised
on UV/Vis. spectral and zeta potential measurements.
CDs serve as a stabilizer for reductants in this situation.
The reaction is given below:
4Ag+ + 2H2 O + 2S2− + → 2Ag2 S + 4OH−
CD scaped with metallic nanoparticles has also put
great emphasis on metal sensing. Studies indicated
colorimetric detection of thiocyanate ions using a
detection device comprised of hydrothermally generated CDs from histidine in PBS-buffer maintained
Al Ragib et al. Carbon Research
(2023) 2:37
Page 21 of 30
Fig. 18 Complexation between CDs and the metal ion
Au-nanoparticles since this probe demonstrated a blue
to pink optical change for SCN−. The amino group’s
nitrogen atom created a link for the attachment of
AuNPs to the CD membrane (AuNPs–CDs), and the
color shift was due to the interaction of S of SCN− with
this Au particle (Zhao et al. 2015b).
Ascorbic acid-based CDs have been implemented for
colorimetric pH determining of HCl-NaOH oriented system. As the pH range shifted from 3.5 to 10.2, a gradual
color change was noticed from grey to brown (Pedro et al.
2014). Further investigation led to the development of a
pH-measuring calorimetric probe founded on 1,2,4-triaminobenzene-derived CDs that showed a noticeable
visual effect from purple-red to orange, then yellow, for
pH 3 to 13. The progressive color change is caused by the
gradual ionization of the –OH and –COOH groups of
CDs to O- and COO- when the primary intensity of sensing media rises.
Paraxon (an Organophosphate—OP) has been noted
to range in hue from colorless to yellow, employing folic
acid-based calorimetric probe-derived CDs with DL of
0.4 µg mL−1 (1.45 nM) (Wang et al. 2018). On the other
hand, in Fructus Lycii-derived CDs tipped with silver NPs, a yellow to red visual shift for phoxim another
organophosphate (OP) is detected, with a limit of detection (LOD) value tenfold lower (0.04 M) than that of the
preceding one. The evident reason for this is that in acidic
media, phoxim containing cyano and ethoxy functionalities attain a positive charge; contrastingly, in the same
medium, moieties in CDs containing – OH, –COOH,
and –NH2 become negatively charged.
Another research showed the identification technique
of cymoxanil (a fungicide) colorimetrically by employing
a CDs-AgNPs system possessing a very small determination limit of 3nM (Jiang et al. 2019). A determination
process similar to that of phoxim was also observed
in this case. The aspiring positively charged group of
cymoxanil was –NH2 at optimum pH as AgNPs stabilized
with citrate ceaseing to be oppositely charged group. This
phenomenon finally resulted in two opposite-charged
moieties’ electrostatic interactions that were observed by
the redshift in absorption spectra.
4.5 Therapy
Recently CDs have been used in many therapeutic processes induced by photodynamic effect and because of
their biocompatibility, greater hydrophilicity, and controllable photoluminescence, hydrophobic photosensitizers can be delivered into cells.
Modified nanosurfaces conjugated with CDs such as
glycol-coated CD/MnO2 nanocomposites were fabricated
by Chen et al. (2018) in 2018 in the tumor microenvironment (TME) for pH/H2O2-responsive PDT (photodynamic therapy) effect where the Hypoxia, Acidosis, and
H2O2 levels were increased. In an acidic H2O2 (pH 6.5)
solution, MnO2 catalyzes the breakdown of H2O2 into O2
resulting in the formation of O2 under hypoxia upon light
radiation that finally ends up demonstrating a fine PDT
efficiency in comparison to the neutral condition. Hela
cell lines and 4-T1 tumor-carrying mice likewise showed
a low pH-dependent PDT effect and excellent output was
guaranteed only due to the reason of this nanocomposite
polyethylene glycol (PEG)-coated CD/MnO2.
Previous study created NIR-triggered photodynamic
and photothermal therapy in association with chemotherapy (DOX loaded) using magneto-fluorescent
Al Ragib et al. Carbon Research
(2023) 2:37
carbon dots coupled with folic acid and riboflavin (GPRf-FA-FeN@CDs) (Zhang et al. 2017). In this study, the
PDT performance of the nanoformulations was noticeably increased solely due to the photosensitivity of CDs
triggered by the conjugation of riboflavin. An excellent
exhibition of NIR light absorption by GP-Rf-FA-FeN@
CDs-DOX is a notable part of the study run by Zhang
and his coworkers. Moreover, due to the photothermal
heating ability, GP-Rf-FA-FeN@CQDs-DOX was utilized for NIR-responsive drug (DOX) release. The latest
synergistic chemo phototherapeutic effects of GP-RfFA-FeN@CDs-DOX resulted in a safe trouble-free drug
delivery system for cancer treatment.
Synthesis of CDs-Ce6-HA, hyaluronic acid-modified
CDs conjugated with chlorine- Ce6 (Ce6, a photosensitizer) increased the chance of suppressing melanoma cells
in tumor mice. In this study, Beack and his colleagues targeted this therapy for skin cancer treatment (Beack et al.
2015). It is noticed that Ce6 in conjugation with CDs
increased the photodynamic reaction of Ce6 resulting
in more singlet oxygen-free Ce6. Under laser irradiation,
transdermal application of CDs-Ce6-HA managed to
suppress B16F10 melanoma cells effectively in vivo. Yang
et al. (2016a) then managed to produce Mg/N doped CDs
to use as a carrier of Ce6, which increased the PDT effect,
subsequently followed by a high FRET efficiency. However, the study showed the production of singlet oxygen
twice for the case of Mg/N doped CDs allowing for a significant enhancement in the PDT effect in HepG2 cells
compared to pure Ce6.
Zhang et al. (2020) prepared a new nanomaterial
combining PDT/starving therapy/photothermal therapy (PTT) and checkpoint-blockade immunotherapy
to enhance tumor treatment. They formed unique
immune-adjuvant nano-agents (γ-PGA@GOx@Mn, CuCDs) by integrating the gamma-glutamyl transferase
(GGT) enzyme-induced cellular uptake polymer-poly
(γ-glutamic acid) (γ-PGA), self-supplied oxygenator nanodots and finally a glucose-metabolic reaction agent—
glucose oxidase (GOx), Mn along with CDs doped with
Cu as a photosensitizer. γ-PGA@GOx@Mn, Cu-CDs
nanoparticles (NPs) are likely to target the cancer cell
after completing the long-term retention period at the
tumor acidic microenvironment. Under laser irradiation,
this NP exhibited both photothermal and photodynamic
effects. Interestingly enough, the harmful by-product
hydrogen peroxide (H2O2) from the nanoreactors would
deliberately perish tumor hypoxia following the increase
of in vivo PDT. The treatment efficiency was significantly
enhanced by combining the NPs-based starving-like
therapy/PDT/PTT and check-point-blockade therapy.
Gadolinium (Gd) has long been utilized as a contrast
agent and radio-sensitization enhancer in MRI. The Gd
Page 22 of 30
ions released by complexes build up in the body and are
unable to be digested. By blocking calcium channels, Gd
ions can induce significant biological damage, including
nephrogenic system fibrosis in patients with renal failure. A group of researchers generated Gd-doped CDs
employing simple hydrothermal carbonization of gadopentetic acid (Gd-DTPA) as the gadolinium source and
glycine as the interfacial agent. Gd-doped CDs could
reduce Gd leakage even under extreme biological circumstances due to the nontoxicity of carbon cages. These
multipurpose theranostic nanostructures with effective
metabolic pathways in vivo and better longitudinal relaxation efficiency have a huge potential as MRI contrast
agents. More crucially, Gd-doped CDs operate as radiosensitivity boosters, revealing a novel way to overcome
solid tumor radiation (Du et al. 2017).
4.6 As electrodes/supercapacitors
Because of distinct electrical characteristics and their
vital role in hosting various functional groups on the surface, CDs, one class of CQDs, have drawn more interest
in the field of energy storage. Recently, CDs have gained
popularity either functionalization by additive or derivative material in electrode materials, enhancing the energy
density of supercapacitors. Researchers from all over the
world are trying to show a great potential of CDs as an
application in electrochemical supercapacitors (Xiao
et al. 2021). For example, Chen et al. (2016) successfully
applied C60 powder as a precursor to producing CDs
which is a amorphous microstructure (size < 10 nm),
and UV–Vis–NIR indicated that the two picks (~ 260
nm, ~ 206 nm) demonstrated the n-π* transition (C = O)
and π-π* evolution (aromatic C = C) respectively to validate the perfect preparation of CDs whereas the photoluminescence (PL) emission effect justifies this formation.
His research groups found a result of a voltage limit
from 0–0.9 V by using cyclic voltammetry (CV) curves
at different scan rates. At current densities of 5 A/g and
8 A/g, they were successful in producing specific capacitances of 106 F/g and 84.4 F/g, respectively (Chen et al.
2016). To create composite materials, Yu et al. (2021)
uniformly deposited CDs over activated carbons derived
from lignin, revealing an internal surface embellished
with CD binding sites. After the introduction and increment of CDs, it was interestingly observed that the times
of the charging and discharging gradually increased, and
the high capacitance of the CDs@AC-11 electrode, which
was double that of the AC electrode (125.8 F/g), could be
achieved at 0.15 A/g (Yu et al. 2021).
4.7 Plants and agriculture
Among different applications, one of the most significant
at present time is CDs application in the field of plants
Al Ragib et al. Carbon Research
(2023) 2:37
and agriculture because of its outstanding properties
such as higher biocompatibility, and lower concentration of environmental toxicity. CDs treatments or CDs
performance, in case of the physiological process of
plants and increment of agricultural production, plays a
significant role in food production. Enhancement of plant
growth, photosynthesis, bio functional contribution on
nitrogen fixation, nano-fertilizer, delivering SiRNA in
the model plant, in situ imaging (bioimaging), biotic or
abiotic stress resistance, disease resistance etc. are recent
discoveries by researchers for sustainable developments
of agro system for minimizing nutrition (Li et al. 2018b,
2019; Chandra et al. 2014; Das et al. 2014b). For instance,
Kou et al. (2021) for the first time explained clearly how
yield, nutrition capability, and quality are correlated
to CDs. In his study, a hydrothermal process was used
to produce CDs in which L-cysteine and glucose were
combined with CDs to apply lettuces and tomatoes in a
hydroponic solution consisting of all necessary nutrients
liquids to examine the mechanism and its development
(biofunctional effects) of plants. They got an excellent
result in terms of seed germination rate, development
of seedlings, and enhancement of plant maturity. In this
assessment, actually, CDs improved the activity of photosynthesis as well as boosted the absorbance of macro or
micro minerals which ultimately could increase the rate
of germination, elongate (hypocotyl) the seedling and
root enhancement, and as a result, yield and mature plant
development in case of nutritional qualities appeared.
Table 3 summarizes the information obtained from comprehensive reports on plant systems in which CDs play
a key role as a plant growth enhancer. CDs also proved
their potential as a nano fertilizer in the case of sustainable agricultural production. For example, to produce CDs
(nitrogen 20%) based nanofertilizer, Wang et al. (2019b)
used thiourea and citric acid as precursors followed by a
solid-state method. They used mung beans as plant species to investigate the effects of CDs. They found that
relying on the higher content of Nitrogen with CDs was
more efficient than those of urea which showed strong
potential as a nano fertilizer (luminescent). One of the
most significant results came out when mung bean seeds
were cultivated in 0.2 mg/mL aqueous solution of the
CDs as opposed to the control that used pure water; they
produced 17.45% more bean sprouts.
5 Overview of noteworthy key information
of materials used for CD synthesis and surface
modification
Nowadays researchers are trying surface modifications
of CDs for different application purposes. In this review,
we mainly focused on the covalently assisted mechanism,
interaction reaction techniques, chemical complexation,
Page 23 of 30
and sol–gel mechanism. Amide coupling mechanism,
silylation, and esterification sulfonylation copolymerization which are classified as covalent modification systems, are well-established modification techniques for
researchers of CD surface modification to apply different
applications. The hydrothermal route, pyrolysis, chemical
oxidation technique, microwave method or microwaveassisted hydrothermal process, and electrochemical are
the most popular protocols to synthesize CDs. Table 4
summarizes the information of materials types treated
as well as their synthesis of CDs which are sorted from
different literature reports based on interaction reaction
routes. These reaction mechanisms play a significant
role in surface modification, which greatly influences the
application.
Actually, in the overall discussion in the case of CD
surface modifications and synthesis, we mostly focused
on the organic nature of these materials. In the overall
discussion, the synthesis procedure of CDs with different
functional groups significantly affects its morphology like
a uniform, monodisperse, amorphous, spheroidal, sometimes quasi-spherical, semi-crystalline in which the size
ranges from 1.5 nm to 450 nm were reported in different articles. sp2 or sp3 hybridized mechanism is normally
established in CDs nucleation when different functional
groups like carboxylic acid (–COOH), an amino group
(-NH2), epoxy/ether (–O–), hydroxyl (–OH), carbonyl
group (–CO–), etc. are attached in the surface of CDs
(D’Angelis do E. S. Barbosa et al. 2015; Sun et al. 2017;
Liu et al. 2014).
6 Research gaps and future work scope
Though CDs are independently used in several large-scale
facilities nowadays, the competency of CDs modified
surfaces is imperialized most often, and the potentiality is huge to be addressed now. The pleasant photosensitive CDs made their place as one of the very exciting
nanoparticles for emergent chemical, biomedical, and
biochemical fields with the maturity of controlling bioimage, chemical sensors, drug delivery, and potentiality and
displaying far beyond the regular outputs. This paper is
mainly organized with the main modification processes
of CDs with other nanoparticles and their surfaces for
various functionalities that dramatically influence the
activities of biomedical, chemical, and technology fields.
Basically, the PL and FL characteristics of CDs are well
addressed as prudent and sky-touching research gigs for
researchers all around the globe. In the future, the potential use of CDs is assumed to make a mesmerizing change
in humanity due to their vast use as a life savior. The use
of CDs is not very rare even today, considering their
properties of resistance in adverse conditions, precise
biomonitors, promising semiconductors, etc., however,
Al Ragib et al. Carbon Research
Precursor of CDs
Synthesis
technique
Plant species
Size (nm) &
fluorescence
Concentrations of
CDs
Exposure time
Application
Effect
References
Carbon soot (mustard
oil lamp)
Chemical
Wheat
20–100
150
10 days
Seed grown (germina- Increment of plant growth
tion) in liquid CDs
under light and dark condi(aqueous)
tions
(Tripathi
and Sarkar 2015)
Graphite rods
Electrochemical
etching
Rice seedling
5 & blue
0.56 mg/mL
6, 90, 120 days
Seed pretreatment
Promotion of seed germination, root increment
and length of seedling,
enhancement of disease
resistance, and crop production
(Li et al. 2018b)
Citric acid and cysteine
Hydrothermal
Mung bean
4–8 & blue
L-CDs 500 μg/mL
5 days
and D-CDs 100 μg/mL
Seed pretreatment
D-CDs are better than L-CDs
in case of plant growth
(Zhang et al.
2018)
Reduced glutathione
Microwave
N. benthamiana
3–8 nm & near- NIR-CDs 0.05 mg/mL
infrared
5 days
Foliar spray
Increase size of leaf, light
(UV) harvesting, and photosynthesis enhancement
(Wang et al.
2021)
Empty fruit bunch
biochar
Microwave
Rice and corn
1–4 nm & blue
150 mg/mL
1 day
Foliar spray
CO2 assimilation increment
and rice yield are compared
to corn
(Tan et al. 2021)
Microalgae spirulina
Thermal pyrolysis
Lentil seeds
10 nm & blue
0.1–0.5 mg/mL
6 days
Seed pretreatment
Increased lentil seedling
growth
(Agnol et al.
2021)
Rapeseed pollen
Hydrothermal
Rome lettuce
5.2 nm & blue
10–30 mg/L
25 days
Hydroponic solution
treatment
Enlarged and increased
leaf area and nutritional
absorption
(Zheng et al.
2017)
(2023) 2:37
Table 3 Overall information about the effects of CDs on plant growth system
Page 24 of 30
Reaction mechanism
Others
Carbon source/
precursor
Modifier
Quantum yield Modified CDs
surface
Application
References
Amide coupling
Hydrothermal
Fluorescent CDs
Glucose
Ethylenediamine
3.0%
CDs–antibody
Bioimaging
(Dong et al. 2015)
Silylation
Hydrothermal
Fluorescent CQDs AEAPMS
Rhodamine B,
ethylenediamine,
methoxysilane
groups
–
Dye-doped CDs–
silica nanoparticles
Fluorescence
nanosensor
(Liu et al. 2014)
Esterification
Solid-state synthesis
Fluorescent CQDs Ammonium
citrate
Mannose and folic 9%
acid
Man–CQDs,
Fa–CQDs
Targeted therapies, selective
labeling of bacteria
(Lai et al. 2016)
Sulfonylation
Hydrothermal
Fluorescence
Citric acid
and ethylenediamine
Phenolic group
–
CDs@βcyclodextrin
Nanoprobe
(Lin et al. 2018)
for detecting
catechol (CC)
and hydroquinone (HQ) at trace
levels in water
samples
Fluorescent CDs
α-cyclodextrin
Hyperbranched
polyglycerol
1.2%
CDs-OH
Bio-imaging,
biosensors
12.4%
Si-CDs@DA
Biosensor and cell (Jiang et al. 2016a)
imaging
Copolymerization Hydrothermal
treatment
Interaction reaction route
Types or nature
(Li et al. 2017b)
π interaction
Rapid microwave- Carbon nanomaassisted irradiation terials
Glycerol,
(3-aminopropyl)
triethoxysilane
(APTES)
Dopamine
Electrostatic
interaction
Green synthesis
(hydrothermal)
CDs-nanocomposite
Fresh and clean
carrot
Polyethyleneimine –
(PEI) and Nile Blue
(NB) chloride
CDs/PEI/NB
Up-conversion
fluorescence
sensing
(Jin et al. 2017)
Chemical complexation
Modified hydrothermal route
Fluorescent CDs
Ethylenediaminetetraacetic (EDTA)
Carboxyl
–
and amino groups
CDs-Tb
Biomarker
(Chen et al. 2015)
Sol–gel
Pyrolysis and condensation
Photoluminescent Citric acid
CDs
Methoxysilyl
groups
CDs-silica
Medical diagnostics, catalysis,
photovoltaics,
optical-gain
(Wang et al.
2011a)
47%
(2023) 2:37
Covalent
modification
CDs synthesis
method
Al Ragib et al. Carbon Research
Table 4 Overall information about the precursor of CDs, types, synthesis route, QY, and applications
Page 25 of 30
Al Ragib et al. Carbon Research
(2023) 2:37
this is not the end of this era. Modified surfaces with
CDs are those significant nano-surfaces that will allow
another innovative era of medical science, chemical/
mechanical industry, focusing on extremely economic,
facile and effective in nature.
Although a lot of achievements have been made with
CDs modified surfaces, the modified surfaces with CDs
have yet been explored for drug delivery purposes. Silver nanoparticles are replaced with CDs and modified
surfaces with CDs, and they are found heavily effective
in insulin fibrillation; resistance to breast cancer and
a specific type of liver cancer, however, they are not yet
employed for noble purposes. Deep research in vivo and
in vitro is essential for extending its maturity in medical
science (Hoang et al. 2019). Though phosphorodiamidate morpholino oligomers (PMO)-CDs can potentially
be used as an active tool to diagnose early breast cancer
with the help of FET (Field Effect Transistor Biosensor)
looking at the presence of miRNA in plasma samples, the
data of sensitivity is only counted for 1 μM to 100 μM.
The detection sensitivity could be improved by nanoparticle-based DNA probes. Thus, that cannot be taken into
consideration for a foolproof procedure to enhance the
best output. Further research methods are needed to be
applied to image the presence of these highly proliferating carcinogens (Li et al. 2022).
7 Conclusions
A plethora of modification methods of CDs is
described in the whole article along with the characteristic properties of these processes and applications followed by the properties of the modified conjugates in
the whole article. Modifications are carried out in several methods. However, the amide coupling reaction
is the most significant, as it contributes to the amide
structure’s stability, and CDs’ surfaces are rich in carboxyl and amino molecules. The silylation procedure
surrounds CDs and another fluorophore in a silicon coating, which can develop CDs’ water solubility and selectivity, and considerably lower their cytotoxicity, making
it useful in organisms. Eventually from the studies, it is
clear that the esterification, sulfonylation, and copolymerization reaction, and sol–gel methods are such reaction
processes that are difficult to carry out. All of these strategies boosted the optical performance of CDs by utilizing the physicochemical properties of target molecules
on the surface of the CDs that, in addition, revealed a
viable link between nanoparticles and biological systems.
Regarding properties like cytotoxicity, photostability, and
biocompatibility, the CDs-based nanomaterial-modified
surfaces exhibited excellent in vivo and in vitro performance. CDs are the best additive for cancer and tumor
drugs and therapeutic methods for their versatile nature.
Page 26 of 30
Modification of CDs may potentially lead to their usage
in a range of biosensing and nanomaterial science sectors. Now it is high time to shift carbon dots modification
and preparation to the industrial level. This will, however,
broaden the way of agents based on CD for biomedicine
that show high-quality sensing, analysis, therapeutic
methods, and drug delivery techniques than the currently
used agents. Undoubtedly, CDs retain some promising
therapeutic applications that will play a significant role in
the biomedical sector very soon.
Abbreviations
CDs
CQDs
QY
PL
EDC/NHS
EDA
TYR
β-CD
MRSA
FAM
FRET
AuNPs
PAMAM
HAP
FHAP
PEA
CdTe
TEOS
APTES
AEAPMS
CC
HQ
SEC
HPG
DTCS
Si-CDs
NB
PEI
TPF
E2
CCDs
ER
EDTA
DPA
MRI
DTPA
AEAPMS
MIP
DA
FL
PVP
CCTs
UCPL
PPEI-EI
PEI
EI
BPEI
ECL
CB
ORR
AOR
OER
Carbon Dots
Carbon Quantum Dots
Quantum Yield
Photoluminescence
N-ethyl-N-(3-(dimethylamino)propyl)carbodiimide/Nhydroxysuccinimide, or 1-ethyl-3-(-3-dimethyl aminopropyl) carbodiimide hydrochloride/(N-hydroxysuccinimide)
Ethylenediamine
Tyrosinase
Cyclodextrin
Methicillin-resistant Staphylococcus Aureus
Fluorescein amidites
Förster resonance energy transfer
Gold nanoparticles
Poly-amidoamine dendrimer
Hydroxyapatite
F-substituted hydroxyapatite
Phosphoethanolamine
Cadmium telluride
Tetraethyl orthosilicate
3-Aminopropyl triethoxysilane
N-(β-aminoethyl)-γ aminopropyl methyl-dimethoxy silane
Catechol
Hydroquinone
Selenocysteine
Hyperbranched polyglycerol
N-(dithicarbaxy) sarcosine
Si-doped CDs
Nile Blue
Polyethyleneimine
Two-photon fluorescence
Estradiol hemisuccinate
Cationic Carbon Dots
Estrogen receptor
Ethylenediaminetetraacetic acid
Dipicolinic acid
Magnetic resonance imaging
Diethylenetriamine pentaacetate
N-(b-aminoethyl)-c-aminopropyl methyl dimethoxy silane
Molecularly imprinted polymer
Dopamine
Fluoroluminescence
Polyvinyl pyrrolidone
Correlated color temperatures
Up-conversion photoluminescence
Poly-propionylethyleneimine-co-ethyleneimine
Polyethyleneimine
Ethylenimine
Bi-Propionlylethyleimine
Electrochemical luminescence/Electrochemiluminescence
Carbon black
Oxygen reduction reaction
Alcohol oxidation reaction
Oxygen evolution reaction
Al Ragib et al. Carbon Research
HER
DDSs
ROS
FA
Gem
CD-HAP
CD-Oxa
PEG-(PAH/DMMA)
GA
CS
HA
MSNs
DOX
GSH
ssDNA
dsDNA
FRET
TPP
IO-CDs
SiCDs
FT-IR
LUMO
AgNPs
LOD
TME
PDT
PTT
GGT
Gox
NPs
H2O2
Gd
CV
PMO
FET
(2023) 2:37
Hydrogen evolution reaction
Drug Delivery Systems
Reactive Oxygen Species
Folic acid
Gemcitabine
Carbon dots/hydroxyapatite
CD-Oxaylation
PEG-poly-(allylamine) and poly-dimethyl maleic acid
Gum Arabic
Chitosan
Hyaluronic acid
Mesoporous Silica Nanoparticles
Doxorubicin
Glutathione
Single-stranded DNA
Double-strand DNA
Fluorescence resonance energy transfer
Triphenylphosphonium
Iron oxide doped CDs
Silicon-doped CDs
Fourier transform infrared
Lowest unoccupied molecular orbital
Silver nanoparticles
Limit of detection
Tumor microenvironment
Photodynamic therapy
Photothermal therapy
Gamma-glutamyl transferase
Glucose oxidase
Nanoparticles
Hydrogen peroxide
Gadolinium
Cyclic voltammetry
Phosphorodiamidate morpholino oligomers
Field Effect Transistor Biosensor
Supplementary Information
The online version contains supplementary material available at https://doi.
org/10.1007/s44246-023-00069-x.
Additional file 1: Fig. S1. Schematic representation of modification
route of CDs via amide coupling reaction to detect S. aureus (Zhong
et al. 2015). Fig. S2. CDs modification method via silylation reaction and
detection of Cu2+ (Rao et al. 2016). Fig. S3. Modification process of CDs
via sulfonylation reaction (Wang et al. 2015). Fig. S4. Complexation modification of CDs and determination process of DPA (Chen et al. 2015). Fig.
S5. (a) Diagram illustration of UV/Vis. absorption and PL emission spectra
in the inset, the emission spectral intensities are normalized. (b) Optical
photograph attained under excitation at 365 nm. Fig. S6. Luminescence
images (all scale bars 20 nm) of the CQDs with (a) argon ion laser excitation at 458 nm and (b) femtosecond pulsed laser excitation at 800 nm; (c)
is an overlap of (a) and (b). Fig. S7. Preparation of CDs from biodegradable
wastes, conjugation of CD-HAP nanocomposite, and behavior in drug
delivery system. Fig. S8 Intravenous injection of CDs: (a) bright field, (b)
as-detected fluorescence (bladder; urine), and (c) color-coded images. The
same order is used for the images of the dissected kidneys (a’–c’) and liver
(a”–c”) (Sun et al. 2009). Fig. S9. Electron transfer from CDs to the analyte
(Omer et al. 2019).
Acknowledgements
The authors would like to acknowledge the Researcher’s Supporting Project
Number (RSP2023R511), King Saud University, Riyadh, Kingdom of Saudi Arabia.
Authors’ contributions
Abdullah Al Ragib and Ahmed Al Amin: Conceptualization, Data collection,
Writing- original draft, Writing- review & editing. Yousef Mohammed Alanazi:
Fund acquisition, Supervision, Writing- review & editing. Tapos Kormoker:
Investigation, Writing-review & editing. Minhaz Uddin: Data checking and
Page 27 of 30
validation, Writing- review & editing. Md. Abu Bakar Siddique: Writing—
reviewing and editing, Software, Visualization, Supervision. Hasi Rani Barai:
Writing—reviewing and editing. All authors read and approved the final
manuscript.
Funding
No funding was received for conducting this study.
Availability of data and materials
Not applicable.
Declarations
Competing interests
The authors state that they have no conflict of interest that may have influenced the findings described in this review study.
Author details
1
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China. 2 Chemical Engineering Department, College of Engineering,
King Saud University, P.O. Box 800, Riyadh 11421, Kingdom of Saudi Arabia.
3
Department of Science and Environmental Studies, The Education University
of Hong Kong, Tai Po, New Territories, Hong Kong. 4 Institute of National
Analytical Research and Service (INARS), Bangladesh Council of Scientific
and Industrial Research (BCSIR), Dhanmondi, Dhaka 1205, Bangladesh.
5
Department of Mechanical Engineering, School of Mechanical and IT Engineering, Yeungnam University, Gyeongsan 38541, Korea.
Received: 28 March 2023 Revised: 28 August 2023 Accepted: 12 September 2023
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