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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5658_Библиотеки_им_академика_М_И_Перельмана
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188 Sonali Loya and Swati Chandravanshi
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Mahdie Matin, Mahtab Mirhoseinian, Alireza Alikhanian,
https://t.me/medicina_free
Golnar Bayatani, Mohammad Nazari Montazer, Mohammad Mahdavi,
Burak Tüzün
✶
and Parham Taslimi
Chapter 9
Carbon dots in photodynamic therapy
Abstract: Carbon dots (CDs) as a subclass of carbon-based nanoparticles were first dis-
covered in 2004 and attracted the attention of scientists worldwide to their extinguish
physiochemical properties; nowadays CDs have a broad range of applications including bioimaging, photocatalysis, fluorescent ink, sensors, lasers, and LED. In this chapter we will have a look into the synthesis, structure, and applications of CDs on
biomedical science such as bioimaging, biosensors, drug and gene delivery, and photodynamic therapy. Photodynamic therapy is the method to transfer light energy to
its surrounding using photosensitizer structure trials, which showed meaningful response to this approach in many types of malignancies, CDs could be a suitable option
to use as photosensitizers.
Keywords: Carbon dots, Photodynamic therapy, Cancer, Nanoparticles, Biomedical
sciences
9.1 Introduction
Carbon dots (CDs) are a subclass of carbon-based nanoparticles that were first discovered from arc-discharge soot during the purification of single-wall nanotubes in 2004.
CDs immediately attracted significant at tention due to their no ntoxic (or l ess toxic),
water-soluble, highly fluorescent, photoluminescent properties [1–3]. Carbon-based
materials have unique optical properties, including acceptable biocompatibility and
low toxicity. Carbon nanotube, fullerene, and CDs are the most famous carbon-based
materials [35]. In this chapter, we focus on CDs and explain some researches that
✶
Corresponding author: Burak Tüzün, Plant and Animal Production Department, Technical Sciences
Vocational School of Sivas, Sivas Cumhuriyet University, Sivas, Turkey,
e-mail: theburaktuzun@yahoo.com, http://orcid.org/0000-0002-0420-2043
Mahdie Matin, Mahtab Mirhoseinian, Alireza Alikhanian, Golnar Bayatani,
Mohammad Nazari Montazer, Mohammad Mahdavi, Endocrinology and Metabolism Research
Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences,
Tehran, Iran
Parham Taslimi, Department of Biotechnology, Faculty of Science, Bartin University, 74100 Bartin,
Turkey
https://doi.org/10.1515/9783110799958-009
190 Mahdie Matin et al.
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have been reported in the past years. The therapeutic method with CDs and other carbon-based materials is hel pful in the canc er therapy as treatments for skin cancer,
bladder cancer [36], lung cancer [37], and other diseases like covid_19 [38] and atherosclerosis [37]. As mentioned, CDs can produce reactive oxygen species (ROS) which is
an essential factor in photodynamic therapy. CDs have little use in photobleaching,
1
unlike fluorescent intensity which is more practical. The CDs have excellent
O2quantum yield, dazzling fluorescence, minimal toxicity, and good dispersity. The longer the
irradiation time, the greater the concentration-dependen t cytotoxicity of CDs. There
are drawbacks employing CDs in photodynamic treatment, including limited exclusivity and a short-effective lifespan for ROS synthesis.
9.1.1 Structure and application of carbon dot
9.1.1.1 Structure
Their size is reported to be less than 10 nm, mainly in the range of 2 to 8 nm, which
facilitates their use in biological applications. However, the size value of CDs can be
adjusted by different nanocomposites; for example, the diameter of CDs coated by hydroxyl groups was reported to be 3.1 ± 0.5 nm [2, 3].
CDs consist of clusters of carbon (53.93%) with various other atoms such as nitrogen (1.30%), oxygen (40.33%), hydrogen (2.56%), and some doped elements such as sulphur and phosphorus [3, 5]. The position of heteroatom doping has been studied in
CDs, not just for the surface structure but also hypothesized in the core. Some organic
functioning groups are also believed to be in the core, such as carbonyls or different
kinds of nitrogen-containing groups [1].
Nuclear magnetic resonance (NMR) measures showed that carbon atoms in C-dots
were an amorphous core of pure sp
carbon atoms, implying that C-dots are conjugated systems [1, 5].
Most CDs are hydrophilic with good solubility because the oxygen-containing
functioning groups emanated from precursors or are produced during synthesis. Nevertheless, hydrophobic CDs have been prepared through partially carbonizing hydrophobic precursors and surface modification by hydrophobic molecules. Lately, it has
been shown that hydrophilic CDs can be made hydrophobic following the covalent
attachment of dodecyl amine, as revealed by the spontaneous transferring of CDs
from water into a toluene phase [2].
Due to the diverse structure of CDs and their varied cores, we cannot assign a single structure to them, and each CD has a different structure, so here we discuss the
structure of some of the CDs on which research has been completed. A quasi-spherical
morphology defines CDs. A pure carbon core for CDs would be obtained from different
structures may be either a collection of 2D structures (e.g., graphitic) or a structure with
3D bonding (e.g., diamond-like) or an amorphous structure [1–3]. Furthermore, based
3
carbon or sp2hybridized with unsatu rated sp
3
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on what groups are used as CD starting materials, it is possible to have different morphologies, for example:
– If a banana is the starting material, CDs will have a mean size of 3 nm; are spheri-
cal-shape; and include carbon, oxygen, and potassium. Also, they contain sp
bon groups and hydroxyl connected carbon, which made the interlayer spacing
ofCDstobe0.42nm,whichishigherthan the interlayer spacing of graphite
(0.33); thus, these CDs are crystalline in nature.
– If food caramels and orange peel wastes are the starting material, CDs will be
amorphous and has no crystalline nature as the XRD displayed a broad amorphous peak.
– If graphite is the starting material, CDs will have a diamond-like structure.
– If the CDs derive from multiwalled carbon nanotubes by electrochemical oxida-
tion, will show graphitic nature [3].
The CDs have well-defined chemical structures and surface morphology, additionally
chiral performances. These properties are mainly responsible for the various chemical and physical properties.
The three substantial and beneficial CDs in biomedical applications are Y-CD (yellow
CDs), B-CD (black CDs), and CND (carbon nitride dots). For this reason, we also review their
structural properties. CND and Y-CD are very closeinsizebuthavedifferentopticalproperties, which lead to different structural models. Based on the results of AFM (Atom force
microscope) and TEM (Transmission microscope), it seem that these three CDs have a
spherical shape li ke the rest of the CDs, and the results of Raman spectroscopy, ESR
(Erythrocyte sedimentation rate), and XRD (X-Ray diffraction analysis) suggested an
amorphous structure for B-CD an d CND and a crystalline structure for Y-CD [1].
3
car-
9.1.2 Application
C-dots have various applications in broad fields like bioimaging, photocatalysis, fluorescent ink, sensors, lasers, and LED, due to their advantages such as low cost, ease in
preparation, fluorescence with photobleaching, and biocompatibility [5, 8]. Here we
discuss their biological applications.
9.1.2.1 Bioimaging
Bioimaging refers to capturing images of biological material by treating it with a fluorescent molecule. The use of quantum dots (QDs) such as CdSe in optical imaging and
particular sensing of toxic metals in vivo and in vitro conditions has been reported,
but it is a less explored area of optical sensing, and they have imposed severe health
and environmental risks. Highl y fluorescent CDs that are sy nthesized from natural
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sources wi th good pr operties such as solubility, high chemical, physical and o ptical
stability, low toxicity, and the presence of many hydrophilic surface functional groups
can overcome the limitations of organic dyes and other synthetic fluorophores; They
can serve as a biocompatible alternativ e to QDs in bioimaging applications (both in
vitro and in vivo) [4] [5, 9].
9.1.2.1.1 In vitro imaging
C-dots have been used for taking fluorescence images of mammalian cells, plant cells,
and microorganisms, and for long-term cell tracking due to their fluorescent properties and excellent optical stability [8].
Ya-Ping Sun et al. imaged Escherichia coli ATCC 25 922 cells incubated with
PEG1500N-passivated C-dots using a confocal microscope, showing cyan, green, and
red colours in the whole-cell region each using 475, 530, and 560 nm long-pass filters.
Cell bioimaging results of mammalian Caco-2 cells, Ehrlich ascites carcinoma cells
(EAC) from mice, pig kidney cell line (LLC-PK1 cells), murine P19 progenitor cells, and
MG-63 cells showed that when the CDs entered cells, they were mainly localized in the
cytoplasm. Using water-dispersible CDs that use green tea as starting material, images
of MCF-10A, MCF-7, and MDA-MB-231 were taken, which CDs localized on the membrane and cytoplasm. Although CDs are mostly placed in the cytoplasm in biological
imaging, carbon dots prepared by electrochemical method from ascorbic acid, m-phenylenediamine, and L-cysteine are suitable for imaging nuclear areas in fixed and living cells [5, 8].
9.1.2.1.2 In vivo imaging
There are many reports on the use of CDs for fluorescence imaging in vivo, which
indicate that this method has no or little toxicity to cells and can effectively penetrate
the skin and tissue of mice. Bioimaging of mice has obtained after injection of red
fluorescent C-dots with a wavelength greater than 600 nm when excited at a wavelength of 535 nm, indicating their penetration. Also, CDs functionalized with oligomeric poly ethylene glycol (PEG) inside the mouse body was evaluated, and the
results showed that these fluorescent dots are not toxic to the selected cell lines [5, 8].
9.1.2.2 Biosensor
Biosensors are devices used to analyse organic and inorganic molecules of living organisms. Optical biosensors work by converting intangible information about target
analytes into detectable optical signals. Compared with traditional nanomaterials, CDs
have various biological advantages for detecting metal ions, biological pH, sugars,
proteins, enzymes, and nucleic acid, due to their excellent properties, biocompatibility, and luminescence properties [5, 10].
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When C-dots interact with metal ions, their fluorescence can be quenched through
electron transfer or the inner filter effect. This property detects Hg
2+
,Ag+,Fe3+,andCu
2+
ions. However, it should be noted that the detection of each ion was achieved by conjugating the C-spots with corresponding ligands [5, 8]. Moreover, C-dots can detect the physiological pH of living cells and tissues. C-dots-TPY probe, which emits fluorescent light in
the visible region with the excitation of two photons at a wavelength of 800 nm, monitors
the pH gradient in the range of 6.0–8.5. It was successfully employed in living cells and
tumour tissues [5].
Gaikwad et al. presented a practical solution for directly detecting fungal spores
from the environment. For the first time, they used CD thin film to detect fungal
spores in the environment using fluorescence spectroscopy, which shows high sensitivity for detecting fungal spores [11].
C-dots-based fluorescence resonance energy transfer (FRET) ratio metric fluorescent sensor was developed for detecting H
S in aqueous media and serum, as well as
2
inside living cells. They used C-dots anchored with naphthalimide-azide served as an
energy donor. The C-dots-naphthalimide-azide sensor showed a detection limit of
10 nm, the lowest among fluorescent H
S sensors. Furthermore, it showed a signifi-
2
cant shift (190 nm) between donor excitation and acceptor emission, which could exclude any influence of excitation backscattering effects on fluorescence detection [5].
9.1.2.3 Disease-detection system
The importance of fluorescent nanoprobes in biomedical researc h and practice has
been rapidly increasing due to recent advances in fluorescence microscopy, l aser
technologies, and nanotechnology. C-dots are particularly suitable for biological sample analysis [5]. For example, to detect diseases related to the abnormal expression
and distribution of SA (surface area) on the cell surface or in body fluids, such as various cases of cancer and disease, as well as heart and neurological diseases, the fluorescence sensor caused by C-dot functionalized with boronic acid can be used as an
alternative analytical tool to investigate diseases without the need for an instrument
[12]. Also, for the detection and quantification of dopamine hydrochloride, serotonin,
and glutamic acid as potential molecular biomarkers for Alzheimer’sdiseaseand
other neuro-related diseases, they used highly fluorescent and spherical (water-soluble) C-dots, formed using citric acid, as a MALDI-MS matrix [13].
9.1.2.4 Gene and drug delivery system
Gene therapy, involving the delivery of ap propriate exogenous genes (DNA or RNA)
into cells and their expression for specific enhancing or suppressing effects, is a good
cure for life-threatening diseases. Moreover, imaging is indispensable in tracing,
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diagnosis, treatment, and confirmation of therapy, promoting the development of bioimaging and simultaneous disease diagnosis and therapy, in both gene and drug delivery systems. As mentioned before, C-dots are becoming a c ompetent candidate for
imaging-concomitant gene and drug delivery due to their excellent fluorescence performance, trim sizes, low cytotoxicity, and good transmembrane ability [5].
Yu-Fen Wu et al. synthesized a multifunctional theran ostic nano agent, fc-rPEICdots/siRNA, which absorbs at 360 nm and emits at 460 nm, the wavelength of blue
light. Their size is 143 nm, and they disperse well in an aqueous solution. Also, their
positive surface charge can be complexed with negatively charged siRNAs; therefore, it
acts as a siRNA carrier and releases siRNA in a reducing environment. Enhanced accumulation of fc-rPEI-Cdots was observed in lung cancer cells compared to normal fibroblasts. The viability of H460 treated wit h fc-rPEI-Cdots/ pooled siRNA com plex for 3
days is significantly reduced to nearly 30%. In conclusion, our novel theranostic fc-rPEICdots/ siRNA nanoagents have the potential for lung cancer targeting and treatment
[14]. In another report, C-dots were used as a visual tool to monitor the association and
dissociation of polymeric carrier/plasmid DNA (pDNA) complex during transfection in a
non-labelled manner, providing an efficient strategy to study the mechanism of polymer-mediated pDNA delivery [5].
Most of the recent pharmaceutical agents suffer from severe secondary side effects
due to systemic delivery, which could potentially be avoided by using tissue-specific
drug delivery systems. Various drug delivery systems, such as lipid- or polymer-based
nanoparticles, have been designed to improve drug pharmacological and therapeutic
properties. For example, we expect efforts to develop novel bone-targeting C-dots biomaterials to benefit the treatment of skeletal diseases such as osteoporosis potentially
[5, 15].
9.2 Carbon dots synthesis
In general, carbon dots synthesis strategies are categorized into “top-down” and “bottom-up” [16]. Top-down methods rely on breaking down macro-scale materials for
producing carbon nanoparticles [17–19]. On the other hand, bottom-up methods include polymerization and carbonization of molecular precursors [20].
The top-down strategies consist of ultrasonic synthesis, chemical exfoliation, electrochemical oxidation, arc-discharge, and laser ablation. The bottom-up methods include microwave synthesis, hydrothermal method, solvothermal metho d, pyrolysis/
carbonization, and chemical vapour deposition (Figure 9.1) [16].
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Figure 9.1: Main synthesis strategies of CDs. Bottom up technic: CDs are synthesized from smaller carbon
precursor via applying energy (electrochemical/chemical, thermal, and laser). The source molecules make
CDs by ionization, dissociation, evaporation, and then condensation. Top-down technic: larger carbon
structures transform to ultra-small fragments and then CDs, via applying energy (thermal, mechanical,
chemical, and ultrasonic) [20].
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9.2.1 Top-down approaches
9.2.1.1 Chemical exfoliation
Chemical exfoliation is an easy way for large production of high-quality CDs without
complex equipment. Precursors include carbon fibers, graphene oxide, and carbon
nanotubes that separate by strong acids or oxidizing agents [16].
9.2.1.2 Laser ablation
Laser ablation is a short period and a simple operation [16]. Researchers prepared
CDs from toluene and graphite powders by this technique. The size of the CDs and
photoluminescence properties can be controlled by laser furnace, spot size, and irradiation time; for example, smaller CDs can be made by expanding the irradiation time
[21, 22].
9.2.1.3 Ultrasonic treatment
In this convenient technique, large carbon materials collapse through high energy ultrasonic sound waves. Researchers fabricated CDs by ultrasonic treatment using oligomer-polyamide resin, ascorbic acid, and ammonia as carbon source [23, 24].
9.2.2 Bottom-up approaches
9.2.2.1 Microwave synthesis
This is a green and cost-effective strategy that is widely used to synthesize CDs in less
time and can provide uniform heat to form CDs.
9.2.2.2 Pyrolysis/carbonization
Pyrolysis is a great method for making fluorescent CDs via using macroscopic carbon
structures as precursors. Advantages of this strategy are short reaction time, low cost,
easy operation, solvent-free approaches, and scalable production. Four critical processes
consist of heating, dehydration, degradation,andcarbonizationathigh temperature. Carbon precursors are converted into carbon nanoparticles using high concentration alkali
or acid in the pyrolysis process [16].
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9.2.2.3 Hydrothermal
The advantages of hydrothermal method are low cost and non-toxicity and in comparison, to other synthetic strategies, this method is a simple approach for making CQDs
(Carbon quantum dots); generally, the water solution of mixtures surrounded with Teflon in an oven and reacted hydrothermally at high pressure and high temperature [16].
9.2.2.4 Solvothermal
This fabrication strategy has the advantage of low cost and requires simple equipment. This method is different from the hydrothermal method and the water solution
is replaced with one or more solvents enclosed with Teflon equipped with a steel autoclave. The reaction of solvent and raw carbon source mixture occurs at high pressure and high temperature [16, 25].
9.2.2.5 Chemical vapour deposition
Chemical vapour deposition (CVD) method has been widely investigated in recent
years. In the CVD method, the final product size can be determined by adjusting these
parameters including carbon source, growth time, hydrogen (H
) flow rate, and sub-
2
strate temperature in Table 9.1 [16].
Table 9.1: Various methods of carbon dots synthesis [16].
Synthetic methods Merits Demerits
Top-down Chemical exfoliation Most accessible, various
sources
Laser ablation Fast, effective, highly
tunable
Ultrasonic-assisted
treatment
Bottom-up Microwave synthesis Fast, scalable,
Hydrothermal Inexpensive, eco-friendly,
Solvothermal Inexpensive, eco-friendly,
Easy operation Instrumental wastage, high energy cost
inexpensive, eco-friendly
non-toxic
non-toxic
Harsh conditions, drastic processes,
multiple-steps, poor control over sizes
Low quantum yield, poor control over
sizes, modification is necessary
Poor control over sizes
Poor control over sizes
Poor control over sizes
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