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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5416_Библиотеки_им_академика_М_И_Перельмана
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168 Sonali Loya and Swati Chandravanshi
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This mixture was then transferred into water bath at 50 °C for at least 2 h. NaOH solution was used to neutralize it, and dialysis was done to obtain pure CDs [54].
Figure 8.7: (a) Synthesis of water-soluble fluorescent C-dots from watermelon peel [51] (Copyright 2012,
Elsevier) and (b) cutting of hair fibre into S–N–C-dots [53] (Copyright 2013, Elsevier).
8.2.2.5 Solvothermal method
Solvothermal method is similar to the hydrothermal approach. The only difference is
that in solvothermal method, the water solution is replaced by one or other several
solvents sealed with Teflon equipped with a steel autoclave. The mixture of solvent
and the raw carbon source is made to react at high temperature and high pressure.
In 2016, Tian et al. prepared GQDs by the application of H
in N,N-dimethylforma-
2O2
mide environment by solvothermal method, as shown in Figure 8.8a [55]. Concentrated
sulphuric acid and nitric acid were completely avoided to treat the raw material. The
prepared GQDs show strong blue emission, and the QY was 15%.
In 2016, Liu et al. synthesized fluorescent CDs using one-pot hydrothermal treatment of rose-heart radish as shown in Figure 8.8b [56]. About 2 g of freshly chopped
rose-heart radish was added into 10 mL of ultrapure water, which was then transferred into 25 mL Teflon-lined autoclave and heated at 180 °C for 3 h in an oven. The
QY was 13.6%.
Chapter 8 Carbon dots in anticancer detection and therapy 169
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Qian et al. prepared N-doped CQDs by simple solvothermal process using CCl
and diamine mixture at 200 °C [57].
4
Figure 8.8: (a) Preparation of GQDs by solvothermal method [55] (Copyright 2018, Elsevier)
and (b) synthesis of N-CDs from rose-heart radish, along with photograph of the sample under 365 nm UV
lamp excitation [56] (Copyright 2017, Elsevier).
8.3 Applications of carbon dots
8.3.1 Carbon dots for cancer diagnosis
CDs have several properties, that is, less harmful, biocompatibility, photostability, and
chemical inertness in medical fields. Due to these properties, CDs are considered for
cancer diagnosis [58].
170 Sonali Loya and Swati Chandravanshi
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8.3.1.1 Fluorescence imaging probe carbon dots
FL CDs have excellent multicolour emission, hydrophi licity, biocompatibility, lower
toxicity, low photodamage, and less auto FL disruption of biological samples, and
their ease in preparation. Because of their properties, FL CDs have been used as imaging probe for cancer [59, 60]. Many research groups reported that cancer cells could
be specifically identified using CDs by improving the FL properties using different
precursors (Table 8.1). For example, solid-state fluorescent CDs wer e synthesized by
using boric acid and ethylenediamine as an initial material by hydrothermal method.
This became boron-doped CDs, which showed favourable solubility and robust FL in
each aqueous and solid medium [61]. Sun et al. prepared highly efficient pure red
emission CDs (R-CDs) with the high QY (22.9%). Citric acid and formamide were used
in the form of precursors for the formation of R-CDs with 43.9% (high) photothermal
conversion efficiency (PCE) under irradiation of 671 nm laser light. R-CDs were proved
to be excellent in cancer diagnosis because of their high PCE [62]. Similarly, R-CDs
were prepared by using pulp-free lemon juice as a precursor. R-CDs were of low cost,
eco-friendly, have high QY (28%), and were monodispersed (diameter was 4.6 nm) by
using this method. R-CDs were used as a luminescentprobeforcancerdiagnosis
through these properties [63]. Highly fluorescent near-infrared (NIR)-emitting CDs
were synthesized by using lemo n juice and formamide as precursors with QY (31%)
via a solvothermal method [64].
Table 8.1: Different precursors and preparation method for FL-CDs.
S. no. Precursors Preparation
method
Boric acid and ethylenediamine Hydrothermal B-doped []
Citric acid and formamide Microwave . N-doped []
Pulp-free lemon juice Solvothermal N-doped []
Pulp-free lemon juice and
formamide
Gelatin Hydrothermal . − []
Chitosan and acetic acid Hydrothermal − []
Citric acid and urea Thermal pyrolysis ., .,
k-Carrageenan and folic acid Hydrothermal . N- and
N,N-Dimethyl, N,N-diethyl, and
N,N-dipropyl-p-phenylenediamine
Solvothermal N-doped []
Solvothermal N-doped []
Quantum yield
(%)
and .
Remarks Reference
[]
[]
S-doped
Chapter 8 Carbon dots in anticancer detection and therapy 171
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Liang’s group synthesized highly fluorescent CDs from gelatin by hydrothermal
method with the QY of 31.6%. CDs were prepared by a simple approach for cancer diagnosis due to their long emission lifetime, low toxicity, steady emission, good dispersibility,
and good compatibility with cells [65]. Functionalization increases the fluorescent properties. So, amino-functionalized fluorescent CDs were prepared by using chitosan and acetic
acid with QY of 43%, showing low cytotoxicity and excellent biocompatibility [66]. Multiple colours from blue to red emissive CDs were reported by Miao’s group in 2018, in
which CDs were synthesized by thermal pyrolysis of citric acid and urea by managing the
surface functionalization and graphitization. The QYs for blue, green, and red emission
were up to 52.6%, 35.1%, and 12.9%, respectively [67]. Das group synthesized photoluminescent CDs by using k-carrageenan and folic acid (FA) as precursors with nitrogen and
sulphur doped by hydrothermal method. CDs were simple and efficient for cancer diagnosis with high QY of 76.12%, and have good water solubility, excellent photostability,
and biocompatibility [68]. Efficient red bandgap emission CDs were synthesized by using
N,N-dimethyl, N,N-diethyl, and N,N-dipropyl-p-phenylenediamine as initial materials by
solvothermal method. The QY was up to 86.0% in ethanol [69]. Wang’s group reported
that trichrome–tryptophan–sorbitol CDs (TC-WS-CDs) were prepared from natural bio-
compatible tryptophan and sorbitol by one-pot hydrothermal method for diagnosis of hepatocellular carcinoma (Figure 8.9) [70].
Figure 8.9: Synthesis and light-induced antitumor mechanism of trichrome–tryptophan–sorbitol carbon
quantum dots [70] (Copyright 2022, Open access).
172 Sonali Loya and Swati Chandravanshi
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8.3.1.2 Photoacoustic (PA) imaging probe carbon dots
FL imaging probes have various properties such as biocompatibility, ease to preparation, lower toxicity, excellent multicolour emission, hydrophilicity, and low autofluorescence interference to biological samples, but have intri nsic limitation like limited
penetration depth [71]. Therefore, photoacoustic (PA) imaging probe is used as a new
emerging bioimaging method for the diagnosis of cancer with deep tissue penetration
and great resolution [72]. A non-invasive biomedical imaging technique is PA imaging.
When pulsed laser is irradiated to a material, ultrasonic wave (acoustic wave) is
formed, which reconstructs the image of the light when the pulsed laser is irradiated to
a material, an ultrasonic wave (acoustic wave) is formed, which reconstructs the image
of the light [73]. Lee’s group was synthesized NIR-absorbing N-doped CDs (N-CDs) for PA
imaging for liver cancer by employing nitric acid as a source of nitrogen and citric acid
as a source of carbon. NIR-N-CDs showed good photostability and absorbance in the
NIR region. Figure 8.10 shows the synthesis of N-CDs and PA imaging [74]. Moreover,
CDs were prepared by using natural biomass parasitic fungus Hypocrella bambusae (HB)
Figure 8.10: (a) Synthesis of N-CNDs; (b) TEM image of N-CNDs; (c) partial graphitic structure in the core
of N-CNDs; (d) electronic structure; (e) optical absorption spectrum of CDs; and (f) PA amplitude
spectrum [74] (Copyright 2016 Ivspring International, Open access).
Chapter 8 Carbon dots in anticancer detection and therapy 173
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in bamboo as a precursor by solvothermal method. HB-CDs were applied for bimodal FL/
PA imaging and PDT/PTT to cancer diagnosis because of their properties such as wide
absorption (350–800 nm), red emission (at 610 nm), low toxicity, and good water solubility
[75]. Citric acid and urea were used as precursors by Xu and his co-workers for preparing
supra-CDs. Supra-CDs were used as contrast agents for PA imaging with good irradiating
−2
power densities to 1 W cm
and photothermal agent for PTT realized under 655 nm laser
irradiation [76]. Wu’s group also synthesized CDs for PA imaging by using porphyrin for
breast cancer ablation [77].
8.3.1.3 Magnetic resonance imaging probe carbon dots
The most potent imaging techniques, such as MR imaging, have been primarily utilized in diagnostic imaging. They have also been used to offer morphological, physiological, and even molecular information about the body because of their non-invasive
characteristics and high spatial resolution. Hence, many MR imaging tools described
cellular and molecular changes in cancer [78]. MR imaging is used to provide good
contrast image of soft tissues and verify that tumours have been removed surgically [79].
ManyCDswereusedasMRimagingprobeswithincorporation of metal ions and metalfree CDs for the diagnosis of cancer. For example, Du et al. formed gadolinium-doped
CDs (Gd@CDs) by one-step hydrothermal method for MR imaging of tumours, in which
gadopentetic acid (Gd-DTPA) is used as Gd source and glycine as the surface passivation
agent. With a longitudinal relaxivity rate (r
) of 6.45 mM–1s–1and great biocompatibil-
1
ity, Gd-CDs show excellent performance. Gd-CDs have excellent T1 contrast agents and
good for radiotherapy of tumours [80]. Similarly, Gd@CDs have been synthesized by
using 3,4-dihydroxyhydrocinnamic acid, 2,2′-(ethylenedioxy)bis(ethylamine), and gadolinium chloride via hydrothermal method, as shown in Figure 8.11. DOX@IR825@Gd@CDs
have been formed by using doxorubicin (DOX) hydrochloride drug and NIR photothermal agent, IR825, MR imaging for triple-negative breast cancer [81].
Ramos’s team als o prepared CDs that were combine d with nitrogen and lanthanides (such as Gd and Yb) using a microwave-assisted hydrothermal technique for
multimodal contrast agent for imaging of cancer with ex cellent QY (66%) [82]. Gd
ion has toxicity which is produced by Gd-CDs so for bio safety concerns Wang’s group
3+
sythesized fluorine and nitrogen co-doped carbon dots with Fe(III) complex. Fe
@F NCDs were synthesized by using glucose and levofloxacin via microwave-assisted thermal
decomposition method. The longitudinal relaxivities (r
3+
and Fe
have large coordination constant (1.06 × 10
@F, N-CD complex were 1.59, 4.23, and 5.79 mM−1s−1, respectively. Fe3+@F, N-CDs
7
), high relaxivity rate, low toxicity, good
photoluminescence, and less synthesis cost. Therefore, Fe
) of free Fe3+,Fe3+@CDcomplex,
1
3+
@F, N-CDs were used for
MR imaging probe for cancer diagnosis [83]. Similarly, non-toxic magnetofluorescence
Mn-CDs were synthesized by manganese(II) phthalocyanine as a precursor at 180 °C
with simultaneous bimodal FL/MR imaging characteristic via solvothermal method.
3+
174 Sonali Loya and Swati Chandravanshi
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With a maximal peak at 745 nm and a T1-weighted magnetic resonance relaxivity rate
)of6.97mM–1s–1for a multifunctional nanotheranostic method, Mn-CDs can be
(r
1
employed as a smart contrast agent for FL [84]. Nimi’s group reported zerovalent iron
(ZVI)-CDs for MR imaging, which was citrate-stabilized (C@ZVI@CDs). C@ZVI@CDs are
of 10 nm size, show paramagnetic properties, and have longitudinal magnetic relaxiv-
−1s−1
ity rate of 4.93 mM
. ZVI@CDs were used as multifunctional CDs, C@ZVI@CDs as
MR angiogram in vivo, and paramagnetic ZVI-CDs (P@ZVI@CDs) in optical imaging
[85]. All the above-mentioned CDs were meta l-incorporated CDs. Novel metal-free CDs
have been developed to act as safe contrast agents for T1-weighted MR imaging.
Metal-free boron-doped CDs were reported for MR imaging of cancer diagnosis by
Wang’s group. It was formed by applying 4-vinylphenylboronic acid and boric acid as
initial materials. B-CDs have a high r
value of 18.27 mM–1s–1, which improves the con-
1
trast in in vivo T1-weighted imaging [86].
Figure 8.11: Gd@CD-based multifunctional carbon nanoplatform design method for triple-negative breast
cancer MRI-guided photothermal chemotherapy [81] (Copyright 2021 Hindawi, Open access).
8.4 Carbon dots for cancer therapy
Several uses of CDs in cancer therapy were reported. CDs have been used in drug delivery, PDT, PTT, and multimodal cancer therapy.
Chapter 8 Carbon dots in anticancer detection and therapy 175
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8.4.1 CDs for drug delivery
Chemotherapy drugs have some drawbacks such as poorly soluble in water, some
side effects, potential in drug delivery as a result of luminescence and adaptable surface chemistry, high biocompatibility, simple internalization by cells, increased drug
solubility, and bioavailability. Wang and co-workers synthesized CDs by using citric
acid monohydrate as carbon source and grafting FA on CDs (FA-CDs) with active targeted drug deliv ery ability. DOX is an anticancer drug, which was loaded in FA-CDs
and then formed FA-CD-DOX. It provides outstanding FL imaging capabilities for liver
cancer cells (Figure 8.12). FA-CD-DOX has 97% (high) FL QY and high targeting ability
than free DOX [87].
Similar to this, Yang’s team described nuclear localization signal (NLS) peptide CDs
loaded with DOX via an acid-labile hydrogen bond, which were demonstrated to have a
higher ability to prevent tumour growth than free DOX. Consequently, NLS-CDs containing DOX serve as promising drug delivery systems for the treatment of cancer [88].
Green fluorescent HP-CDs were prepared by using hyaluronic acid (HA) and polyetherimide by hydrothermal method. Ferrocenylseleno-dopamine (FcDA) is an anticancer
drug which is assembled on the surface of HP-CDs, and then formed CDs@FcDA nanoprobe. It has been used for redox-gated cancer cell imaging and drug delivery [89].
Yang’s group developed CDs conjugated with β-cyclodextrin (β-CD/CDs), which act as a
nanocarrier for DOX (anticancer drug). According to the host–guest chemistry, DOX
was bound into the cavity of β-CD with maximum loading ratio of 27.3% at pH 7.4 and
released drug at pH 5.0 [90]. Neodymium-doped CDs were synthesized and fabricated
with poly-β-CD, which show photoluminesce nce and magnetic behaviour. CDs were
used as a nanocarrier for camptothecin (anticancer drug). The host–guest chemistry is
pH dependent [91]. Mathad’s group synthesized CDs from neem (Azadirachta indica),
which was anchored with β-CD for anticancer drug delivery by the host–guest inclusion
chemistry. β-CD/CD glassy carbon electrode (β-CD@CDs/GCE) was prepared for the simple, eco-friendly, sensitive, cost-effective determination of anticancer drug (lapatinib).
β-CD@CD/GCE is a good efficient electrochemical sensor for cancer treatment [92].
8.4.2 CDs for photodynamic therapy
A highly promising and newly developed non-invasive approach of treating cancer that
is activated by light is called PDT. PDT can be used alone or in conjunction with ionizing
radiation, chemotherapy, or surgery. In PDT, photosensitive species irradiated with specific wavelength light forms reactive oxygen species, such as
icals, when it comes into contact with oxygen, which can induce cancer cell lysis and
death [93, 94]. Some photosensitizing drugs like porphyrin-related drugs are used in PDT
and for cancer diagnosis (FL diagnosis). Photosensitizer has some drawbacks such as
low selectivity, reduced water solubility, photostability, and photosensitivity. Therefore,
1
O2,O
∙–
,H2O2,andOHrad-
2
176 Sonali Loya and Swati Chandravanshi
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Figure 8.12: Imaging and targeted therapy of liver cancer using FA-CD-DOX [87]
(Copyright 2020, Elsevier).
various techniques have been tried to blend photosensitizing medications with other
carriers, including CDs, gold nanoparticles, and carbon nanotubes or fluorescent CDs
used as a photosensitizer [95]. A unique green fluorescent CQD was recently prepared
by Yue’s team using the natural vitamin riboflavin (VB2) as a photosensitizer. Some
characteristics of VB2-CDs include their good water solubility, biocompatibility, and
strong singlet oxygen generation capacity, in which VB2-CDs showed bright green FL for
PDT, and CDs inhibited the growth of tumours [96].
Similarly, Wu’s group reported F-, N-CDs for PDT of hypoxia tumour. F-, N-CDs were
−2
irradiated with LED light (400–500 nm, 15 mW cm
produce hydroxyl radical and superoxide anions (O
), which emit bright green FL and
–
). F-, N-CDs have shown as bioimag-
2
ing agents and photosensitizers with excellent water solubility and low cytotoxicity [97].
In 2021, Xu’s group developed new R-CDs by using phosphate and methylene blue by
hydrothermal method. R-CDs have biocompatibility, photostability, and good singlet oxygen yield of 0.91. So, R-CDs were used in PDT materials [98]. Huang and co-workers synthesized a chlorine e6-conjugated CDs (C-dots-Ce6) with good water solubility, low
cytotoxicity, good biocompatibility, good photosensitizer FL detection (PFD), and good
photostability. Excellent imaging and tumour homing capabilities for PFD and PDT of cancer in vivo were demonstrated by C-dots-Ce6 [99]. Similarly, CD-chlorin e6-hyaluronate
(C-dots-Ce6-HA) was prepared by the interaction between diaminohexane-modified HA
and Ce6 carboxylic group, which produced more singlet oxygen as compared to free Ce6
for facile PDT of melanoma skin cancer (Figure 8.13) [100]. Moreover, natural biomass
Figure 8.13: (a) The synthesis of C-dots-Ce6-HA conjugate using the EDC/NHS chemistry and (b) photo images showing the therapeutic effect of photodynamic
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therapy [100] (Copyright 2015, Elsevier).
Chapter 8 Carbon dots in anticancer detection and therapy 177
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