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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5936_Библиотеки_им_академика_М_И_Перельмана
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Saima Ashraf, Fahmida Jabeen, Sabeen Iqbal,
https://t.me/medicina_free
Muhammad Salman Sajid, Muhammad Naeem Ashiq
and Muhammad Najam-ul-Haq
✶
Chapter 10
Carbon dots in photothermal therapy
Abstract: Cancer is one of the global health threats and several developed therapies
are undergoing evolution with advancements in nanotechnology and awarene ss of
tumor microenvironments. Low-dimensional carbon-based nanomaterials like carbon
dots (CDs) and their derivatives have the potential of treating cancer at the preclinical
level. Zero-dimensional CDs are unique in their physical, chemical, and biomedical
properties. Characteristics such as high surface area, broad absorption spectrum, high
hydrophilicity, tunable fluorescence, photo-stability, and biocompatibility are significant in healthcare applications like fluorescence sensing, imaging, and drug delivery.
As a photosensitizer, CDs produce reactive oxygen species under light and convert
light energy to heat as a photothermal agent. Thus, CDs have applications in photodynamic therapy or photothermal therapy (PTT) of cancer. In this chapter, the functionalized CDs and their synthetic approaches are discussed to provide photothermal
aspects of CDs. The mechanism of PTT and scope of therapeutic efficacy of CD-based
phototheranostic is highlighted. An insight into the challenges of limiting the clinical
application of CDs is provided to prompt advances in phototherapy.
Keywords: Carbon dots, photothermal therapy (PTT), cancer, nanotechnology
10.1 Carbon dots
Carbonaceous materials have a role in material engineering. From common carbonic
materials like carbon black and activated carbon to high-tech carbon substances (e.g.
carbon nanotubes (CNTs), graphite, carbon fibres, and graphene oxide) have gained
importance because of their physical and mechanical properties, improved conductivity, and biocompatibility. These materials have high surface-to-v olume ratio, lightweight, high density, strength, and hardness [1]. Carbon materials are fluorescent like
fullerenes, nano-diamonds, single walled CNTs (SWCNTs), and graphene sheets [2].
✶
Corresponding author: Muhammad Najam-ul-Haq, Institute of Chemical Sciences,
Bahauddin Zakariya University, Multan 60800, Pakistan, e-mail: najamulhaq@bzu.edu.pk
Saima Ashraf, Fahmida Jabeen, Sabeen Iqbal, Muhammad Salman Sajid,
Muhammad Naeem Ashiq, Institute of Chemical Sciences, Bahauddin Zakariya University, Multan
60800, Pakistan
https://doi.org/10.1515/9783110799958-010
220 Saima Ashraf et al.
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Lack of significant band gap in macroscopic carbon materials makes it difficult to be
employed as an efficient fluorescent material [3].
Carbon dots (CDs) are a current addition in the group of nanotechnologies with
prime properties. CDs are quasi-spherical and fluorescent with size below 10 nm [4].
CDs of size above 50 nm are also reported. CDs have high quantum yield (QY), adjustable photoluminescence, biocompatibility, low cytotoxicity, water solubility, small
size, good conductivity, inexpensive precursors, and stable at room temperature [5, 6].
CDs are made from carbon. They show amorphous and crystalline properties. CDs
2
-hybridized carbon networks, whereas, in some cases, sp3hybridization is
are sp
also reported [7]. Their applications are explored in various fields, including catalysis, biomedicine, bioimaging, and optoelectronic devices [8]. CDs show se nsing
characteristics such as selective, specific, and complex detectability. Surface passivation of CDs is easy with groups like carbonyl, hydroxyl, amino, carboxyl, and
epoxy. The surface functionalities provide benefit of binding with organic and inorganic groups [9]. The functional groups on CDs result in colloidal stability and solubility in polar organic or aqueous solvents. The fluorescence properties of CDs are
due to various surface groups [10]. The classification of carbon dots, different synthesis approaches, unique optical and electrochemical properties and applications
in health care are given in Figure 10.1.
Figure 10.1: Outline of CD classification, synthetic approaches, properties, characterization techniques,
and healthcare applications.
Chapter 10 Carbon dots in photothermal therapy 221
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10.2 History of carbon dots
The pho toluminescent CDs were discovered by Xu et al. in the purification process
of SWCNTs [11]. In 2006, laser ablation method was utilized to synthesize CDs with
strong photoluminescence. It was the first time when C Ds were synthesized; however, some properties like low QY and com plicated preparation strategies limited
their applications [78]. Later, CDs having QY of 80% were made with ethylene diamine and citric acid as precursors. CDs obtained from citric acid precursor were
the easiest dots to be prepared, and this helped to understand why and how synthetic methods affect CD p roperties. The achieved QY enhanced the chemical characteristics of CDs. These CDs can be applied to printing inks and used as precursors for
synthesizing functional composites [12]. High QY, facile approach, resistance to photobleaching of CDs, and low toxicity further enhance their potential. Various strategies have been adopted for the low- and high-scale manufacturing of CDs and their
applications.
10.3 Classification of carbon dots
Based on the fabrication strategies, surface functionalities, and properties, CDs are categorized into (a) carbonized polymer dots (CPDs), (b) carbon nanodots (CNDs), (c) carbon
quantum dots (CQDs), and (d) graphene quantum dots (GQDs) [13]. This classification is
attributed to their nanostructures, and characteristics can be changed by changing the
graphene layer and degree of carbonization [14]. GQDs are zero-dimensional and anisotropic, which constituted single or multiple graphene sheets. GQDs exhibit properties
like edge effect and quantum confinement due to the presence of chemical functionalities in their interlayer defect and on their edges. GQDs have optoelectrical properties
along with excellent dispersibility, biocompatibility, and tunability. GQDs are employed
in catalysis, energy devices, photodynamics, sensing, bioimaging, targeted drug delivery,
and photothermal therapy (PTT) [15]. CQDs are nanocrystalline and possess functionalities that impart quantum confinement effect to CDs and intrinsic state luminescence.
CNDs have high degree of carbonization with functional groups on the surface, but without showing polymeric and crystalline structure. CNDs lack the ability of quantum confinement effect [16].
CPDs are aggregated/cross-linked hybrid nanostructures of carbon and polymer.
They show bright luminescence, low cytotoxicity, chemical inertness, and biocompatibility [17]. CPDs consist of cross-linked and graphitized inner core and hydrophilic
polymer chain on the outer surface [18]. In CPDs, photoluminescence is due to crosslink-enhanced emission (CEE) and their surface, molecular, and subdomain states.
The predominant optical property is due to molecular state and CEE effect. All other
types of CDs do not show these photoluminescence features [19].
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10.4 Synthetic methods of carbon dots
CD synthesis is influenced by factors such as surface state, molecular state, and QEE
effect. These factors can be controlled by altering the synthetic strategies [20]. During CD synthesis, their surface can be modified by functional moieties such as carbonyl, epoxide, ether, carboxyl, amine, and hydroxyl [21]. The doping of CDs with
heteroatoms like P, N, S, a nd B can be done by treating polymeric, biological, and
organic substances [22]. CD modification is critical for attain ing the surfac e properties for favourable applications [23]. The physicochemical properties such as carbonization, size, crystallinity, morphology, and photoluminescence can be modified
by synthetic methods and precursor molecules. For instance, the pyrolytic method
is harsher than the hydrothermal method but the former produces graphitic core
structure and the latter produces incomplete carbonization, amorphous CDs, and
molecular fluorophores. The surface moieties of CDs c an alter the physicochemical
characteristics, stability, and biocompatibility allowing modification, sensitivity,
and selectivity of CDs in analytical applications [24].
CDs are synthesized by top-down and bottom-up approaches [25]. In “top-down”,
the carbonaceous materials such as graphite is chemically, electrochemically, or physically dissected into nano-sized fragments [26]. Bottom-up strategy involves either
stepwise incorporation of small aromatic compounds or the carbonization of organic
moieties. Therefore, CDs may be denoted as graphene nanodots and CNDs, respectively [27]. These synthetic approaches are classified as shown in Figure 10.2.
Figure 10.2: Synthetic approaches of carbon dots.
Chapter 10 Carbon dots in photothermal therapy 223
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10.4.1 Top-down approach
Nowadays, carbon materials including graphite, activated carbon, and CNTs are used
for the synthesis of CDs by laser ablation, ultrasonic treatment, electrochemical oxidation, and arc discharge methods [28]. These approaches are administered in conditions like high potential, energy, and acidity. Therefore, the top-down approaches are
laborious as compared to bottom-up, due to harsh reaction conditions [29].
10.4.1.1 Laser ablation method
Laser ablation employs laser beam to irradiate carbonaceous materials in thermodynamic environment that results in high temperature and pressure. The high temperature produces plasma followed by evaporation. Subsequently, crystallization results
in the conversion of generated vapour into CDs [30]. In 2006, luminescent CDs were
synthesized by laser ablation in which the carbon target was ablated by argon as a
carrier gas. In another study, photoluminescent CDs were prepared through laser ablation of bulk graphite as carbon source in ethanol via Nd:YAG laser irradiation [31].
Fluorescent CDs having size of 3 nm were prepared via laser ablation of carbon glassy
particles immersed in polyethylene glycol (PEG) by flow jet configuration and batch
process [32]. In 2021, quasi-molecular fluorophores with an average size of 5 nm were
prepared by nanosecond laser ablation of bulk graphite dipped in ethylenediamine
and polyethylenimine [33].
Nitrogen-doped CDs can be made by single-step laser ablation from graphite powder by using organic solvent like amino-toluene. The synthesized CDs exhibit excitationindependent emission, which is applied for monitoring the ratiometric pH because of
excess surface oxygen and amine moieties [34]. CDs prepared via double-beamed laser
ablation have attributes such as high surface-to-volume ratio, ultra-small size, homogeneity, and stability as compared to single-pulsed laser beam [35].
10.4.1.2 Arc discharge method
CDs can be prepared from crude CNT soot through the arc discharge method. The carbonaceous material is oxidized by nitric acid to introduce carboxyl groups followed by
treatment with NaOH and purified by gel electrophoresis. In 2004, CDs were prepared
by arc discharge using SWCNTs and multi-walled CNTs as carbon source through oxidation reacti on [11]. This method is not useful for producing CDs as it produces small
amount of product, and purification process is difficult.
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10.4.1.3 Chemical oxidation method
CDs are prepared by the chemical oxidation method due to their advantages like
low cost, greater yield, bulk production , pu rity, and controllable size [36]. CDs are
chemically or electrochemically synthesized by the redox reaction under normal
temperature and pressure [37]. Oxidizing agents like sulphuric acid (H
gen, nitric acid (HNO
), and hydrogen peroxide are used. CD functionalization with
3
2SO4
), oxy-
hydrophilic moieties like carboxyl, amine, and hydroxyl can be done by controlling
the oxidation–reduction reaction [38].
10.4.1.4 Ultrasonic treatment
Ultrasonic treatment is useful for producing CDs as the bulky carbonaceous materials
could break down by high-energy ultrasound waves. By using single-step ultrasonic
treatment, N-doped CDs were synthesized by ammonia and ascorbic acid precursor [39].
10.4.2 Bottom-up approach
Bottom-up methodology includes pyrolytic processes, supported synthesis, template
methods, chemical oxidation, microwave-based methods, and reverse micelle processes. Bottom-up approaches are popular due to cost-effectiveness, easy instrumentation, non-toxic precursor molecules, p recise control over size, convenient, facile
methodology, an d practical app licability.
10.4.2.1 Hydrothermal/solvothermal method
CDs prepared by this method are non-toxic, inexpensive, and eco-friendly. In this
method, reaction occurs between carbon precursor and organic solvent in the hydrothermal reactor at high temper ature and pressure. Countless raw materials can be
used as precursors such as glucose, protein, chitosan, wheat bran, orange peels, cereals, grains, sugar cane brass, and citric acid. Nitrogen-doped CDs (N-CDs) are reported
with carbon tetrachloride and sodium amide (NaNH
) as source material via the sol-
2
vothermal method [40]. Wu et al. synthesized nitrogen-doped quantum CDs (NQCDs)
by using microcrystalline cellulose as carbon source and ethylenediamine as nitrogen
source. The prepared NQCDs with an average size of 3 nm are applicable as a fluorescent probe for metallic detection [41]. In another work, CDs are synthesized using
L-histidine and citric acid sources via the one-step hydrothermal technique [42].
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10.4.2.2 Microwave-assisted method
Due to broad electromagnetic radiation spectrum range (1 mm to 1 m), variety of chemical bonds present in precursor molecules can be decomposed by their accelerated energies. The approach is applied for the synthesis of CDs as it has the advantage of high
speed and uniform heating of precursor materials. Due to penetration of microwave
radiations, uniform heating of reaction mixture is possible, which results in the formation of narrow sized crystal [43]. Using microwave-assisted synthesis, CDs produced
from citric acid precursor are reported to evaluate antimicrobial photodynamic effect.
By in vitro assays, effectiveness of CDs against Staphylococcus aureus biofilm and sus-
pension is assessed. The results show that the use of CDs in antibacterial photodynamic
therapy (PDT) is a viable treatment for Staphylococcus aureus infected wounds [44]. In
another study, fluorescent CDs were synthesized via microwave irradiation from glucosamine@PEG@chitosan graft co-polymer. The resultant CDs show good fluorescence intensity, chemical stability, and efficacy of delivering chemotherapeutics [45].
10.4.2.3 Thermal method
Thermal decomposition involves the pyrolysis of bulky carbon materials at high temperatures to synthesize CDs. This method has advantages of bulk production, costeffectiveness, ultra-fast, solvent free, choice of precursors, and easy synthesis. The
fluorescence of CDs can be controlled through optimizing the pH of reaction mixture,
temperature, and reflux time [46]. Photoluminescent CDs with adjustable size can be
achieved by the pyrolysis of carbon microcrystal precursor in mesophase pitch. CDs
exhibit high QY of ~ 87%, owing to oxygen-free character. These prepared CDs are
3+
used as a biosensor for Fe
ion detection with greater sensitivity and specificity [47].
Different carbon dots fabricated by top down and bottom up approaches reported in
literature are listed in Table 10.1.
Table 10.1: Methods for the synthesis of carbon dots, their precursors, size range, and applications
in various fields.
Carbon source Methods C-dot size Applications Ref.
Graphite in ethylenediamine
and polyethylenimine
Graphite powder Laser ablation Ultra-small size of
TiO
nanoparticles coupled
with CDs
Laser ablation – nm Fluorescent CDs for
different applications
Catalytic and sensing
nm
Arc discharge Average size of
nm
applications
Sensing application []
[]
[]
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Table 10.1 (continued)
Carbon source Methods C-dot size Applications Ref.
Boron-doped GQDs Arc discharge Zero-dimensional
GQDs
Sodium citrate + urea Electrochemical
carbonization
Citric acid, thiourea, and urea Microwave-
assisted
Graphite target irradiation Laser ablation – nm Potential related
Activated carbon Ultrasonic – nm Biosensing and
Uric acid and ascorbic acid Electrochemical Nanofibres Selective and sensitive
Wheat bran and tartaric acid Hydrothermal Approx. . nm Detection of Cu
Approx. . nm Sensing application []
nm Detection of metals in
Optical application []
[]
water samples
[]
applications
[]
biomedical applications
[]
dopamine detection
+
ions []
10.5 Characteristic properties of CDs
CDs as the class of carbon materials have unique chemical, physical, and optical properties like absorption, chirality, and photoluminescence. CDs act as electron donors
and acceptors.
10.5.1 Optical properties
The fluorescent CDs find their ways in fields such as biosensing, molecular imaging, and
therapy. It is important to study the optical behaviour of CDs for diverse bioapplications.
10.5.1.1 Absorption
CDs synthesized from various sources of carbon or through artificial strategies show
excellent absorption. They show sturdy absorption in the UV region (200–400 nm).
The absorption occurs due to π–π* transition of C = C bond or n−π* of C=O/C=N
bonds [57]. The absorption range may change depending on the nature of CDs, surface
passivation, and functional groups [58].
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10.5.1.2 Quantum yield
The ability of converting the absorbed light to the emitted light is known as quantum
yield. Fluorophores with high QY show strong fluorescence, which decreases t he
quantity of fluorophores required for an application [59]. QY values for CDs, especially for bare CDs without surface passivation, are below 10%. The surface functionalization or doping can change the QY value of CDs with improved fluorescence
intensity and QY. For instance, the carboxyl content of N-doped CDs is altered to improve the quality. The hydrothermal treatment of m-aminobenzoic acid to create CDs
results in high QY of 30.7% when N is doped to CDs. A crude CD sample can be purified to separate batches of CDs with various QYs. When purified, CDs with comparable
physiochemical characteristics can be separated with similar QY values. The purification of CDs functionalized with oligomeric PEG diamine (PEG1500N) does not alter the
fluorescence although the QYs of each fraction vary [60]. QY values increase until
they reach the levels of 55–60%. CDs with QYs up to 78% are more than double of the
QY prior to fractionation. They are retrieved by purification through an aqueous gel
column (Sephadex G-100) [61].
10.5.1.3 Fluorescence properties
ThefluorescenceisobservedinCDssynthesized via the ultrasonic treatment. The excitation wavelength is longer than the emission wavelength due to the decrease in background autofluorescence. The luminescent process of CDs is still not fully investigated.
ThefluorescenceofCDsisdependentonfreezig-zag sites, quantum confinement effects,
multi-emissive centres, special edge defects, self-trapped excitons, surface states, and
their conjugated structures [62]. Fluorescence emission properties of CDs can be controlled by changing their excitation wavelength, which can be attained during CD synthesis by controlling the physicochemical parameters [63].
10.6 Phototherapy theory
The treatment of diseases by using light is known as phototherapy. In heliotherapy,
from 1400
century, scientific documentation for phototherapy could be found. The first treatment of disease (lupus vulgaris) by filtered sunlight was done by Niels Finsen in 1893
for which he received Nobel Prize in 1903 [64]. Phototherapy is classified into two
types: (i) PTT and (ii) PDT. In PDT, photosensitizers (PSs) by light irradiation produce
cytotoxic chemical agents. PSs can generate overheating under photoactivation [65].
BC, the treatment of disease was done by sunlight. Later in the nineteenth
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