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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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Another essential feature of structure t hat is used in photodynamic therapy is
biocompatibility. In this study, biocompatibility of CCOF-2PEG was investigated by
staining i mportant organs such as heart, liver, lung, and kidney with haematoxylin
and eosin (H&E). Result confirmed the biocompatibility of CCOF-2PEG [39].
9.4.2 Porphyrin-based carbon dots
A valuable study was do ne by Yang Li et al. and published in advanced healthca re
materials Journal about porphyrin-based CDs. In future, we will explain the results
and methods of this study momentarily.
Photoluminescent CDs have excellent properties that make them suitable for photodynamic therapy [40, 41]; therefore, other CDs would not be considered. Although,
porphyrin-based CDs can be helpful as they are synthesized from 3-phenyl porphyrin
and chitosan. Electron microscopy studies reveal a diameter of porphyrin-based CDs
about 2.9 nm and spectroscopy showed high absorbance of 410 nm. As mentioned, the
important mechanism of photosensitizers in producing ROSs, thus the ability of produced ROS should be measured in porphyrin-based CDs structure. For this purpose,
1,3-diphenyl-isobenzofuran (DPBF) was used. The extraordinary reaction between
DPBF and ROS demonstrates that porphyrin-based CDs are effective in producing ROS
[42]. Moreover, the vici nity between lysosome’s prob and porphyrin-based CDs display this structure as an option for specific place in cells. Post irradiation, cell death
in incubation with porphyrin-based CDs was impressive, while cells that were only
incubated didn’t have a high death rate [42]. This observation indicates that porphyrin-based CDs although with acceptable cell death, don’t have cytotoxicity. For in vitro
studies, H22 tumour-bearing KM mice were divided into 4 groups in Table 9.2 [42].
Table 9.2: Four groups and their conditions (information displayed is based on article [42]).
Group TPP CDs + nm radiation Tumour size decreased to nm
Group TPP + nm radiation Tumour size increased to nm
Group TPP CDs Tumour size increased to nm
Group saline Tumour size increased to , nm.
9.4.3 Carbons dots that interact white the nucleus
Nucleusisacrucialpartofcells.Tumour cells divide at high speed and they need
ribosomes in order to accomplish this. Nucleolus is fundamental for ribosome synthesis, thus two CDs have been introduced. The first one is red emissive two-photon CDs
[43] and the second one is Se/N-doped CDs [44]. In future, we will explain these
structures.
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9.4.3.1 Red emissive two-photon carbon dots
A comprehensive research was done by Shangzhao Yi et al. and published in a carbon
journal. In future, we will explain that briefly.
For synthesizing this structure, solvothermal synthesis method was used (Figure 9.6)
[43]. Employing electron microscopy, X-ray method, and spectrophotometry, two-photon
carbon dots (TP-CDs) were characterized: average size is about 4 nm; two-photon absorption is between 680 to 1,000 nm, and emission is approximately 600 nm [43].
Figure 9.6: This schematic shows the synthesis and effect of two-photon carbon dots [43].
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One of the important properties of TP-CDs is lacating near the nucleolus [43]. Fluorescence spectra confirm this subject. Three basic macromolecules were added to the
TP-CDs solution, and fluorescence is measured per solution. According to the evidence,
fluorescence in TP-CDs containing RNA is higher than both DNA containing TP-CDs and
protein containing TP-CDs. Moreover, if RNAse is added to TP-CDs with RNA, fluorescence decreases. Three results suggest that RNA interacts with N doping or without N
doping has an essential role in interaction with RNA and TP-CDs [43]. (1) If the N doping
is removed, fluorescence is not changed in TP-CDs without N doping and RNA. (2). TPCDs have positive charge, and RNA has negative. Consequently, there is an electrostatic
interaction between them. (3) When cells were incubated with TP-CDs and irradiation,
their RNA was extracted and RNA electrophoresis was done; there was no evident
bond for the reason of effect of TP-CDs damages the RNA [43] (Figure 9.7).
Figure 9.7: RNA electrophoresis of (a) cells that do not incubate
with TP-CDs, (b) cells that incubate with TP-CDs and irradiation,
and (c) cells that incubate with RNAse [43].
TP-CDs have effective ROS inducing in irradiation at 638 nm [43]. And MTT assay suggests that TP-CDs don’t have cytotoxicity [43].
9.4.3.2 Se/N-doped carbon dots
We will explain practical studies by Ning Xu that were published in the carbon journal field [44]. Se/N-CDs are synthesized by the solvothermal method. Their diameter is
about 3.6 nm. They have radiated emissions at 591 nm [44].
ROS made in photodynamic therapy by photosensitizer have a short lifetime;
therefore, in order to increased photodynamic therapy performance, ROS should
make near overriding organelle, for instance, nucleus or mitochondrial field [44, 45].
Se/N-doped CDs are located in the nucleus and intricate with RNA. RNA is expected to
be a carrier for Se/N-doped CDs [44]. Se/N-doped CDs enter nucleus after they arrive
near it; this subject will reveal by staining the nucleus and Se/N-doped CDs. This
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structure enters the nucleus after being illuminated. It is assumed that Se/N-CDs, by
inducing ROS, destroyed nucleus membrane pores.
Furthermore, the use of Si nanoparticle suggests that after irradiation, fluorescent
increases in the nucleus. Staining and using RNAse and DNAse with incubated cells by
Se/N-CDs confirmed that this structure interacts with RNA more than DNA [44].
To study cytotoxicity, cell viability, and inducing ROS, some cell lines such as HeLa
and 4T1 were employed. Standard MTT assay and Calcein-AM/PI test are efficient methods. For this purpose, cells were incubated at different concentrations of Se/N-doped CDs
for a definite time both with irradiation and without irradiation field [44]. This study
− 1
shows that in 7.5 μgmL
of Se/N-CDs without irradiation, cell viability was about 90%.
This means Se/N-CDs have low cytotoxicity. 2′,7′-dichlorofluorescein diacetate (DCFH-DA)
is a structure that reacts with ROS. After irradiation, the green fluorescence that has
been used is high, so that Se/N-CDs can induce ROS [44].
In vivo studies reveal proper biocompatibility and helpful effect of Se/N-doped
CDs on tumour. For this purpose, BALB/c tumour-bearing mice were used. These mice
were divided into four groups. The first group is injected with PBS, the second ones
are injected with PBS and irradiation. The third ones are injected with Se/N-CDs, and
the fourth ones are injected with Se/N-CDs and irradiation. (Time of irradiation in
each group was 20 min, the wavelength was 550 nm, and the amount of each injection
−2
was 50 mW cm
) [44]. After that, two factors were measured; body weight and tumour size. No weight loss was observed, although tumour size was decreased in
group four. This was an influential act in cancer treatment [44].
9.4.4 Copper-doped carbon dots
We will explain valuable studies by Jingmin Wang et al., which were published in inorganic chemistry journals. Such metal ions have an essential role in cells. Therefore,
this idea is born that synthesized CDs structure with this metal ion, for instance, copper-doped CDs (CU-CDs) [46]. Electron microscopic study and spectroscopy methods
reveal some properties of CU-CDs like, diameters (about 2.8 nm). Since CU-CDs have
different bonds, they have emission peaks between 200 and 650 nm [46]. CU-CDs have
bigger diameters than CDs [46].
Cytotoxicity measurement of photosensitizer in photodynamic therapy is critical.
For measuring the cytotoxicity of CU-CDs, MTT assay was used in different concentrations of CU-CDs with or without irradiation. It demonstrates that the cytotoxicity of
CU-CDs is low [46].
Another property of photosensitizer is the ability to induce ROS. ESR can be used
for this purpose and revealed ROS increase in cells that incubate with CU-CDs after
irradiation. This ability can be attributed to copper doping [6–7].
CU-CDs with irradiation decrease cell viability [46] (Figure 9.8). Calcein-AM/PI test
and MTT assay show this matter. Two-factors play a critical role in the effect of CU-
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Figure 9.8: Illustration of effect of CU-CDs on cell viability [46].
CDs in cell viability; first one is concentration of CU-CDs and the second one is time of
irradiation [46].
The decrease in cell viability of CU-CDs is higher than CDs. On the other hand, the
cytotoxicity of CU-CDs is more elevated than CD, because cellular uptake of CU-CDs is
more than CDs [46]. 3D microscopy studies suggest that CU-CDs influence cell growth
and decrease the size of cells [46]. One advantage of CU-CDs is that they have copper.
It changes Ca
copper increases stimulation and synthesizes ROS [46].
+
concentration in cells and decreases cell viability [46]. Furthermore,
9.4.5 Carbon quantum dots
Carbon quantum dots have valuable properties similar to other carbon-based nanomaterials, such as low cytotoxicity, good solubility, acceptabl e optical properties for
photodynamic therapy, and high ability to induce ROS [47, 38]. They have different
types, for instance, Curcumin cationic carbon dots (CCM-CDs) or carbon dots whose
precursor is acetic acid [38].
Several studies reported that photodynamics by CDs can be helpful for virus diseases treatment, for instance, CDs that are synthesized from 4-aminophenyl boronic
acid. It can be used to reduce virus cell entry. Another CDs can induce ROS that react
with DNA, RNA, or essential viral proteins [38]. Furthermore, the CD’s effects can stimulate immunological responses by increasing some cytokines or interleukins [38, 47].
Briefly, CDs can disturb different steps of the virus cycle, like attachment, and entry
or replication [38].
SARS-CoV-2 is a member of Betacoronaviridae, it started a pandemic in 2019, and
since it had begun, millions of people have been infected [38]. For this virus, various
drugs, vaccines, and therapeutic methods have been reported and photodynamic therapy by CDs is one among them. As mentioned, CDs are an option as photosensitizer.
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Figure 9.9: This schematic illustrates the effect of carbon dots in virus infection by increasing ROS [38].
CDs rest rict viruses from entering cells by induci ng ROS [38] (Figure 9.9) . Other reports also reported CDs can help to treat herpes simplex type 1 [38, 48].
9.4.6 Diketopyrrolopyrrole-based carbon dots
A valuable study was done by Haozhe et al., which was about diketopyrrolopyrrolebased CDs (DPP CDs) and was published in nanoscale journal. We will explain this valuable study later.
Diketopyrrolopyrrole-based CDs are an appropriate choice for photodynamic
therapy. They have unique properties such as low cytotoxicity, high cell uptake, and
good tumour destruction [49]. DPP CDs are synthesized by one-pot hydrothermal
method and their precursor is chitosan (Figure 9.10). DPP CDs were characterized by
few methods such as TEM and UV‒vis absorption and the result shows that DPP CDs’
diameters are about 10 nm [49]. When the wavelength increases between 350 and 550,
the absorbance decreases [49].
To measure ROS generation, 1,3-diphenyl-isobenzofuran (DPBF) UV‒vis spectroscopy
is used [49]. In this test, decreased absorption of DPBF means that ROS is generated.
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Figure 9.10: synthesis and mechanism of diketopyrrolopyrrole-based carbon dots [49].
Results show that DPP CDs have a good ability to generate ROS (the ability of DPP CDs in
ROS generation is about 27.6%). This test was also done on the DPP; results show that
DPP’s ability to generate ROS is similar to DPP CDs and it was concluded that ROS generation in this structure is not affected by CDs [49].
Targeting cancer cells and cellular uptake are difficult matters in photodynamic
therapy. This study used confocal laser scanning microscopy and fluorescence colocalization analyses. HepG2 cells were incubated with DPP CDs. After that, cells were
fixed with formaldehyde and the nucleus was stained with Hoechst; while lysosomes
were stained with Lyso-Tracker red DND-9. And result showed that there were more
DPP CDs in the cytoplasm and their entry to the lysosome was by endocytosis.
For in vivo studies, female Kunming (KM) mice were suggested, and other studies
were explained. Mice were divided into four groups (1) injected with PBS, (2) injected
with PBS, and irradiated with laser, (3) injected with DP CDs, and (4) injected with DP
CDs and irradiated with laser (wavelength was 540 nm, 20 min) [49]. The tumour size
was decreased in group four (Figure 9.11). And no significant weight loss was measured. Histology studies with H&E staining were done to measure w hether DPP CDs
are damaged to their critical body organs [49]. And results suggest that there is no
tissue damage and nor necrosis [49]. Other important matters in photodynamic therapy by CDs are tumour permeability. For this purpose, fluorescent imaging of tumour
and other organs was done [49] and results revealed that the florescent signal in
other tissue was low [49].
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Figure 9.11: Tumour size decreases in mice that was injected with DPP CDs and irradiation but there was
one injected with PBS with or without irradiation tumour rapidly grows [49].
9.5 Future suggestions
As mentioned, photodynamic therapy by CDs has some weaknesses such as low exclusivity and short time of useful ability to synthesize ROS and non-selective in most
cases to select the location in cells. It is necessary to focus on these subjects in future
studies, also in recent articles, molecular analysis such as PCR and proteome analysis
such as western blotting and immunoblotting were used, the effect of CDs and ROS
that are synthesized by them on gen expiration and protein synthesized and struc tures must be measured.
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