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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Carbon Quantum Dots Based Materials for Drug Delivery 275
Fig. 4 Overview of synthesis of CNPCP. a Schematic representation of synthesis of carbon dotchitosan-PEG (CD-CP) and fluorescent iron oxide nanoparticle (CNPCP). b Images of aqueous
solutions of CNPCP and NPCP. Reproduced with permission from Frontiers [69]
3.4 Carbon Quantum Dot/Nanomaterial-Based Materials
for Drug Delivery
Nowadays, nanomaterials are playing key roles in drug delivery applications due
to their ultrafine structures, which can be employed as carriers for encapsulating
drugs and delivering them in the targeted manner within stimuli-sensitive conditions. In this regard, CQDs have been employed in diverse drug delivery applications due to their inherent physicochemical properties such as good biocompatibility,
permeability, active surface area with remarkable loading capability, and sustained
release behavior. It is also worth mentioning that due to the ultrafine size range of
CQDs (<10 nm), CQDs are more prone to diffusion transport than other conventional
nanomaterials, which has made CQD-based nanocomposites more permeable into
impermeable areas such as BTB for treating various cancers and BBB for treating
diverse neural diseases. This particular characteristic and photoluminescence properties have introduced CQDs as promising nanomaterials for theragnostic applications. In this regard, Li et al. [44] utilized a modification process by employing
covalently conjugated transferrin to CQDs for diffusing into the BBB in an in vivo
experiment, demonstrating the great potential for treating neurological disorders.
Moreover, Seven et al. [71] implied the promising potential of employing carbon
dots in drug delivery applications for treating central nervous system (CNS) diseases
like neurodegenerative disorders. They fabricated the CQDs from glucose resources
without any ligand modifications and conducted their in vivo studies on zebrafish
and rats. By tracking the loaded fluorescein to CDs as the fluorescent tracer, the
successful diffusion through the BBB has been approved, indicating the great potential in targeted drug delivery applications. In another similar study, Zhou et al. [46]
276 M. Pourmadadi et al.
employed CDs with amphiphilic features and emission capability to show its penetration into the BBB of a zebrafish in the in vivo stage. Their findings showed that
the synthesized CDs have crossed the BBB and diffused to the cells with prohibiting
the amyloid beta, which is one of the most important factors in Alzheimer’s disease,
denoting to great advantages of the CQD-based nanoparticles over conventional
nanomaterials in drug delivery applications. Furthermore, Cutrim et al. [47]developed a pH-sensitive delivery nanoplatform composed of 5-FU loaded CQDs with
electrostatic and hydrogen bonds as the predominant intermolecular interactions
between the functional groups on the surface of the CQDs and 5-FU. They obtained
a size range of 4.82–5.57 nm and the highest drug loading capacity of 62.5% for
the fabricated 5-FU-CQDs drug delivery system and employed it for treating breast
cancer. Their cytotoxicity outcomes on MCF-7 cancer cells and GM07492A normal
cells indicated an enhanced apoptotic effect on cancer cells and cytotoxicity decline
against normal cells. Yuan et al. [48] employed the nano carbon dots (NCDs) as
the nanocarrier for pH-sensitive delivery of DOX to treat adenoid cystic carcinoma
in a targeted manner. They took the advantage of electrostatic interaction between
DOX and NCDs for drug delivery applications. Moreover, their cytotoxicity assessments demonstrated an enhanced apoptotic effect against ACC-2 cancer cells and
reduced side effects on L929 normal cells. Table 1 and Fig. 1 represent severalCQDs-
based delivery systems, which have been applied efficiently in diverse drug delivery
applications and targeted drug delivery through receptor-mediated endocytosis with
apoptotic pathway activation, respectively. Figure 5 illustrates a schematic diagram
outlining the preparation route for g-GQDs and b-GQDs, as well as the preparation
and application of soluble CDs derived from mango leaves. In addition, Fig. 6 (a)
shows how DOX-Loaded Fe
/CQD is prepared, and (b) displays its uses in MRI,
3O4
targeted drug delivery, and cellular uptake.
3.5 Carbon Quantum Dot/Supermolecular-Based Materials
for Drug Delivery
Synthesis of nanoparticles from a combination of polymer chemistry, supermolecular chemistry, and their interaction can form various nanostructures. For instance,
cyclodextrins can form multiple 3D nanostructures based on host–guest interaction.
In this regard, Pei et al. synthesized a pH-responsive nitrogen-doped CQD structure
based on sodium citrate as the core element. Subsequently, the CQDs are decorated
with β-cyclodextrin as the shell to form hybrid nanosponges with 300 nm diameter and DOX loading capacity of around 40%. The DOX@β-CD-CQD theranostic
nanomedicine can penetrate the HepG2 cell resulting in the accumulation of DOX
in the cell nuclei, which can enhance drug efficacy [79]. Figure 7 depicting the
in vitro anticancer effectiveness of a nanoconjugate using CQD and 5-FU, highlighting its efficacy as a drug delivery system. In another study, a supermolecular
assembly of C-dots and Dihydroartemisinin (DHA) as a drug model was fabricated
Carbon Quantum Dots Based Materials for Drug Delivery 277
Fig. 5 Schematic diagram of a Preparation route for gGQDs and bGQDs, Reproduced with permis-
sion from Wiley [72], b Preparation process and application of the fluorescence CDs from proteinrich eggshell membranes by microwave-assisted approaches Reproduced with permission from
Taylor & Francis [73], c Synthesis of the CDs from crab shell, Reproduced with permission from
ACS [74], d Preparation and application of the soluble CDs from mango leaves, Reproduced with
permission from ACS [75], e Preparation of the fluorescent CDs composites from raw cashew gum
Reproduced with permission from SciELO Brasil [76]andf Synthesis of fluorescent N-GQDs from
triethanolamine and sodium citrate, Reproduced with permission from ACS [77]
to enhance water solubility, stability, and effectiveness of DHA for hepatic carcinoma treatment. Studies on the anticancer effect of the nanocarrier indicate that cells
treated with the carrier have typical alternation in morphology, including a decline
in each of nuclear sizes, fluorescent spots, and blebbingverifying inducement apoptosis of HepG2 cells. Furthermore, CDs-DHA can suppress glycolysis by decreasing
Pyruvate kinase isozymes M2 (PKM2) expression and protein kinase B (AKT)/
mammalian target of rapamycin (mTOR) signaling pathway in HepG2 cells. Moreover, in vivo research exhibits more than a 30% difference between the treatment with
CDs-DHA and DHA, suggesting the promising effective anticancer nanocarrier [80].
In another study, an assembly of CQDs and zwitterionic surfactants was synthesized,
forming a pH-responsive photoluminescent biomaterial. In this assembly, before
278 M. Pourmadadi et al.
Fig. 6 Schematic diagram of a Preparation of DOX-Loaded Fe3O4/CQD and b applications of
nanocomposite in MRI, targeted drug delivery and cellular uptake Reproduced with permission
from ACS [78]
interacting surfactant unimers with CQDs self-associate in micelles. Furthermore,
the positively-charged micelles interact with negatively-charged CQDs forming a
higher-order structure. By loading the carrier with R6G as a drug model, studies
show cumulative release of up to ~ 58% at pH 5, indicating appropriate drug release
and pH-responsiveness [81].
In order to create a dual-responsive drug delivery system with the capability of
combining near-infrared (NIR) light and pH responsiveness along with photothermal
treatment, Wang et al. engineered a biomaterial based on supramolecular structures.
This material involved fluorescent porous carbon-nanocapsules embedded in carbon
quantum dots (FPC-NCs@CQDs-DOX). The hollow cavity structure of the shell
provides high drug-loading efficiency and the drug release and photothermal treatment in the system are enhanced by absorbing and converting the NIR light to heat.
As a result, after 120 h, the nanocarrier exhibits 38.1% and 68.1% drug release at
pH 7.4 and 5.0, respectively. Furthermore, the cell viability sharply decreased by
injecting the carrier into a DU145 cell-based tumor-bearing mice [82]. Table 9.2
summarizes the various types of CQDs and their notable features utilized as a drug
delivery system reported in literature.
Carbon Quantum Dots Based Materials for Drug Delivery 279
Fig. 7 Schematic illustration of in vitro anticancer performance of nanoconjugate based on CQD
and 5-FU as an efficient drug delivery system Reproduced with permission from Elsevier [47]
4 Challenges and Future Perspective
Current research indicates that nanoscale particles, particularly CQDs, have shown
great promise as efficient drug nanocarriers for drug delivery applications. CQDs
possess several advantageous properties, including an ultrafine size range below
10 nm and an extended active surface area adorned with diverse functional groups
[61]. These attributes make CQDs ideal candidates for targeted drug delivery, especially in challenging diffusional conditions, such as the blood–brain barrier (BBB)
and blood-tumor barrier (BTB) [101]. Despite their potential, achieving a uniform
size distribution for CQDs remains a challenging task using conventional fabrication methods. It is essential to address this issue to optimize their drug delivery
capabilities [102]. Additionally, the cytotoxicity of CQDs is a critical concern that
needs careful consideration before employing them in biomedical applications. The
source and fabrication process of CQDs play pivotal roles in determining their cytotoxicity and biocompatibility, thus warranting thorough evaluation and optimization
[103]. Given the ultrafine size range of CQDs, their photoluminescent properties,
and exceptional permeability, they offer exciting prospects for precisely tracking
drug delivery processes [104]. This potential tracking capability can greatly aid
in understanding drug distribution and assessing therapeutic efficacy in real-time.
To enhance the t argeting and delivery efficiency, researchers have explored surface
functionalization techniques for CQDs [105]. By attaching active ligands like FA,
antibodies, aptamers, or other molecules to CQDs, they can be guided to specific
280 M. Pourmadadi et al.
Tabl e 2 Some characteristic properties of CQDs-based drug delivery systems
CQDs based drug delivery system Materials of drug carrier system and its
References
drug release properties
Fe3O4@MOF-DOX-CQDs-Aptamer An assembly ofFe3O4core and
[83]
Metal–organic frameworks (MOFs)
shell conjugated with CQDs, loaded
with DOX, and capped by
nucleolin-binding aptamer is
synthesized with the pH-responsiveness
property. The carrier displayed 47.3%
of drug release over four days at pH 5.5,
and caused more than 77%
MDA-MB-231 cell death after 24 h
Fe2O3-CQDs-UN It is prepared from hydroxypropyl
[84]
cellulose cross-linked chitosan and
ulvan (UN) and showed 30.5% and
73.4% drug release after 20 h at pH 6.0
and 7.4, respectively
Fe3O4@OCMC@IRMOF-3/FA-DOX A composite system was synthesized by
[85]
combining nano MOF (IRMOF-3) with
the encapsulation of Folic acid (FA)
onto the surface of O-carboxymethyl
chitosan (OCMC) that had been
modified with magnetic nanoparticles.
This composite system was designed
for the delivery of the drug DOX
MOFs/CQDs@OCMC The CQDs are synthesized and
[86]
encapsulated into MOFs, coated by
OCMC, and loaded with DOX to form a
nanocarrier with pH-responsiveness
properties. The nanocarrier can
simultaneously be employed as an FOI/
MRI dual-mode imaging and drug
delivery. Studies on drug release
behavior showed total drug release at
pH 3.8 in 60 h and 20% release at pH
7.4
(continued)
Carbon Quantum Dots Based Materials for Drug Delivery 281
Tabl e 2 (continued)
CQDs based drug delivery system Materials of drug carrier system and its
References
drug release properties
FZIF-8/DOX-MIPs A core–shell assembly was constructed
[87]
wherein the core region consists of
fluorescent zeolitic imidazolate
framework-8 (ZIF-8) nanoparticles
loaded with DOX, while the shell is
formed by a molecularly imprinted
polymer (MIP). Within ZIF-8, both
CQDs and DOX are encapsulated,
serving the purpose of targeted imaging
and creating a biomaterial for GSH/pH
dual-stimulated drug delivery. In vivo
fluorescence signal is strongly observed
at 24 h in the MCF7 tumor site of mice.
Furthermore, in favor of coating
imprinted polymer, the leakage of DOX
to the body is highly reduced
Fe3O4@CQDs@mSiO2@PTX@mSiO2A NIR-responsive nanocarrier is
[88]
synthesized, featuring a magnetic
Fe
core and a mesoporous silica
3O4
shell embedded with carbon quantum
dots (CQDs) and paclitaxel (PTX). This
nanocarrier is further coated with an
additional layer of silica. High-capacity
drug loading is achieved in favor of a
dual silica shell structure. Furthermore,
by applying NIR irradiation for 5 min,
40% of the drug releases within 30 h
Sil@chitosan-CQDs hybrid nanogel A fluorescence pH-responsive hybrid
[89]
nanogel from CQDs embedded in
chitosan fabricated to deliver silibinin
(Sil) as a drug model. The studies
showed the drug delivery carrier had
35% and 69% of loading capacity and
encapsulation efficiency, respectively.
Furthermore, in vitro studies revealed
more than 60% MCF7 cancer cell
mortality in 48 h
(continued)
282 M. Pourmadadi et al.
Tabl e 2 (continued)
CQDs based drug delivery system Materials of drug carrier system and its
drug release properties
CS-PEO-CQDs/CMC-PVA A core and shell nanofiber for local
delivery of temozolomide (TMZ) is
synthesized from chitosan, polyethylene
oxide (PEO), CQDs, carboxymethyl
cellulose, and polyvinyl alcohol (PVA).
The cumulative release of the drug was
about 90% at pH 4.5 within 24 h. To
evaluate the morphology change of
cancer cells, U251 MG cells are
employed; the results suggest not only
the carrier internalized by cell lines but
also the cells are poisoned by the drug
leading to cell death
CQDs-HA-Hep/DOX A pH- and Hyaluronic acid (HA)-
responsive carrier based on CQDs is
synthesized and conjugated with DOX
and HA. HA, the chief receptor of
CD44, not only can create CD44-HA
affinity but also can persuade the drug
to enter cancer cells more efficiently. At
acidic conditions without HAase, the
carrier shows no drug release; however,
in the presence of HAase, 66% drug
release was observed
CDs/protoporphyrin IX The fabricated system can be applied as
the potential targeted drug delivery,
photodynamic therapy, and imaging
capability of the therapy process
CQDs/quinic acid/gemcitabine (Gem) In this delivery system, N-doped CQDs
have been modified by quinic acid as
the antioxidant and targeted ligand with
high affinity to breast cancer cells for
targeted Gem delivery. Results
indicated the sustained and targeted
release with high loading capacity and
enhanced cytotoxicity without
considerable side effects
CQDs/L-Arg-Ag@Cu) This CQDs-based system has been
developed by functionalizing Cu by Ag
nanoparticles and L-arginine as the
precursor for employment in chemo/
photodynamic therapy through
controllable ROS production in a
targeted manner. Their results showed
the in situ DOX release, prohibiting
metastasis and tumor growth
References
[90]
[91]
[92]
[93]
[54]
(continued)
Carbon Quantum Dots Based Materials for Drug Delivery 283
Tabl e 2 (continued)
CQDs based drug delivery system Materials of drug carrier system and its
5-FU/chitosan (CS)/CQDs/aptamer
(Apt)
CQDs/DOX This study has proposed the
N-doped CDs@DOX and @Gem This study has focused on the N-doped
Lycorin e/ CD s In this case, lycorine has been employed
drug release properties
In this case, the anticancer drug 5-FU
has been encapsulated into the prepared
water-in-oil emulsion of CS/CQDs/Apt
with good stability due to the + 31.2
mv zeta potential. MCF-7 cells have
been treated effectively under the
sustained release of 5-FU
red-emissive CQDs as a promising
nanocarrier for delivering DOX with a
loading concentration of 30 μg/mL.
Their cytotoxicity outcomes revealed
around 30% more apoptotic effects
against HeLa cancer cells compared to
free DOX. Moreover, they showed that
both cancer cells and cancer stem cells
have been destroyed by this drug-loaded
system
CDs derived from persimmon fruit in
the size range of 3–6 nm to carry DOX
in a targeted behavior to treat cervical
cancer. They employed both Gem and
DOX as the active agents on HeLa cell
lines, which indicated an accumulation
in the cytoplasm instead of the nucleus,
and through the bioimaging process,
they showed the caspase activation
pathway
as the active agent and loaded on CDs
acquired from Morus alba L in the
ultrafine size range of 2–4 nm. They
employed HepG2 as the cancer cell line,
and their results indicated drug
accumulation in cytosol
References
[94]
[56]
[57]
[95]
(continued)
284 M. Pourmadadi et al.
Tabl e 2 (continued)
CQDs based drug delivery system Materials of drug carrier system and its
References
drug release properties
CQDs functionalized with estradiol
hemisuccinate for targeted delivery of
DOX
This work has been dedicated to
targeted DOX delivery through the
functionalized CQDs as the nanocarrier
[96]
to treat breast cancer. The CQDs have
been fabricated by citric acid and
ethylenediamine combinations, after
getting exposed to heat for 2 h and at
200 °C, extracting, and freeze-drying
process. They functionalized CQDs by
estradiol hemisuccinate and their results
showed an effective targeted DOX
delivery to MCF-7 cells compared to
normal cells
CQDs/DOX This study reports the photo-sensitive
[97]
P-doped CQDs with over 50% quantum
yield as a targeted DOX delivery
platform to treat breast cancer
synergistically. They fabricated the
CQDs through citric acid and obtained
98% DOX loading efficiency. They
employed NIR irradiation to
synergistically treat MCF-7 cells while
an enhanced apoptotic effect has been
indicated and biocompatibility of the
synthesized CQDs-based delivery
system has been approved
N-doped-CQDs/ methotrexate (MTX) In this research, MTX has been loaded
[98]
on the fabricated N-doped CQDs to treat
breast cancer. Their MTT colorimetric
assay outcomes revealed an enhanced
apoptotic effect against MCF-7 with
lower than 20% cell viability, which was
50% more effective compared to normal
cells, indicating reduced side effects
and achieving targeted drug delivery
(continued)