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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5604_Библиотеки_им_академика_М_И_Перельмана.pdf
Fullerene Based Materials for Drug Delivery 355
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Graphene Quantum Dots-based Nanomaterials for Drug Delivery
Md Emamul Kabir, Adib Bin Rashid, and Md Enamul Hoque
Abstract Implementing graphene quantum dots (GQDs) as zero-dimensional nano-
materials for drug delivery is obvious due to exceptional physicochemical, optical
(photoluminescence and electrochemiluminescence), and biological properties such
as good photostability, emission of multicolor, biocompatibility, less toxicity, and
chemical inertness. Moreover, surface adhesion to organic molecules and planner
structure increases surface area compared to volume, quantum confinement, and
edge effects, facilitating drug delivery applications. Specific properties related to drug
delivery of GQDs are emphasized at the beginning of this chapter. Several synthesis
procedures of GQDs, including bottom-up and top-down methods with newly developed preparation of GQDs for drug delivery applications, are highlighted. Finally,
this chapter will summarize novel applications in medication administration, stating
limitations, challenges, and future scope of research.
Keywords Graphene quantum dot
Chirality · Drug delivery
· Synthesis procedures · Optical properties ·
Abbreviations
B-GQDs Boron-doped GQDs
W-GQDs White-light-emitting graphene quantum dots
N-GQDs Nitrogen-doped GQDs
M. Emamul Kabir
Mechanical Engineering Department, Military Institute of Science and Technology (MIST),
Dhaka, Bangladesh
A. B. Rashid
Industrial and Production Engineering Department, Military Institute of Science and Technology
(MIST), Dhaka, Bangladesh
M. E. Hoque (
Biomedical Engineering Department, Military Institute of Science and Technology (MIST),
Dhaka, Bangladesh
e-mail: enamul1973@gmail.com
B
)
357
358 M. Emamul Kabir et al.
A-GQDs Aminated GQDs
sEV Small extracellular vesicles
FRET Fluorescence resonance energy transfer
5
3T3 3-Day transfer, inoculum 3×10
cell
CC8 Cell Counting Kit-8
FA Folic Acid
HEK Human embryonic kidney
PEG Polyethylene glycol
APTES (3-Aminopropyl)triethoxysilane
RGD Arginylglycylaspartic acid
BHC Benzene Hexachloride
MCF Michigan Cancer Foundation
DOX Doxorubicin
WST Water soluble tetrazolium
LDH Lactate dehydrogenase
MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
HFF Human foreskin fibroblasts
MGC Multinucleated giant cells
fGQDs Functionalized graphene quantum dots
mGQDs Mangifera indica (mango) assisted graphene quantum dots
cGQDs Carboxylated graphene quantum dots
MDA-MB-231 The MDA-MB-231 cell line is an epithelial, human breast cancer
cell line that was established from a pleural effusion of a 51year-old caucasian female with a metastatic mammary adenocarcinoma1
1 Introduction
The process of administering pharmaceutical substances is known as drug delivery.
Nowadays, more extensive research and development of new materials or carrier
systems is done to treat people or animals effectively. Drug loading, targeting, and
efficacy can all be improved by Drug Delivery Systems (DDS) made up of nanoparticles, which also have better pharmacokinetic and biodistribution profiles [1–3]. To
increase medication delivery to target tumor cells while limiting damage to normal
tissue, the surface of nanoparticles can be enacted with targeting molecules such
as folic acid, arginine-glycine-aspartic acid (RGD), and antibodies. Consequently,
due to their higher photostability rather than organic dyes and lower toxicity than
semiconducting material quantum dots, GQDs enable tracking of internalization,
dispersion within cells, and discharge [4–6].
The next peers of nanomaterials based on carbon are thought to be GQD, which are
single-layered, graphene fragments with tremendous potential in biology [7] because
of their high inherent fluorescence, surface area compared to volume, delocalized
Graphene Quantum Dots-based Nanomaterials for Drug Delivery 359
electrons, and several closest functional groups, incorporating carbonyl, hydroxyl,
epoxy and carboxyl groups. GQDs can be applicable for the delivery of several drugs
[8, 9]. Since GQDs are made of “all carbon” material and, unlike mineral quantum
dots, may not degrade into harmful metal ions, they have recently attracted many
people’s attention. Additionally, they are highly desirable for drug administration
applications due to their constant photoluminescence, distinctive excitement reliant
on emission, solubility in a range of solvents, chemical dullness, natural functional
groups at the boundaries, and ease of modifying size and form. The history and
evaluation of GQDs nanomaterials are previously discussed [10].
Additionally, GQD effectively accelerates the nuclear enhancement of these
medicines’ cytotoxicity and DNA-breaking activities. These exceptional biological
characteristics [11] demonstrate how GQD is advanced to alter graphene, GO, and
other nanoparticle-based delivery technologies. These nanoparticles have demonstrated excellent biocompatibility and the capacity to deliver medications to cancer
cells. Further, the ability provided by their multimodal conjugation enables the incorporation of both medications using several ligands inside the same nanostructure t o
lessen the general deadliness of anti-cancer drugs and conventional chemotherapy’s
negativeeffects.All these advantages make GQDs nanomaterials a good candidate for
drug delivery applications. However, toxicity concerns should be vital for developing
new methods or preparation techniques that will lessen the toxicity of nanomaterials
both in the synthesis process and drug delivery to avoid damage to the soft tissue or
biological properties. Therefore, in this chapter, we will summarize the GQDs nanomaterial’s properties related to drug delivery, discuss different synthesis methods,
and cite different characterization processes of GQDs and existing approaches to
apply GQDs for drug delivery. To complete the overview, toxicity related to GQDs
is also studied. At the end of the chapter, we will clarify the limitations and future
opportunities of research of GQDs for drug delivery applications.
2 Synthesis of GQDs
To date, new approaches to GQD synthesis have achieved tremendous strides. Topdown/ bottom-up methods are the two overarching strategies for GQDs. The first
method relies on the abrasive cleavage and exfoliation of large quantities of graphite.
Most GQDs are constructed from polycyclic fragrant compounds or molecules with
scented compositions, both used in the bottom-up method. We can divide topdown/bottom-up methods among the currently available GQDs synthesis methods
(Fig. 12.1a) [12, 13]. Synthesis of GQDs is complex, requiring multiple reaction
stages and very particular organic ingredients, making it challenging to optimize
conditions as with other bottom-up approaches (Fig. 12.1b). As a result, the top-down
method involves splitting into huge blocks of carbon composites. This approach is
uncomplicated and simple to synthesize GQDs, and carbon compounds are abundant,
cheap, and straightforward sources of the necessary basic materials.
360 M. Emamul Kabir et al.
Fig. 12.1 a Multiple GQD synthesis strategies. Reproduced with permission from MDPI [13]and
b fluorescent GQDs can be made in two main approaches: the “top-down” splitting technique,
which uses a variety of carbon sources, and the “bottom-up” approach, which employs either tiny
polymers, molecules etc. Reproduced with permission from Springer [14].
Despite being less expensive, the top-down method has several limitations,
including several synthesis stages, harsh reaction environments, and a lack of structural control. However, the main benefit of this process is that the resulting GQDs
contain oxygen-rich groups that can improve their solubility and functionalization.
The downsides of bottom-up methods include the necessity for costly precursors
and complex synthesis stages, even though they allow for fine-grained control over
morphology, size, and form. The high aggregation tendency of the synthesized
GQDs severely restricts the method’s usefulness. Table 12.1 provides high-level
introduction to the most cutting-edge methods for synthesizing GQDs [15].
3 GQD’s Properties for Drug Delivery
3.1 Optical Properties
The chemical functions, imperfections, doping, pH, and size all affect how brightly
GQDs shine under excitation [25]. Photoluminescence refers to the discharge of light
by GQD after it has taken i n photons, excited its electrons to a higher energy level, and
allowed them to relax to their original state. When excited, GQDs exhibit remarkable
luminescent properties and a nonzero band gap. Developing optical sensors and
drug delivery applications is hindered by the fact that for band gaps that are not
zero, ordinary QDs do not glow. The PL band length of GQDs sets them apart
from regular QDs. The PL band spectra will look very different depending on the
excitation wavelength, which can be anywhere from 300 to 470 nm for GQDs. The
assignment of the PL band spectra is made possible by the move from the lowest
vacant to the highest populated atomic orbital (LUMO to HOMO). GQD’s band
gap was found to be decreasing as their sizes grew larger and vice versa. Band
Graphene Quantum Dots-based Nanomaterials for Drug Delivery 361
Table 12.1 Synthesis method, precursor and parameters, and corresponding size of GQDs. Adapted
and reproduced with permission form ACS [15]
Synthesis
method
Precursor for GQD The GQD synthesis
reaction flow
GQD size References
process parameters
Solvent-free
synthesis
aided by
sonication
Graphite powder >
graphene oxide (GO) >
GQDs
The conditions
were: pH greater
12, temperature
higher than 200 °C,
Diameter
averaging
5.3 nm
[16]
time greater than
5 h, solvent > DMF,
and yield greater
than 1.6%. Before
solvothermal
treatment, 30 min
of ultrasound
treatment at 120 W
and 100 kHz were
used on GO in
DMF
Chemical
synthesis with
ultrasonic
heating and
agitation
Graphite powder >
expanded graphite > GQDs
The yield was
using DMF and
H
at a
2O2
temperature of
170°C for 5 h.
Size averaging
35 nm
[17]
Membrane
filtration was used
to isolate and
isolate GQDs.
Before undergoing
for 5 min,
expanded graphite
was treated with
ultrasound in DMF
as a solvothermal
treatment
Green
synthesis
Biomass waste The reaction of
used tea leaves in
Size of 0.5 to
4nm
[18]
ethanol at 200 °C
for 8–12 h,
followed by
exposure to
ultraviolet light
(continued)
362 M. Emamul Kabir et al.
Table 12.1 (continued)
Synthesis
method
Precursor for GQD The GQD synthesis
reaction flow
GQD size References
process parameters
Hydrothermal
microwave
assist in
treatment of
glucose
Glucose > GQDs Microwave ovens
were used to heat a
glucose-water
solution for various
times and
Diameter
averaging
3.4 nm
[19]
temperatures (1, 3,
5, 7, 9, and 11 min
at 280, 336, 462,
595, and 700 W)
Citric acid
pyrolysis
Oxidation by
an electrical
current
Citric acid > GQDs Pyrolysis of citric
acid occurred at
200 °C for around
30 min
Graphene film > NGQDs CV inspecting over
a 3.0-V probable
window produced
Radius of
circa ∼7.5 nm
(0.5–2.0 nm
thicknesses)
Radius of
cirka1-2.5 nm
[20]
[21]
N-GQDs. The
electrolyte was
acetonitrile-TBAP
Hydrothermal
synthesis
aided by
ultrasonic and
microwave
irradiation
Graphite powder > GQDs >
WGQDs
After2hof
ultrasonication in
acid (HNO
H
2SO4
/
3
1:3), 4 h of
heatingina
microwave at
Size averaging
2.5 nm
[22]
100 °C, and
neutralization with
sodium carbonate,
graphite
nanoparticles were
produced.
Membrane
filtration and
dialysis were used
to achieve purity in
GQDs. At a pH
value of 13,
additional
microwave
treatment
transformed GQDs
into WGQDs
(continued)
Graphene Quantum Dots-based Nanomaterials for Drug Delivery 363
Table 12.1 (continued)
Synthesis
method
Hydrothermal
synthesis
Fullerene C
oxidation
using the
Hummers’
technique
Precursor for GQD The GQD synthesis
Graphite powder > GO >
oxidized graphene sheets
(GSs) > GQDs
Buckminsterfullerene (C60)
60
> GQDS
reaction flow
process parameters
The conditions
were pH 8,
temperature of
200 °C for 10 h,
time of water as
solvent, and yield
of 5%. Filtration
and dialysis were
used to obtain pure
GQDs
C60was treated
with sodium nitrite,
KMnO
,and
4
H
in water at
2SO4
various
temperatures and
for variable
amounts of time.
NaOH was used to
neutralize the
H
used to
2O2
remove the excess
KMnO
4
MnO
. Dialysis
2
was used to clean
up the GQDs
and
GQD size References
Limits of
5–13 nm
(9.6 nm
average
diameter)
Size ranging
from∼2to
3nm
[23]
[24]
gap narrowing is attributed to the delocalization of electrons [26]. Researchers have
discovered that the diameter of GQDs is 0.46 nm to 2.31 nm, emitting light across
the visible spectrum, from the extreme UV to the NIR. GQDs between 0.89 and
1.80 nm generate fluorescence that spans the visible light band (400–770 nm). As
a result, the excitation and emission spectra of GQD combinations of varying sizes
can be used to assess the effect in the context of medication administration.
3.2 Physicochemical Properties
GQDs’ potential for use in DDS is contingent on their physicochemical characteristics. Compared to conventional QDs, GQDs have superior qualities such as chemical
inertness, biocompatibility, stability, versatility to conjugate with organic molecules,
and low toxicity. GQDs also have high-quality electrical and magnetic properties
for their better edge architecture and the impact of quantum confinement. On the
other hand, charge transfer between the sp
2
carbon chain and states at the surface
364 M. Emamul Kabir et al.
(such as chemical moieties, edge states, and heteroatom dopants) is associated with
extrinsic or surface-related emissions. The effect of surface functionalities on GQD
emission wavelength has been the subject of extensive study. The emission strength
and photoluminescence color of GQDs change as the intensity of surface functionalities is oxidized, reduced, or otherwise manipulated. GQDs are excellent candidates
for drug delivery applications due to their strong interactions with organic molecules
and drugs.
3.3 Mechanical Properties
There are therapeutic applications in which mechanical qualities are indispensable.
Compared to pure graphene, the properties of GQDs switch as their size decreases,
and they have a higher surface capacity to volume proportion. Because of their size
dependence on physical properties, biocomposites of GQDs are employed for drug
delivery in biological processes because of their exceptional structural integrity and
resilience.
3.4 Biocompatibility and Cytotoxicity
For many biological uses, i ncluding medication delivery, biocompatibility is a crucial
quality in GQDs. When an agent is biocompatible, it can work in tissue without
affecting adverse biological results like toxic reactions. The idea of biocompatibility must be evaluated considering the material’s intended use. One way to assess
a substance’s biocompatibility (hazardousness to grown cells) is to test its cytotoxicity. The key part is to impact the hazardous manners of GQDs in diverse in vitro
alongside in vivo uses, even though nanoscale GQDs have distinct advantages. Cytotoxicity was negligible, however, for GQDs attached with clusters other than-COOH,
-OH doped with a heteroatom or amino group. Also, GQDs have been proven to be
less cytotoxic than both carbon nanomaterials and nanoparticles derived from other
metals. Compared to other carbon nano-allotropes, which exhibit enhanced cytotoxicity due to aggregation, GQDs have superior water stability and may be considered
a non-toxic alternative. In addition, unlike metal-based nanoparticles, the carbonbased structures of GQDs render any lingering metallic residues harmless. GQDs
with tiny lateral widths cannot disrupt lipid membranes in cells, and hence, they can
be employed in a wide range of biomedical applications, including drug delivery, as
shown by many theories and experimental studies on GQD cytotoxicity.