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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5362_Библиотеки_им_академика_М_И_Перельмана.pdf
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 415
1 Introduction
1.1 Drug Delivery
Drug delivery is a technique or process of administration of pharmaceutical agents at a
specific site to accomplish therapeutic effects in humans or animals through an appropriate transportation pathway [1]. Various drug delivery routes, mainly pulmonary
and nasal, have drawn attention in recent years for the effective curing of human
diseases. These routes enable alternative ways which are different from parenteral
drug delivery routes to administrate conventional drugs, and protein and peptide therapeutics [2]. However, for the delivery of therapeutics through the abovementioned
routes, an advanced drug delivery system is required to obtain desired results. Also,
there is an upsurge in demand to develop advanced therapeutic delivery vehicles due
to the safety concerns, time consuming method and problematic drug release monitoring process of conventional systems [3]. Therefore, to overcome these difficulties,
new chemical entities have been engineered since the late 1950s. It has been seen that
the development of new drug delivery systems starting from discovery, clinical trial,
designing to regulatory approval generally takes more than a decade and costs around
$120 million [2]. Therefore, implementation of preferable and advanced options in
designing drug delivery carriers is necessary for economical and satisfactory development. Nanotechnology has played a pivotal role in developing the drug delivery
vehicles by entering the realm of drug administration since it helps different components to match the sophistication and precise structure of biomolecules by extending
its potential for effective delivery of therapeutics. The way of disease treatment has
been changed due to the emergence of nanotechnology, but its clinical implementation still possesses huge challenges. Testingvarious methods to control the interaction
of nanomaterials with the body and to overcome the barriers to transforming these
methods into therapies related purpose is the centre of the current research topics.
Investigationshave been continuously executed to increase the therapeutic action and
to minimize the toxic aftermath of the drug delivery system [4–6]. To achieve results
in this application, different drug administrative vehicles like gel [7], microsphere
[8], cyclodextrin [9], liposome [10], nanomaterials [11] etc., have been formulated
and scrutinized. Out of these, nanoparticles and biodegradable polymers have shown
assurance in accomplishing requirements to create drug delivery vehicle for stable
and target specific drug delivery at the predetermined site [12–14]. Carbonaceous
nanomaterial are some burgeoning materials that are used as the drug delivery system
[15, 16]. However, systems with stimuli responsive behavior have more successful
applications in the drug delivery area [17, 18].
416 A. M. Mahmoud et al.
1.2 Cardiovascular Diseases
Cardiovascular diseases (CVDs) are the preeminent reason for mortality around the
globe. Based on the World Health Organization’s data [19], CVDs were accountable
for 32% of all global deaths and the estimated number of people who died was 17.9
million in 2019. The current figure is anticipated to reach 23.6 million annually
by the year 2030 [20]. Further, heart attack and stroke were linked to 85% of the
people died from CVDs [19]. Despite the great progress in the treatment modalities,
the incidence of CVDs rises globally [21]. CVDs represent a huge socio-economic
burden for the treatment, and it is on the rise annually which costs $320 billion in
USA [22]. The development and progression of CVDs are associated with several
threat factors, namely high blood pressure, age, smoking, high cholesterol, diabetes,
obesity,and family history [23]. Threat factors for CVDs are classified into adjustable
and non- adjustable threat factors. The adjustable risk factors are obesity, unhealthy
eating habits, smoking, alcohol ingestion, hypertension, and diabetes, and the nonadjustable include sex, age, and hereditary factors [ 24, 25].
CVDs include a range of disorders affecting the heart and blood vessels. These
include coronary artery disease (CAD), coronary heart disease (CHD), cerebrovascular disease, peripheral arterial disease (PAD), rheumatic heart disease, congenital
heart disease, venous thromboembolism (VTE), heart failure, stroke, and cardiomyopathy (Fig. 1)[19, 26]. Most of these diseases exhibit long-time symptoms and
prevent the patients from practicing normal life exercises. CAD is the primary
contributor to global mortality and is developed because of the formation of plaques
along with inflammation in the coronary arteries. Plaques are generated because of
the deposition of cholesterol, fatty substances, and fibrous tissue inside the inner wall
of the arteries that clog the coronary artery and obstruct the flow of oxygen affluent
blood to the heart leading to heart myocardial ischemia and angina pectoris [27, 28].
In cerebrovascular diseases, an important part of the brain is transiently or indelibly
stimulated by ischemia or bleeding resulting in the restriction of blood flow. Stroke,
carotid stenosis, aneurysms, transient ischemic attack (TIA), subarachnoid hemorrhage (SAH), and vascular dementia are among the cerebrovascular diseases [29].
Stenosis, thrombosis, embolism, or hemorrhage can cause insufficient blood flow
that affects the brain, leading to a stroke. TIA is a temporary loss of blood flow in
the brain that leads to neurological dysfunction [30]. Although TIA is not like stroke
and results in no tissue damage, the chance of stroke incidence for patients with
TIA significantly increased [31]. SAH occurs due to bleeding into the subarachnoid
space of the brain [32]. The presence of blood close to the brain increases seizures
and vasospasm incidence [33]. Additionally, the formation of a blood clot in the
subarachnoid space, filled with cerebrospinal fluid (CSF), elevates pressure on the
brain, leading to brain herniation and eventual fatality [34]. Vascular dementia occurs
post-stroke and causes impaired cognitive function and loss of memory [35]. VTE
refers to the blood clot originating in the vein and is classified into deep venous
thrombosis (DVT) and pulmonary embolism (PE). DVT is a clot in the lower limbs
usually in the legs and PE occurs when the clot breaks off from the vein wall and
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 417
travels to lodge in pulmonary arteries in the lung. PE is considered a serious lifethreatening condition because it restricts the blood flow and increases the pressure
on the right cardiac ventricle [36]. PAD occurs due to blockage of the vessels that
carry the blood towards the leg. This pathological condition is poorly understood,
and it shows severe symptoms of cramps in the hip, calf muscles, claudication,
fatigue, and gangrene [37]. Rheumatic heart disease is caused by rheumatic feverdriven inflammation and scarring that damages the heart valves and myocardium.
Abnormal immune response to streptococcal infection, particularly in children, is
the main underlying cause of rheumatic fever and is responsible for 2% of deaths
from CVDs [19].
There are several conventional treatment methods that are used to mitigate the
symptoms of CVDs and open the narrowed arteries. These include the administration of pharmaceutical drugs such as anticoagulants, statins, β-blockers, and ACE
inhibitors. In addition, surgical interventions are required in severe cases like coronary artery bypass graft surgery (CABG) which diverts the blood around the clogged
region of the arteries to enhance the oxygen supply and blood flow to the heart
[38–40]. However, these methods fail to regenerate damage of the cardiac tissue.
Therefore, innovative treatment approaches are required. The usage of bioactive
Fig. 1 Different type of cardiovascular diseases
418 A. M. Mahmoud et al.
materials for tissue engineering and biodegradable delivery systems for pharmaceutical drugs and cells has emerged as an interesting research area during last decades
[41]. Also, exact formulation for clinical purposes in CVD drug delivery applications is a challenging process for regulatory and experimental limitations. Despite
the presence of biomaterial-based drug administration carriers for CVD treatment,
nanomaterial-based systems have garnered attention owing to their promising characteristics. Chitosan (CS) and carbon nanomaterials are the perfect combination for
the diagnosis of CVD [42].
1.3 Chitosan and Its Properties
CS is a naturally occurring linear polysaccharide and comprises of glucosamine
and N-acetyl glucosamine components associated together with β (1–4) glycosidic
bond. It exhibits structural similarities with glycosaminoglycans (GAGs) which are
distributed through connective tissues and are the main components of the ECM.
This advantage enabled it to show great potential for interaction with the biological
macromolecules and to be utilized widely as scaffolds for tissue engineering purposes
[43]. CS is obtained through partial alkaline hydrolysis of chitin and the existence of
free amino groups on the backbone of CS offersseveral chemical modification opportunities for different biomedical applications. The polycationic nature of CS due to
the protonation of the free amino groups supports ionic interaction with negatively
charged components like anionic GAG and DNA [44]. Starting from the early 1990s,
CS has entered the arena of the pharmaceutical industry and since then a huge amount
of research articles have been published based on its promising applicability in drug
delivery applications. Contrary to other polysaccharides, the existence of a primary
amino group helps in mucoadhesion, transfection, in situ gelation, enhanced permeation ability and controlled drug administration. Chemical modification and addition
of nanomaterials have also enhanced its potential in biomedical applications [45].
Further, it is seen that the protonation of the free amino groups is pH-dependent.
Once the ionic complex is brought to the physiological pH, the anionic partner is
detached from the CS. This character is exploited further for drug delivery applications. For example, CS forms a complex with heparin to achieve the controllable
release of heparin to stimulate the inflammatory cells to release growth factors and
enhance the wound healing process [46].
CS can form a complex with nucleic acids and hence could be used for gene
delivery applications. Naked genes have the capability to undergo degradation by
serum nucleases and cannot cross the cell membrane. The electrostatic interactions
occur between negatively charged nucleic acids and CS assists in the formation
of a condensed complex that helps in the protection of the delivered genes from
the action of nucleases [47]. Also, the negatively charged cell membrane attracts the
positively charged CS and enhances the translocation of the gene into the nucleus. M a
et al. demonstrated that CS nanoparticles can efficiently administrate nuclear factorkappaB (NF-κB) p65 antisense oligonucleotides within the nucleus of RAW264.7
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 419
macrophages [48]. Therefore, CS holds promise as a nongenotoxic delivery carrier
and as a potential variative to viral systems due to its immunogenicity and toxicity
concerns [49]. Moreover, CS has unique porous properties that can be exploited for
3D structure development for tissue engineering applications [50].
CS has biodegradable properties and could be degraded by the effect of lysozyme
in vivo. The extent of degradation of the implant must be equal to the tissue regeneration rate [51]. The degradation nature of CS is subordinated with the degree of
deacetylation, molecular mass, and tissue response for the implants [52]. Nevertheless, the mechanical strength characteristics of CS can be enhanced by the addition
of either natural or synthetic polymers [53]. CS implants and their fragments don’t
provoke inflammation during the tissue regeneration process and normal granulation
tissue with vascularization is always observed [54]. From the investigation, Suh et al.
concluded that CS can enhance cell proliferation and the unification of scaffold with
the host tissue [44]. Furthermore, CS has bactericidal property against varieties of
bacteria due to its interaction with the negatively charged bacterial cell wall. This
engagement of CS and bacteria helps in increasing the probability of permeability
and attachment of CS with DNA. So, this action can lead to bacterial cell death
by inhibiting DNA replication [55]. This criterion could be another advantage for
tissue engineering applications. In addition, CS has certain wettability and swelling
properties [56, 57]. Qiu et al. fabricated a 3D-printed polycaprolactone (PCL) stent
and modified the surface with sulfated CS to treat atherosclerosis. This modification
enhanced the mechanical properties of PCL, enabling it to withstand 0.7 N of force
without displacement and protect the stent from enzymatic rejection for 60 days [58].
1.4 Chitosan/Carbon Nanocomposites
CS and carbon nanomaterials have emerged as significant platforms for the treatment of CVDs and drug administration application. Recent scientific reports have
suggested the implementation of carbon nanotubes (CNT) in the drug delivery
process because of their applicability in the fabrication of drug administration vehicles, improvised technique and quality for the administration of therapeutic agents.
Major factors that influence the efficacy of CNT in the drug delivery process are large
surface area, high drug accommodation ability and biocompatibility. Its biocompatible nature mainly depends upon the preparation process, shape, size, degree of
aggregation and dispersion on the applied platforms, presence of impurities, and
most importantly, cellular uptake and the path of administration. In the last few
decades, researchers have given more efforts to add CNT with polysaccharides, like
CS to investigate their surface chemistry and hydrophobic and hydrophilic characteristics in cell behavior especially in control of tumor cell growth and therapeutic
administration [59, 60]. Chemical grafting is a competent method to attach CNT
with CS via covalent functionalization techniques. Grafting assists in amplifying
hydrophilic nature, dispersion capability and prolonged stability of CNT. With the
help of grafting method, CS-CNT forms a stable nanocomposite material for diverse
420 A. M. Mahmoud et al.
applications [61]. Aryaei et al. designed a nanocomposite film based on multi-walled
CNT (MWCNT) and CS that displayed strong interaction between MWCNT and CS.
The prepared material showed great relevancy in biomedical applications [62].
2
Graphene is an atomically thick nanosheet and is comprised of sp
hybridized
carbon atoms. It acts as the building block for other carbonaceous nanomaterials like
fullerene and nanotubes [63]. Graphene oxide (GO) is the modified oxidized version
of graphene nanosheet. Since GO is derived from graphene, it inherits some prominent conductive, chemical, and mechanical properties from graphene. Hydroxyl,
carboxyl, and epoxy groups of GO avail new paths to interact chemically or physically with a variety of polymers. GO can be employed as both filler and matrix
to procure exceptional properties. Further, it possesses bactericidal and anticancer
activities. Hence, it has been largely implemented in biomedical areas like drug
administration, biosensing, tissue engineering, bioimaging and others. However, it
is only safe to use in lower amounts. Utilization of a higher amount of GO can
create complexity; therefore, its usage in human is restricted. Toxicity of GO can be
obliterated by the coalescence of GO with CS. The presence of numerous functional
groups leads to the association of CS and GO via electrostatic interactions, hydrogen
bonding or covalent bonding. This advantageous combination has great importance
in in vitro and in vivo biomedical and pharmaceutical applications. Research reports
revealed that in the treatment of CVDs and for the effective therapeutic loading and
release, materials made from GO and CS are highly exceptional [64].
Since 2004, carbon dots have secured immense popularity as a multifaceted mate-
rial for biomedical applications. Carbon dot is a quasi spherical shaped particle
2
having 10 nm of average diameter size. This nanoparticle comprises of sp
conjugated carbon atoms along with different oxygen accommodating functional groups
such as hydroxyl, carboxyl, and aldehyde groups. On account of several distinct
features of carbon dots such as hydrophilic property, easy functionalization ability,
equitable cell permeability, good water-soluble capacity and ability of showing fluorescent properties on UV exposure, these materials have been widely exploited in
targeted drug administration, bioimaging, wound healing, cancer therapy, curing of
CVDs etc., [65]. One of the prominent examples of the carbon dot is the graphene
quantum dot (GQD). Owing to the edge effect and potent quantum confinement,
GQD has received recognition by the scientific community. Further, it is seen that
the fabrication methods determine properties of GQD. Moreover, GQD is composed
of carbon, it is less toxic as compared to other inorganic quantum dots. Peculiarities
like solublity in various solvents, chemical inertness, excitation-related emissions,
fluorescent characteristics, presence of functional groups on the edges, and capability
to accommodate drug molecules via π-π interactions have made GQD a talented
material for drug administration and cellular imaging [66]. Si et al. fabricated GQD
from GO and incorporated GQD within the CS/Collagen (CG) hydrogel matrices to
prepare an efficacious material for cardiac regeneration. Further, they encapsulated
human mesenchymal stem cells (hMSCs) within the hydrogel and implemented it for
cardiac therapy after the diagnosis of acute myocardial infarction (MI). The outcomes
of the in vivo study revealed improvement in angiogenic ability and minimization
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 421
Fig. 2 Preparation procedure and cardiac regeneration process of hMSCs encapsulated GQD based
CS/CG hydrogel. Reproduced with permission from Elsevier [57]
of MI site of the heart after injecting the developed material. The preparation procedure and cardiac regeneration process of hMSCs encapsulated in GQD-based CS/CG
hydrogel are schematically illustrated in Fig. 2 [57]. Carbon quantum dots (CQDs) is
another fluorescent nanomaterial that has been employed in biomedical applications
as an individual platform as well as with various polysaccharides like CS [67].
Carbon nanohorn (CNH), also known as carbon nanocone, is a conical shaped
nanostructured material [68]. In comparison with CNT, CNH appears to exhibit many
advantageous criteria like high immaculacy, a less toxic nature, immense reactivity,
and being more spacious to encapsulate drug molecules. The unique combination of
CS and CNH has a significant impact on therapeutic administration of nanomedicine
and fluorescence labeling. Li et al. implemented an approach to prepare CS-, CNH-,
and CQD-based nanocomposite for in vivo imaging and cell labeling. CS assists
to encapsulate CNH to generate an amino-based surface and as a consequence of
this process CNH helps in the attachment of CQD with CS via the carboxylic functional group. The as-synthesized material can also be employed as an effective drug
delivery tool [69]. Another incredible carbon nanomaterial is carbon nano-onion
(CNO). It consists of multishell concentric fullerene structure with 0.34 nm distance
between the layers and the diameter of the CNO lies between 60 and 300 nm. High
surface area and pi-electrons make it appropriate for drug delivery carriers. CNO- and
CS-based nanocomposite have been exploited in biomedical applications [70–72].
2
Nanodiamond (ND), a carbonaceous nanomaterial, exhibits sp
3
shell and a stable sp
hybridized carbon core. Protein binding capacity and ability
hybridized carbon
to enhance chemotherapeutic effect are the two significant factors that help CNO
achieve beneficial outcomes in biomedical applications. Despite these advantages,
the stability of ND in therapeutic administration applications has created issues in its
effective implementation. Therefore, stabilization of ND through different methods
has been carried out by scientists. Entrapment of ND within liposomes and coating
of ND with steric polymer are the two techniques widely used to stabilize ND. It has
already been reported that successful binding of ND with carboxymethyl CS through
422 A. M. Mahmoud et al.
Fig. 3 Advantageous properties of CNT, graphene, carbon dot, CNH, CNO and ND
amide linkage. It is also seen that CS could also be attached to ND through the negatively charged surface of ND. However, in spite of having excellent properties, CS/
ND-based nanomaterials are being recently employed in drug administration and
diagnosis of CVDs [73, 74]. Advantageous properties of CNT, graphene, carbon dot,
CNH, CNO and ND that help in drug administration and treatment of CVDs are
demonstrated in Fig. 3.
2 Chitosan/Carbon Nanocomposites in Drug Delivery
The treatment of fatal diseases through successful controlled drug delivery methods
is an advanced method. Conventional drugs used for the management of CVDs are
mostly available in the oral drug delivery system. The pharmaceutical companies
spend a huge budget annually on the treatment of CVDs. Therefore, these companies show a keen interest in discovering a novel drug delivery system that achieves
controllable drug release and sustainability [75]. As previously described, CS exhibited various desirable properties as a safe and biodegradable carrier for therapeutics delivery. The small drug molecules released from CS composites via divese
mechanisms, encompassing diffusion, swelling, erosion, and biodegradation [76,
77]. However, the drug release behavior is also dependent on its physical properties
such as size, dose, hydrophilicity, and hydrophobicity [78]. Atorvastatin is an effective inhibitor for HMG-CoA reductase that mediates cholesterol synthesis. JB et al.
used CS as a carrier platform for oral administration of atorvastatin in atherosclerosis.
Atorvastatin-loaded CS showed a slow and controllable r elease profile of drug, which
is necessary to avert the probability of drug resistance and minimize the frequency
of the dosages [79]. Metoprolol is a beta-blocker drug that enhances blood circulation and is used to treat angina, arrhythmia, and hypertension. Metoprolol is an
extremely water-soluble drug and its half-life time range is 3–4 h [80, 81]. Consequently, several dosages are required to prolong a sufficient plasma concentration
Chitosan/Carbon Nanocomposites in Drug Delivery and Cardiovascular … 423
inside the body for a better therapeutic response. The frequent administration of metoprolol causes unwanted toxic side effects and decreases the therapeutic response of
the patients. CS was used as a carrier for metoprolol and achieved drug sustainability over a prolonged period. The efficiency of the designed microsystem for
drug delivery is dependent on the drug-to-polymer molar ratio [80, 82]. Valsartan
is a drug that belongs to angiotensin II receptor blockers (ARBs) and used widely
for the treatment of heart failure, diabetic kidney diseases and hypertension [83].
Sohail et al. developed a chemically cross-linked low-molecular-weight hydrogel to
enhance the delivery and improve drug release control [84]. Ezetimibe is an adjuvant therapy that is used to inhibit cholesterol absorption and reduce the delivery
to the liver. It stimulates the synthesis of low-density lipoprotein (LDL) receptors,
leading to a reduction in LDL-cholesterol levels in serum [85]. Shukt et al. designed
ezetimibe-CS nanoparticles that showed superior antihyperlipidemic activity in a
hyperlipidemic rat model in comparison to the marketed product [86]. Mosa et al.
demonstrated the effciency of CS nanoparticles in alleviation of oxidative stress
and cardiac failure induced by oral administration of hydroxyapatite nanoparticles
(HAPNPs) in a rat model. HAPNPs are used widely in tissue regeneration applications; however, they cause severe damage in the cardiovascular system mediated
through the initiation of inflammatory cytokines, oxidative DNA damage, and inhibition of antioxidant mechanisms. CS nanoparticles supplementation showed a beneficial protective effect against the cardiac infarction induced by HAPNPs and lowered
the oxidative stress and inflammatory markers [87]. Not only CS but also the effective amalgamation of CS and carbonaceous nanomaterials has immense influence
in drug delivery applications starting from cancer to CVD. Table 1 summarises
few CS/carbon nanocomposite-based drug delivery vehicles for different biomedical
applications.
Graphitic carbon nanocage (GCNC) is a distinct graphene-based nanomaterial.
The toxicity level of GCNC could be minimized by coating it with CS. NIR and
microwave irradiation-sensitive nanosystems by implementing CS and GCNC was
designed by Guo et al. The s ystem accommodated with 5-fluorouracil (5-FU) showed
controlled and sustainable drug release for effective cancer therapy [ 97]. Jafari
et al. investigated the prolonged administration profile of sumatriptan succinate drug
model using CS/GO nanocomposite. They studied the cumulative release % of therapeutics from the hydrogel beads with different concentrations of GO in two different
release media (i.e. stomach and intestinal pH) and concluded that the variation in
GO concentration determines the extent of drug release percentage. Further, it was
seen that high concentrations of GO assisted in administering drugs in a controlled
way. The fabrication procedure of the CS/GO nanocomposite hydrogel, along with
drug accommodating and obtained findings of the drug release study are illustrated
in Fig. 4a and Fig. 4b, respectively [96].
Tabl e 1 CS/carbon nanocomposite-based drug delivery vehicles for different biomedical applications
Sl.
CS/Carbon
No.
Nanomaterial
Based Drug Delivery
Drug Model Characterization Stimuli
Responsiveness
Drug Release Applications References
pH Time %
Vehi c l e
1 GC1–GO–DOX Doxorubicin
1
HNMR,FTIR,
AFM, TEM, UPLC,
UV–Vis,
pH 5.5 48 h – Tumor therapy [88]
7.4 48 h 6.7
Fluorescence
spectra
2 5-FU-CS-CQD-Apt 5-fluorouracil SEM, Zeta
potential, FTIR,
XRD
3 MOFs/CDs@OCMC Doxorubicin XRD, FTIR, SEM,
pH 5.4 24 h 71 Breast cancer
7.4 24 h 23
PH 3.8 60 h Complete
TEM, UV–Vis
7.4 50 h 20
4 HA1-CS-C60beads Anaesthesinum XRD, FTIR, HPLC,
TEM, SEM
5 DOX-SWNH/
Doxorubicin NIR irradiation – – – Photothermally
– – up to
18 days
DCA-HPCHS
6 DOX/ND-OH/
FA- COS
Doxorubicin
1
HNMR,FTIR,
TEM, XRD,
– – 48 h 35.87 ± 5.64 Drug delivery [93]
UV–Vis,
Fluorescence
spectrophotometry
treatment
FOI/MRI dual
release
mode imaging
and
pH-responsive
drug delivery of
anticancer drugs
– Drug delivery and
bone tissue
engineering
enhanced
chemotherapy
derived
424 A. M. Mahmoud et al.
[89]
[90]
[91]
[92]
(continued)