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Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 305
Fig. 10.3 Treatment modes using carbon-based nanomaterials in non-odontogenic infections
result in a higher rate of mortality and post therapeutic complications in survivors.
Patients undergoing therapy experience alopecia, mucositis, osteoradionecrosis, salivary gland damage leading to xerostomia, dental caries and increased incidence of
infections. Chemotherapy using cytotoxic agents like 5-flourouracil (5-FU), cisplatin
when used by itself or in combination is very efficient in treating advancedmetastatic
lesions. Aggressive therapeutic regimens involving cytotoxic drugs have high post
treatment complications such as: (1) myelosuppression, gastrointestinal (GI) cytotoxicity, drug resistance are associated with 5-FU; (2) Cisplatin in higher doses
affects the ear gastrointestinal, renal, neurological and haematological systems of
the body. Researchers have developed tumour targeting nanoparticulate systems
for enhancing therapeutic effects and to limit the cytotoxicity [97]. Nanoparticles
exhibit passive targeting in case of cancer chemotherapy. Their small size allow
them to show enhanced permeability and retention in cancer cells. Cisplatin loaded
polyethylene glycol (PEG)-polyglutamic acid polymeric micelles are block polymers
with hydrophilic moiety to enhance the time in blood circulation and significantly
lessen the nephrotoxicity in oral carcinoma bearing mice was discovered by Calixto
et al. [98]. With better advancement in research a new horizon has opened up for
biopharmaceuticals due to wide varieties of available nanoparticles.
306 A. Biswal
4 Bio-adhesive Nanoparticles: Novel Treatment Modality
4.1 Bio-adhesive Nanoparticles
The major reason of designing and investigating bio-adhesive nanoparticles for drug
delivery locally is to aim at achieving sustained release of drug to the required target
site, thereby minimising the adverse effects of other routes of drug administration.
They exhibit advantages of both nano particles and bio-adhesive polymers making it
very suitable for sustained drug deliverylocally in the oral cavity. The rapid development of nanoparticles as drug carriers and bio-adhesives has revolutionised the local
drug delivery systems for example, gold and silver nanoparticles when combined
with tissue adhesives exhibit superior antimicrobial and hemostatic properties. The
force acting in between mucosal tissue and biological or synthetic material is referred
to as “Bioadhesion” [99]. The chemical bond that exists amongst the polymer and
biological tissue i.e., mucosal surface plays a key role in bio-adhesion [100]. Popularly bioadhesive nanoparticles are classified according to their origin namely; (1)
Natural bio-polymer based nano particle like chitosan, gelatin and lectin and (2)
Semi-synthetic polymer based nano particle [101, 102]. Nanoparticle systems based
on synthetic or semi-synthetic polymers provide better adherence when compared
to biopolymers occurring naturally but might elicit a higher inflammatory and cytotoxic reaction from the biological tissue and release toxic by-products on biological
degradation. Nanoparticles when combined to bioadhesive polymers they overcome
few of the abovementioned drawbacks like cytotoxicity, weak adhesive forces [102,
103]. Their nanoscale size and larger surface area helps to elongate the drug reten-
tion time in oral environment and improve active compound uptake by the polymer
[104, 105].
4.2 Mechanism of Bioadhesion
Cytoadhesion which signifies binding of biopolymers to the cell surface via covalent
or non-covalent bonding of biopolymers and cell surface components like receptors or
proteins [106, 107]. Mucoadhesion also known as Bio-adhesion to mucous membrane
is a much more complex process consisting of three stages namely; (1) Contact, (2)
interpenetration and (3) Consolidation [108]. In the contact stage the mucoadhesive
polymers tend to bind to the mucosal surface closely which is initiated by wetting
of the polymer, since wetting of polymer increases its hydration which impacts its
contact process and increases interaction region [109, 110]. During interpenetration
stage, mucin glycoproteins are penetrated by chains of the bio polymer as a result the
polymeric chains get entangled [108]. Then appears the last stage of consolidation
where various chemical bonding happens like covalent bonding; hydrogen bonding
and physical entanglement of polymer chains and mucin chains (also occurs due
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 307
Fig. 10.4 Representative mechanism of bioadhesion with oral mucosal area
to mechanical interactions between bioadhesive polymer and surface of the mucosa
making the mucoadhesion stronger than the previous stages) [108, 111] (Fig. 10.4).
5 Carbon Nanomaterials: An Efficient Class of Oral Drug
Delivery System
Carbon based nanomaterials (CBNs) are being used increasingly in bio-medical
applications particularly in drug delivery systems. Their superior optical properties
and larger surface area, makes them possess superior characteristics of lesser cross
reactions with other active compounds, enhanced biocompatibility and better drug
loading on to the carriers. In CBNs the core element is carbon and they are categorised
on the basis of its shape and configuration. Amongst all CBNs most frequently utilised
ones are graphene, nanotubes, nanodiamonds, spherical or ellipsoidal fullerenes,
carbon dots and porous carbon.
5.1 Carbon Nanotubes
Carbon nanotubes (CNTs) as per their name are of tubular or cylindrical shapes. Their
distinction appears on the basis of: (1) length, (2) number of layers, (3) diameter and
(4) chirality.Their unique and useful properties are because of amalgamation of physical characters like strength, rigidity and elasticity etc. CNTs are categorized into (1)
single walled, (2) double walled, (3) multi-walled and (4) functionalized on the basis
308 A. Biswal
of their structural configurations. They can be synthesised by several methodologies like laser ablation, high-pressure carbon monoxide disproportionation, chemical
vapour deposition, arc discharge, etc.
Single-walled nanotubes
Single-walled nanotubes (SWCNTs) are simple structures. Typically, they are a
graphene sheet that is extended and folded. The pattern of graphene sheet here is
dependent on the diameter and C–C orientation [112]. They are sp2 hybridized onedimensional structures with a length to diameter ratio of 1,000:1 having a hollow
cylindrical shape. They have numerous advantageous applications but the high manufacturing cost poses as a hinderance [113]. There has been constant research to
developcost effectivevarieties SWCNTs. SWCNTs are modified forms of nanohorns
which are better suited for drug delivery. When compared to SWCNT, nanohorn basically is a single hexagonal ring of carbon. It has biomedical application of targeted
drug delivery in carcinoma because of its property of greater diameter and length
[114]. Owing to the stronger π-π interaction, SWCNTs exhibit lower solubility and
dispersion in water-based systems with greater strain. SWCNTs have been used as
diagnostic aids and in cell culture studies as scaffolds. To increase the biomedical
and pharmaceutical potential of SWCNTs chemical modification is needed to ensure
their dispersion and solubility in aqueous systems [115].
Double-wall carbon nanotubes
SWNTs when compared in terms of characteristics and morphology are quite similar
to double-wall carbon nanotubes (DWCNTs). Structurally when two graphene sheets
are folded upon one another into a double-layered form, DWCNTs are formed.
It is a newly explored class of CBNs. They have excellent properties of strength,
chemical resistance, thermal stability and superior optical and electronic properties
[116]. For development of biosensors DWCNTs have played a major role. A bioimmunosensor was constructed for adiponectin (a biomarker for obesity) simply by
affixing antibodies on to the surface of DWCNTs. Anti-salmonella was incorporated
on the surface of DWNTs by proper fabrication and used as an electrode [117].
It provides a favourable surface texture for the growth of cells of nervous system
i.e., neurons via tissue engineering which resulted in better differentiation of cell as
compared to SiO
surface [118].
2
Multi-walled carbon nanotubes
Numerous graphene sheets with complex electronic properties comprises Multi
walled carbon nanotubes (MWCNTs). Its diameter ranges between 5 and 50 nm for
MWCNTs. The complex structure and wide range of varieties in this class of nanomaterials is due to multiple layers of graphene sheets wrapped upon another with
a dispersing of 3.4 Å in between layers. Thus, MWCNTs are much less explored
and investigated by researchers. A minor adjustment in its physical properties might
reduce its sorted after material properties [119]. The structural integrity of MWCNTs
is justified by the popular the Russian-Doll and Parchment model [120]. MWCNTs
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 309
are applied in biomedical field to be used as scaffolds for pancreatic cancer cells
[121].
5.2 Graphene
In graphene there is a particular configuration of having one layer of carbon with
2
partially filled sp
orbits and another layer below the plane. It has numerous superior
characteristics namely: (1) excellent optical properties, (2) largerand multifunctional
surface area, (3) superior thermal conduction, (4) high elastic strength and durability
that makes it a superior semiconductor. When electron and graphene interact there
occurs formation of quasi-particles. Amongst graphene as a CBNs two classes exists
namely, (1) graphene nanoribbons and (2) quantum dots. In these particles electrons
travel one micrometre without scattering as shown conventionally, which is called
Ballistic transport [122]. Several modifications are made in Graphene based CNTs so
as to fabricate chemically enhanced graphene, layered graphene oxide and graphene
oxide since despite having better electrical conductivity it has lower solubility in
aqueous vehicles. These modifications are made to fabricate suitable materials. For
the fabrication of biocompatible nanocomposites derivatives of graphene oxide are
used (Fig. 10.5).
Graphene nanoribbons
The type of CBNs which is structurally planar and with quasi-one-dimensional
configuration is called Graphene nanoribbons (GNRs). To synthesize GNRs,
graphene sheets are cut into tiles with a higher aspect ratio to get bandgap of 10 nm
Fig. 10.5 Various CBNs utilized in drug delivery in the field of dentistry
310 A. Biswal
or less in width. There is an alteration in behaviour of GNRs as they transition from
semiconductors to semimetals when there is an increase in width [122]. They have
a wide variety of applications in electrical circuits as it shows better thermal and
electrical conductivity as compared to copper, hence considered as a superior choice
for an integrated circuit. It assumes metallic characteristics in zigzag form, whereas
the armchair form might be semiconductor or metallic. Chemical synthesis of GNRs
is mostly via liquid phase exfoliation or by etching graphene with high-resolution
electron-beam lithography. Dimensionally GNRs have a range of 1 μm in length or
less and ∼10 nm in width [123]. When GNRs are modified and made operative via
oxidation, they possess enhanced properties to utilise in applied biomedical field like
cancer treatment, DNA applications and drug delivery to specific sites. This material
is mostly preferred because of its potential of having nearly no cellular and external
environmental toxicity [124]. Due to efficient uptake by the cell, they are considered as a superior counterpart of silicon- based transistors and commonly used in
biological systems.
Graphene quantum dots
Graphene Quantum Dots (GQDs) are synthesized on slicing graphene in the dimensional range of 2–20 nm. When compared to conventional quantum dots GQDs
are comparatively quite less cytotoxic to biological systems and the environment
[125]. Since they have zero-dimension they are preferred to be utilised in various
biomedical opportunities. They have an edge over conventional nanomaterials due
to various enhanced characters like great photo-stability, no cytotoxicity, ultra-small
size and higher solubility in water. When GQDs are utilised in applications of bioimaging, they have been fruitful in replacing fluorophores as they easily tide over the
difficulties faced when other types of fluorophores are used like (1) better photoluminescence, (2) higher renal clearance and (3) photo-stability. GQDs are utilised to
develop a fluorescent probe for tumour imaging and cellular dynamics due to their
superior photoluminescence [124].
5.3 Nanodiamonds
Nanodiamonds (NDs) are basically a 3D cubic lattice with tetrahedrally bonded
carbon atoms. NDs have the physical properties of diamond. Detonation nanodiamonds (DNDs) and fluorescent nanodiamonds (FNDs) are the two types of NDs
based on their synthesis process and size. DNDs commonly have dimensions near
to 5 nm. They are fabricated via explosive shocks with hexogen and trinitrotoluene.
When synthesised under high pressure and temperature, FNDs exhibit wider size
distribution as compared to DNDs [126]. Because of a pliable sp
showcase certain characters like easy attachment of various ligands, active drug
molecules and severalchemical compounds. NDs are widely under research for their
unutilised potential [127]. NDs possess unique optical and spectroscopic properties, hence they are extensively utilised in bio-imaging [128]. They are successfully
2
/sp3bonds, they
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 311
engaged in transport of certain materials that have marginal solubility [129]. Additionally,they are used in the making of variousappliances for biomedical therapy like
scaffolds, materials for tissue engineering, biodegradable bone and genetic materials
transport to cells via carriers hence functionalized NDs are superior [130].
5.4 Fullerenes
Fullerenes are known as an allotropic modification and a molecular form of carbon.
The fullerene family is composed of cluster of carbon atoms (Cn clusters where
n > 20). On the surface of the fullerene, it forms pentagons and hexagons at the
vertices and carbon atoms are in sp
together. C60 is the most commonly investigated form of fullerene [131]. Fullerenes
have been functionalized chemically to improve its water solubility which enables
the fabrication of a bioactive redox drug [132]. C60 has been extensive investigated
by researchers for its application in biomedical field since pure C60 does not show
any cytotoxicity [133]. Fullerene based CNTs when chemically functionalised focus
on targeted imaging, drug delivery, reactive oxygen species quenching by utilising
operative derivatives [134].
2
hybridisation and covalent bonds hold them
5.5 Porous Carbon
Porous carbons are better called activated carbons and because of their larger surface
area and superior physicochemical characters they are gathering the attention of a lot
of new researchers. Microporous, mesoporous and macroporous are various classes
of porous carbon with respect to their pore size. Activation of organic precursors
physico-chemically at elevated temperatures involving pyrolysis results in synthesis
of porous carbon. Amongst the range of pore, largest surface area is possessed by
mixed porous carbon which is a combination of the three types [135]. For effective
and sustained drug delivery Mesoporous carbon nanomaterials are particularly used.
5.6 Carbon Dots
Quasi-spherical carbon based-nanomaterials are the latest addition to the group.
They have a dimensional range of less than 10 nm. They have a property of killing
pathogen by producing nascent oxygen in presence of light which are one of the
reactive oxygen species. To kill pathogens prior to even initiation of symptoms, CDs
are used for photocatalytic disinfection [136]. These materials are very commonly
used in bio-sensing due to their property of mimicking naturally occurring enzymes
morphologically as well as functionally [137]. CDs as zero-dimensional spherical
312 A. Biswal
allotropes exhibits many desirable characters for therapeutic diagnostics like better
conductivity, unique optical properties, negligible cytotoxicity, and higher biocompatibility, solubility in water and excellent conductivity [138]. For synthesizing CDs
in the bottom-up approach via molecular precursors going through a hydrothermal
treatment but there exists numerous template methods that are better preferred for
synthesis because of the equipment involved being easy to use [139].
6 Drug Delivery Systems Based on CBNs
CBNs have numerous drug delivery systems designed on them. These delivery
systems are majorly categorised into: (1) Surface Modification, (2) Immediate release
drug delivery system, (3) Sustained release drug delivery system and (4) Controlled
or targeted drug delivery system.
6.1 Surface Modification
CBNs have carbonaceous framework which is formed by calcination at high temperature [140, 141]. Originally CBNs are hydrophobic in nature, to make them have
a hydrophilic surface, surface modification is necessary. This surface modification
happens by oxidation of CBNs using an acid that is highly concentrated (e.g., HNO
or H2SO4) and creating functional groups [142] or by using ammonium persulphate
in a gentle method [143, 144]. Abundant functional groups (particularly carboxyl
group) are created on the surface of oxidised CBNs that underwent treatment. Further
modifications are done for a wide varietyof purposes like creating stimuli-responsive
grafts, coating surface of active molecules with polymer, PEGylation and diagnostic
imaging.
3
6.2 Immediate Drug Delivery System (IDDS)
Oral route of drug administration is majorly preferred because of higher patient
acceptance as it is simple and safe accompanied with lower infection risk. But the
hydrophobic nature of molecules here a pose a hinderance, since it leads to lower bioavailability and solubility in the GI. To overcome this, drug carriers were introduced.
For drugs with poor solubility, mesoporous materials act as carriers such as mesoporous metallic oxide, mesoporous silica, mesoporous hydroxyapatite and mesoporous carbon [145–148]. Due to better properties of higher porosity and stronger
adsorption ability, lower density, higher drug-loading capacity that is imperative for
molecules with greater dose requirement; mesoporous carbon nanoparticles (MCNs)
act as a superior carrier agent.
Carbon-based Nanocarriers for Sustained Drug Release in Dentistry 313
6.3 Sustained-release Drug Delivery Systems
When encapsulated drugs are released slowly over a longer period of time to get a
wider curative effect it is called as sustained release. If orally administered sustained
release drug delivery systems (SDDSs) when compared to IDDS do not have the
properties to cause the rise and fall in drug concentration. Prolonged release offersthe
following advantages viz; reduction in frequency of administration, maintaining drug
concentration in the circulation, better patient compliance and lesser adverse effects.
CBNs carriers utilise three mechanisms for SDDSs namely: (1) Diffusion hindrance
effect. (2). Stronger interaction forces amongst the CBNs and drug loaded modified
SDDs like, hydrophobic forces, electrostatic forces and forces of supramolecular
p–p stacking. (3) SDD can also be achieved by manipulating pore s tructure of the
carriers as well as the channel length and its morphology to have a lasting effect on
the rate of release of the loaded drugs. For SDD effect polymeric CBNs are chosen,
since they provide diffusion hinderance and enable a more delayed drug release.
6.4 Controlled Drug Delivery System (CDDs)
CBNs based CDDs are being developed to avert loss of drugs due to precocious drug
release and its related effects. To achieve an advantageous drug delivery systems
CDDs are categorised as: (1) Stimuli responsive DDs, (2) Targeted DDs and (3)
Controlled and Targeted DDs. They are fabricated through modification of several
‘gatekeepers’ by chemical manipulation. Prevention of seepage of active compound
from the SDDs is ensured by manipulating the covalent bonds amongst the molecules
or by pure physical adsorption exterior to the entryway of the pore on exposure to
several stimuli.
7 Application of CBNs in Localised Drug Delivery
in the Oral Cavity
CBNs are widely utilised in biomedicine and allied fields such as diagnosis of
diseases, regenerative therapy as well as treatment of various life-threatening
diseases. CBNs have an unexplored potential in the field of genetic, therapy of carcinoma and localised drug delivery for various active compounds including peptides.
CNTs have gathered immense popularity for their morphology that facilitates a noninvasive pathway into the biological membranes as compared to a wide range of other
CBNs. For this particular reason they have garnered a lot of researcher’s interest to
develop ways of drug transport into biological cells [149]. For the diseases of oral
cavity there is a difficulty to retain a higher levelof drug concentration at the required
314 A. Biswal
site due to continuous presence of saliva. There is a great demand of localised treatment of the diseases of oral cavity via local drug delivery systems. The search and
development of a newer and innovative system for periodontitis treatment has been
one of the most successful and remarkable one for which various new formulations
have been introduced in the market. The success behind these marketable products
is because of the nature of periodontal pocket which allows better placement and
retention of these products. CBNs have immense unexplored capabilities as carriers
because of a larger surface area and pore volume, a surface that is easily modified
and a pore structure that is adjusted as per need; all of which helps to control the drug
release as wanted. CBNs are utilised for bio-detection and bio-imaging when incorporated with carbon nanodots and fluorescent dyes. Hence, CBNs as an advanced
localised drug delivery agent is basically the pioneer of next generation drug delivery
agents with innumerable biomedical applications. For the drawbacks and difficulties
faced by CBNs as a drug delivery system in the treatment of various diseases, their
acceptability and practical in vitro and in vivo studies are currently under research.
8 Conclusion
Oral diseases affect the well-being and attributes of life of the patients apart from the
negative effects on overall physical, mental and emotional health. Poor oral health
can lead to various systemic inflammations and bacteraemia which results adverse
effects such as uncontrolled diabetes, cardiovascular disease and respiratory disease.
For diseases of oral cavity conventionally systemic drug administration via oral or
parenteral route was preferred but their lower bio-availability, cross reaction, higher
dosage need encouraged the researchers to investigate a newer mode of drug administration. Hence, localised delivery of drug in the oral cavity for diseases of the mouth
came into existence. In oral mucosa, drug delivery locally is quite advantageous since
it requires lesser amount of drug for the required effect, lesser systemic side effects,
bypasses the fast pass metabolism and higher bio-availability. Usually, the drugs are
hydrophobic in nature so for better action and absorption drug carriers were introduced to enable solubility. Amongst all the carriers CBNs are the most advantageous
and have great future prospects. To attain sustained local delivery of drug on skin
and mucous membrane often CBNs are used in adjunction with certain bioadhesive materials. A wide variety of research is being carried on the applied aspect of
bioadhesive materials in the treatment of skin disorders (carcinoma and psoriasis),
management of healing of injuries and other carcinomas as well as several different
routes of administration such as nasal and vaginal. The concepts of bioadhesion and
nanotechnology are being utilised in combination for development several advanced
delivery systems. Hence, the bioadhesive CBNs possess the capabilities of being
most suitable for local treatment via nanocarriers. Growth factors or genes encapsulated by nano-particles, or in combination with stem cells, are the advanced drug
therapy of near future. Targeted drug delivery by CBNs is advantageous in many