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xii Contents
12.2.2 How and Where Doxil® Was Developed .................. 312
12.2.3 Doxil® Performance in Humans ............................... 313
12.2.4 Next-Generation Doxil®-Like Liposomes ................ 315
12.3 Docetaxel-PNP from Basics to Clinical Use ......................... 316
12.4 Summary ................................................................................ 317
References ........................................................................................ 319
Index ...................................................................................................................... 323
Preface
It is well known that “Health is wealth” for every individual living on the earth. The
rapid industrialization, pollution, and current living style of humans have created
numerous threats to their health by several death-causing diseases. Meanwhile, these
diseases can be cured by modern medical practices such as allopathic drugs. Still,
these drugs could cause numerous side effects and suffer from a lack of efcacy
due to several factors. It was observed that drugs would react with the substrates
of targeted sites such as cancer cells for employing the therapeutic tasks and may
interact with the normal tissues and result in side effects. However, the application
of suitably designed targeted drug delivery systems (DDSs) via novel drug carriers
can surmount all such obstacles and limitations of drugs. Recent advances in nanotechnology have investigated a variety of nanomaterials with improved surface characteristics for their application in targeted DDSs. Carbon as a parent material and
its nano-derivatives, such as fullerene, graphene, graphene oxide (GO), and carbon
nanotubes (CNTs), have provided great adaptability for targeted DDSs with numerous therapeutics.
This book is designed to give a practical approach to the use of carbon-based
nanomaterials (CBNs) as nanocarriers in targeted DDSs for the treatment of cancer,
neurodegenerative diseases, gene and peptide delivery, and other major therapeutics.
This book deals with the fundamentals and principles of CBNs with their sources,
attributes, classication, and real-world applications. It elucidates the signicance of
DDSs, their historical aspects and classication, followed by the efcacy of CBNs
as drug carriers. The extensive chapters in this book further represent the recent
developments in the synthesis, functionalization, and application of CBNs such as
graphene, GO, graphene quantum dots (GQDs), fullerene, CNT, and their nanohybrids in major therapeutics. In addition, smart carbon-based nanocarriers and toxicological aspects related to the use of these CBNs in DDSs are explored with their
remediation strategies. Subsequently, this book explores various case studies related
to the delivery of Doxil® and Docetaxel-PNP. The chapters will provide a detailed
description of various CBNs, their surface characteristics, synthesis, functionalization methods, and application in targeted DDSs.
The content of the book was designed based on the belief that the recent developments, knowledge gaps related to new research areas, their implications, and
future prospects must be addressed continuously for vigorous research outputs. It
will widen the scope for a better and fundamental understanding of the topic as
well as provide potential future research opportunities in DDS to the reader. Apart
from undergraduate and postgraduate students, this book is strongly recommended
for people concerned with the chemical, biomedical, material science, biotechnology, and pharmaceutical elds of research. We are also grateful to all the owners of
copyright who have kindly allowed us to reproduce diagrams and tables from their
publications (reference in the text).
xiii
xiv Preface
Finally, we continue to acknowledge our families, who provided patience, understanding, and encouragement throughout. We believe that this book is the right blend
of both experimental and theoretical studies providing tremendous potential for
knowledge and helping researchers and academicians to contribute toward a sustainable solution on health.
Prof. Mihir Kumar Purkait
Ankush D. Sontakke
Anweshan
About the Authors
Dr. Mihir Kumar Purkait is a professor in the Department of
Chemical Engineering at Indian Institute of Technology
Guwahati (IITG). Presently, he is Chair Professor of National
Jal Jeevan Mission (NJJM), Ministry of JalShakti (Government of India). He is energetically involved in frontier areas of
chemical engineering with his major research interest in the
eld of advanced separation processes and material science.
Prof. Purkait has made outstanding contributions in translational and applied research. The quality and quantity of his
research are reected in the large number of publications, patents, technology transfers, start-ups, projects, consultancies,
and involvement with various national and international scientic committees. His
work has remarkable relevance in societal as well as industrial sectors.
He has more than 20 years of experience in research and academics. He has
published more than 300 papers in different reputable international journals with
h-index of 69, has 12 granted patents, and made three technology transfers. He has
authored 15 books and completed 42 sponsored projects/consultancies from various
funding agencies. Prof. Purkait has supervised 22 PhD students on fundamental and
applied research.
Ankush D. Sontakke is pursuing his PhD in the Department of
Chemical Engineering from the Indian Institute of Technology
Guwahati (IITG). He received his master’s degree (2016)
in chemical engineering from Sant Longowal Institute of
Engineering and Technology, Longowal, Punjab and B. Tech
degree (2013) from Jawaharlal Darda Institute of Engineering
and Technology, Yavatmal, Maharashtra. He worked at Multi
Organics Private Limited, Chandrapur, Maharashtra, for one
year (2013–2014). Also, he served as an assistant professor
in the Department of Chemical Engineering at Chandigarh University, Gharuan,
Mohali, Punjab, during 2016–2017. His research activities are focused on graphene
and related materials such as graphene oxide (GO), graphene oxide nanoscrolls
(GONS), graphene quantum dots (GQDs), and their application in drug delivery
systems (DDSs). He is working on the advancement in DDS using various structural, morphological, and functional modications of carbon-based nanocarriers to
improve their surface characteristics, biocompatibility, toxicity toward cancer cells,
loading, and release behavior. He has been closely working in the area of carbon-based
nanocarriers and nanohybrids for their sustainable synthesis as well as application in
anticancer drug delivery and stimuli-responsive carriers for the controlled release of
drugs. He is also exploring strategies for therapeutic targeting and controlled drug
delivery. He has published many peer-reviewed articles in reputable international
journals and published several book chapters.
xv
xvi About the Authors
Anweshan received his B. Tech degree (2012) in chemical engineering and technology from the National Institute of Technology Durgapur, West Bengal, India. After
completing his B. Tech, he joined the Tinplate Company
of India Limited (manufacturing sector) and continued his
services there as a senior engineer for three years (2012–
2016). He then explored the start-up ecosystem growing in
India and joined the Grow Green India Foundation as a
junior research associate and then transferred to RD Grow
Green India Pvt. Ltd., an enterprise of the foundation, as a
research associate (2016–2018). He is pursuing his doctorate in chemical engineering
from the Indian Institute of Technology Guwahati, Assam, India. His research work
is dedicated to the detection of contaminants in water and wastewater using low-cost
green synthesized nanoparticles and their subsequent treatment through electrocoagulation. He is working on the fabrication of metallic oxide nanomaterials via green
pathways for sensing trace organic compounds and pathogens in water. He is also
working on synthesizing carbon-based nanohybrids focused on metal-impregnated
nanohybrids and hydrogels for their applications as absorbents to remove pathogens.
Further, his works involve the design of stand-alone electrocoagulation reactors and
integrated systems for the remediation of arsenic, uoride, and iron-infested groundwater. He has several patents and published many peer-reviewed articles in reputable
international journals.
Fundamentals of
1
Carbon-Based
Nanomaterials
1.1 INTRODUCTION TO CARBON-BASED
NANOMATERIALS (CBNS)
Carbon is among the most adaptable element in the periodic table, primarily due
to its enormous, diverse array of types and degrees of bonds that may establish
together with it or with numerous other elements [1,2]. Furthermore, the possibility
of a diversity of allotropes is enabled by the potential of carbon orbitals to hybridize
in the sp, sp2, and sp3 orientations. Up until this point, the three naturally prevalent allotropes of carbon, namely, graphite, diamond, andamorphous carbon,have
been supplemented by those produced articially, likegraphene and its derivatives,
fullerenes, carbon nanotubes (CNTs), quantum dots (QDs),and nanodiamonds (NDs)
[2,3]; contemporary attention on carbon-based nanomaterials (CBNs)hasexpanded
signicantly over the past several decades, beginning with the advent of fullerenes
(1985) and subsequently with those of CNTs (1991) and graphene (2004). Due to
their unique characteristics, these CBNs are employed extensively in a diverse array
of sectors, including material science [4], energy generation and storage [5], environmental studies [6], biological [7,8], and biomedical[9,10].
Graphene and CNTs, two of the myriad carbon nanomaterials, are perhaps the
best-known examples and have been the subject of in-depth research because of their
exceptional mechanical robustness, thermal and electrical conductivity, and optical characteristics.Graphene andCNTs have superiorYoung’s modulus and tensile
strengths, which may approach 1–1.2 TPa and 120–150 GPa, respectively [9,11]. In
comparison to copper, which has a thermal conductivity of 401 W/mK, graphene
has a thermal conductivity of ~5000W/mK. With a conductance of 106 S/m and an
impedance of 31 Ω/sq, graphene’s electrons may move with ultra-high mobility of
(2 × 105 cm2/V. s), which itself is 140 times greater than silicon’s. The sp2 hybridization,
whereby it provides an additional electron to the πbond and results in strong conductivity at ambient temperature, is the cause of this exceptionally high mobility [12].
CNTs exhibit thermal conductivities of around 2000–3500 W/mK, and the current
density in their metallic form was several times greater than that of metals like copper
[13]. Single-layer graphene has a maximum light absorption ratio of 2.5% [14]. Utilizing these features for a variety of applications, such as photovoltaic and energy storage,
membrane processes, ultra-light composites, and biomedical engineering, constituted
a signicant share of scientic research [15,16]. Graphene andCNTsare excellent electrical conductors by nature, and it is possible to regulate their biocompatibility [17].
DOI: 10.1201/9781003358114-1 1
2 Carbon-Based Nanocarriers for Drug Delivery
The potential of CBNsto transport therapeutic drugmolecules and enable the
imaging of cells and tissues essential for diagnosing and treating unhealthy and
destroyed tissues had a signicant inuence on the biomedical domain in recent
years. The potential biological uses of CBNs include drug and gene delivery,photothermaland photodynamic treatment, as well as bioimaging, biosensing,uorescent labeling of cells, andregenerative medicine[10,18]. Since CBNs have inherent
uorescence, a limited emission spectrum that can be tuned, and excellent photostability, they may be used to sequence and diagnose cells and tissues. Additionally,
their surfaces can be altered with a variety of functional groups to improve their
attributes. CBNs are among the most preferred and competent alternatives for drug
delivery applications due to their high surface areas and superior opto-electronic
andelectromechanical features [19].
One of the most important concerns for the real-world applications ofCBNs
istheir toxicityor biological safety, which is associated with their aqueous stability
and interactions with tissues and cells [20]. The potential applications of CBNsin
cancer and inammation therapies have been sparked by certain recent investigations. For instance, when CBN is ingested by cancer cells, it stimulates the generation
of reactive oxygen species (ROS), which causes lipid and DNA destruction as well
as induces cellapoptosis [21]. Additionally, the enzymatic activity of monocytes is
impacted by graphene nanomaterials, which raise ROS levels and damage the mitochondrial membrane, leading to apoptosis, the cell death mechanism [22,23]. Contrarily, biofunctionalized CBN enhances delivery effectiveness by reducing clearance
and promoting retention throughout the body.
As stated, CBNs comprise graphene and related materials, CNTs, fullerene, QDs,
etc. Excluding the capped ends of CNTs, wherein carbon atoms form pentagons,
or active functional groups, each of the previously mentioned nanomaterials contains a substantial portion of sp2-bonded carbon atoms; however, each of them has
various forms based on the way the hexagonal lattice is congured. The fact that
these various forms bestow distinctive and differentiating characteristics despite
being made up of identical atoms is a signicant attribute that must be explored.
The physicochemical properties of CBNs are the deciding parameters for their relevant applications. Therefore, it is necessary to investigate and understand the structure, morphology, and other surface characteristics, such as electrical conductance,
mechanical strength, aqueous stability, and biocompatibility of these nanomaterials
through advanced characterization and biological assay techniques.
In line with this, the present chapter describes the fundamentals of CBNs, including their structural attributes, physicochemical properties, and related application in
the practical world. It also elucidates the classication of CBNs such as fullerene,
QDs, CNTs, graphene nanosheets, nanoribbons, nanoscrolls, and graphene oxide
(GO) based on their dimensionalities along with their surface characteristics and
scope of applications. Numerous characterization techniques generally employed to
investigate the surface morphology and other properties of CBNs are described in
brief. Furthermore, the recent advances in the applications of CBNs in therapeutic,
sensing, environmental remediation, and catalysis are highlighted. It is believed that
the fundamental understanding and recent developments in the applications of CBNs
will provide substantial information to the scientic community working in material
3Fundamentals of Carbon-Based Nanomaterials
science, nanotechnology, biomedical, and pharmaceutical sectors to further explore
the potential of these nanomaterials in real-world applications.
1.2 CLASSIFICATIONS AND ATTRIBUTES OF CBNS
The CBNs are classied into four categories based on their dimensions higher than
the nanoscale (100 nm), namely, zero-dimensional (0-D), one-dimensional (1-D),
two-dimensional (2-D), and three-dimensional (3-D) nanomaterials. In the case of
0-D nanomaterials, all the dimensions are at the nanoscale; therefore, these nanomaterials are known as dimensionless nanomaterials. Examples of 0-D CBNs are
fullerene and quantum dots. The 1-D CBNs such as CNTs, nanoscrolls, and nanoribbons have one of their dimensions above the nanoscale; consequently, two of their
dimensions are at the nanoscale. The 2-D CBNs have one of their dimensions below
the nanoscale, for example, graphene, GO. Similarly, the 3-D CBNs, such as graphite
and nanodiamond (ND), do not have any of their dimension at the nanoscale. The
structural and physicochemical features of these CBNs are elaborated subsequently.
1.2.1 Zero-Dimensional
1.2.1.1 Fullerene
The rst fullerene, C60, was discovered in 1985, but the family of fullerenes also
comprises a large variety of other carbon-based compounds with various symmetries
and atom counts. The most prevalent fullerene, also known as “Buckminsterfullerene,” is made up of 60 carbon atoms organized in 20 hexagons and12 pentagons, giving it the shape of a hollow sphere. The extremely stable and symmetrical structure
of C60 garnered a lot of attention. Zero-dimensional fullerenes are thought to have
highly intriguing chemical and physical characteristics for medical and technological purposes [24].
The primary function of fullerenes is to serve as a photosensitizer for the photoproduction of singlet oxygen (1O2) ROS; as a result, they are used in photodynamictreatment (PDT)and blood sterilization [25–27]. Unfortunately,fullerene dispersibilityis
a signicant barrier to its utilization in nanomedicine. The fundamental issue is their
limited solubility in many solvents, particularly water, where singlet oxygen has a
prolonged lifespan. To increase fullerenes’ solubility in water, a number of techniques have been devised to functionalize them with hydrophilic groups [28,29]. The
ability of fullereneto scavenge free radicals like reactive oxygen species (ROS) and
reactive nitrogen species (RNS) and serve as an antioxidant has boosted its adoption in biological applications. Cells can be shielded against nitric oxide-induced
apoptosis with the use of derivatives of glutathione C60 [30]. The IgE-dependent
mediator produced in human mast cells (hMCs) and peripheral blood basophils was
substantially suppressed when pre-incubated with C60, conrming the function of
fullerenes as a potent inhibitor of allergic reaction [31]. Fullerenes may potentially
act as photosensitizers. Based on the polarity of the media, they can absorb photons
in the visible and UV range, producing photo-excited fullerene molecules in the triplet state and, in some cases, singlet oxygen or ROS. Moreover, to boost the quantum
yield (QY)of ROS generation, fullerenes could be integrated with light-harvesting
4 Carbon-Based Nanocarriers for Drug Delivery
antennas. The utilization of fullerenes inPDTcan thus be exploited to cure cancer
and eradicate germs. The fabrication of molecular or particulate structures with one
or even more organic compounds covalently linked to the fullerene cage surface
in a geometrically regulated fashion is made possible by the cage-like nanoscale
structure of fullerenes. Targeted drug transport across biological membranes and
receptor ligands for antagonizing cellular and enzymatic activities are appropriate
in this situation. An alternate method of preparing fullerenes for use in pharmaceutical applications, with improved dispersion, absorption, and delivery efciency, is
theliposome encapsulation [18].
Signicant scientic advancements have been made in the eld of fullerene therapeutics, although the lack of success in clinical investigations is a consequence of
concerns about the long-term safety and toxicity of fullerenes. On the other hand,
fullerene-based cosmetics have long been used in human skincare and have undergone clinical testing, indicating that, at minimum, external usage of fullerenes is
acceptable [32,33]. Ample capacity is also offered for the encapsulation of atoms,
compounds, and particles owing to the robust cage-like structure of fullerenes. For
instance, water-soluble gadolinium metallofullerenes (gadofullerenes), which have
a high relaxivity, are extremely intriguing MRI contrast agents. Fullerenes have the
ability to self-assemble into fullerosomes, which can function as multivalent drug
delivery systems (DDSs)with the potential for various targeting characteristics [34].
1.2.1.2 Quantum dots
Graphene quantum dots (GQDs) may be produced by slicing graphene into tiny
fragments with diameters of a few nanometers (2–20 nm). The quantum connement and edge effects increase with decreasing size, as has been demonstrated with
graphene nanoribbons (GNRs), especially after their diameters fall underneath the
10 nm barrier [35]. This indicates that GQDs exhibit nonzero band gaps, in contrast to graphene sheets, which have a band gap of zero width and are less helpful
in electrical and optoelectronic applications [36]. The key factors driving the rise
in popularity of GQDs are their ease of synthesis from a virtually innite variety
of organic precursors (such as sugar, proteins, enzymes, etc.) and their robust photoluminescence (PL), which uctuates in tandem with variations in band gap size
[37,38]. Additionally, it has been proven that the chemical modication of GQDs
has an impact on their PL and band gaps [35]. Astrong emission band between
400 and 600 nm may be detected in their PL spectra. Moreover, GQDs are being
researched to provide low-toxicity, environmentally acceptable substitutes that possess identical anddesirable performance attributes as hazardous conventional (CdSe)
QDs [39]. Although this issue is outside the purview of this book, it is essential to
note that there is a large family of carbon quantum dots (CQDs) with outstanding
PL characteristics[40,41].
CQD nanoparticles aremade of carbon that is smaller than 10 nm in size. Sun
etal. (2007) released the very rst study on quantum-sized bright and colorful
photo luminescence CQDsusing laser ablation of a carbon target and a surface
passivation approach [42]. CQDs have recently undergone substantial research to
obtain high uorescenceQYutilizing simple synthesis techniques [43]. Natural
polymers and other organic materials have often been used to produce CQDs.
5Fundamentals of Carbon-Based Nanomaterials
CQDs have also been produced using amino acids [44], grape peel [45], apple juice
[46],and vegetables [47]. Additionally, a number of straightforward and relatively
inexpensive procedures have been devised for the synthesis of CQD, such as chemical and electrochemical oxidation [48], combustion/thermal microwave heating,
hydrothermal carbonization [49], and pyrolysis [50]. Second, utilizing a one-step
solvothermal technique and nitrogen-rich solvents likedimethyl- imidazolidinone
(DMEU) and N-methyl-2-pyrrolidone (NMP), homogenous nitrogen-doped
CQDs can beproduced [51]. Recent advances in chemistry have made it simple to
achieve -C(O)OH-modied CQDs, which is thought to be a novel approach to the
acid assault on CNTs [52]. The uorescence characteristics of the CQDs have also
been tuned by incorporating surface aws, adjusting their size, and implementing
chemical functionalization.
1.2.2 one-Dimensional
1.2.2.1 Carbon Nanotubes
Carbon nanotubes (CNTs)are one-dimensional graphitic morphologies developed
by rolling graphite/graphene sheets, which, along with graphite and fullerenes, may
form a variety of carbon allotropes. Theoretically, a carbon nanotube is distinct
because it is formed from a graphene sheet that has been rolled up and can have one
or more walls [53]. The CNTs are mainly classied as SWCNT and MWCNT based
on the existence of the number of graphene sheets within the nanotubes and the type
of chirality. Single-wall carbon nanotubes (SWCNTs) are a kind of nanotube with a
single wall that was rst discovered in 1993 [54]. In contrast, those having numerous
walls are known as multiwall carbon nanotubes (MWCNTs), and Iijima made this
discovery in 1991 [55].
CNTs are cylindrical nanotubes that resemble buckytubes and have special features that make them useful in a variety of practical applications. CNTs display
superior mechanical, electrical, thermal, and optical characteristics. Nanotubes have
exceptional rigidity and toughness, as well as reversible folding and collapsing. CNTs
are one of the stiffest substances known, but they have the ability to deform after
being compressed. This is owing to the hexagonal network’s high C-C bond stiffness,
which results in an axial Young’s modulus (E) of 1 TPa and tensile strength (σ) of
150 GPa [11]. In addition to simple elements, these carbon assemblages may generate
a variety of congurations and forms. Beneath high pressure, nanotubes can merge,
exchanging numerous sp2 links for sp3 bonds, allowing high-pressure nanotube linking to produce strong, innite-length wires [11,56].
SWCNTs come in a variety of congurations and may be trundled up in several
types of seamless tubes. Depending on their chirality and diameter, SWCNTs may be
able to operate in this arrangement more clearly as a semiconducting, semimetallic,
or metallic structure [57]. New techniques for synthesizing an array or tightly packed
bundle of SWCNTs that meet reaction parameters that are economically possible
and have ideal diameters less than 0.2 µm were disclosed in one of the US patents
for the manufacturing of SWCNTs [58]. The lengths of SWCNT generally fall within
the micrometers range, with diameters ranging from 0.4 to 2 to 3 nm. SWCNTs may
often be bundled togetherand can bearranged hexagonally to produce a crystal-like
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