Journal of Drug Delivery Science and Technology 63 (2021) 102487

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Review article

Nanotechnology based drug delivery system: Current strategies and

emerging therapeutic potential for medical science
Tarun Sahu a, Yashwant Kumar Ratre b, Sushma Chauhan c, L.V.K.S. Bhaskar d, Maya P. Nair e,
Henu Kumar Verma f, *
a
Department of Physiology, AIIMS, Raipur, India
b
Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
c
Department of Biotechnology, Amity University, Raipur, India
d
Department of Zoology, Guru Ghasidas Vishwavidyalaya, Bilaspur, India
e
Department of Molecular Biology and Immunology, University of North Texas HSC (UNTHSC), Fort Worth, Texas, United States
f
Department of Developmental and Stem Cell Biology, Institute of Experimental Endocrinology and Oncology CNR, Naples, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Nanotechnology or Nano medicine has been identified as the dominant and most commercially invented tech­
Nanotechnology nology that aims to improve the quality of health care strategies. Although nanotechnology has some limitations,
Nano medicine many pharmaceutical and medical equipment companies have already adhered to medical nanotechnology. In
Therapeutics
some cases, drugs with high toxic potential, such as chemotherapeutic cancer drugs, can be administered with a
Diagnosis
better safety profile using nanotechnology. It is important to note that Living cells are tiny virtual machines
Drug delivery
Drug development involved in all biological activities, including cell signalling, metabolism, energy generation and nutrient
transport. Therefore it can be considered a major candidate technology to deal with biology and medicine for
therapeutic purposes. In this review, we discuss the importance of nanoscience with different nanotechnology
platforms being used in other aspects of medicine. Besides, we are also addressing the future opportunities of
nanotechnology in human health.

1. Introduction multidisciplinary area invented to engineering biological matters such

Nanoscience is the only platform to discover the new properties of
matter by collaborating with conventional fields such as applied health,
molecular chemistry, molecular science, pharmaceutical science, optics,
and even engineering. In the recent few decades, the combination of
science and technology are often well architected to defence the chal­
lenges in the field of medicinal and health sciences by providing a more
effective health system, nano-medicinal tools, and therapeutic ap­
proaches. Historically, the term nanotechnology was first time coined in
1974 by Professor N. Taniguchi. Soon after, Drexler developed and
published the first concept (Feynman’s ideas) of nanotechnology in the
book entitled “Vehicles of creation: the arrival of the nanotechnology
era” in 1986 [1]. Currently, the impact of nanotechnology on human
and animal can be arising new avenue for investigation and trans­
formation of health science and becomes the imperative subject for
consideration as a therapeutic tool. Nanotechnology is a very shady
as atoms, molecules, and supramolecules at nanoscale range approx
1–100 nm to hold promise against existing challenges by creating new
devices and characterisation of material structure technologies with
unique properties to study and understand the lethal biological prob­
lems followed by diagnosis and cure of disease [2,3]. Nanotechnology
has highlighted as the most dominating and commercially invented
technology of these decades, considerably being very crucial for human
lives. Of note, living cells component are extremely crucial machinery
with very tiny size (nanoscale). They are robustly involved in almost all
biological activity, including cell signalling, metabolism, energy pro­
duction, and nutrient transport. Therefore, it can be deemed that
nanotechnology as an essential candidate that can offer new technolo­
gies at the individual matter level to deal with biology and medicine for
therapeutic purposes [4]. Various nanoscale materials are invented with
several clinical advantages; nano-medicine is emerging as a gold stan­
dard in health sciences [5,6]. The pathophysiological and clinically

* Corresponding author. Institute of Experimental Endocrinology and Oncology CNR, Naples, Italy.
E-mail addresses: tarun.sahu50@gmail.com (T. Sahu), yashwantratre@gmail.com (Y.K. Ratre), sushmadgu@gmail.com (S. Chauhan), lvksbhaskar@gmail.com
(L.V.K.S. Bhaskar), Maya.Nair@unthsc.edu (M.P. Nair), henu.verma@yahoo.com, henu.verma@ieos.cnr.it (H.K. Verma).

https://doi.org/10.1016/j.jddst.2021.102487
Received 2 January 2021; Received in revised form 7 March 2021; Accepted 15 March 2021
Available online 18 April 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
T. Sahu et al.
correlated modulation of diseased/abnormal tissues/cells offers
numerous advantages for producing and delivering several nano­
medicine products. Thus, tissue-specific drug targeting approaches may
have a choice of strategy to overcome disease prognosis [7]. In the
recent few years, nanomaterials, preferentially metal nanoparticles,
have received more attention in the diverse area of medical science.
Optimising the synthesis of nanomaterials such as polymers, micelles,
dendrimers, liposomes, emulsions, nanocapsules, and nanoparticles has
now become a prolific area of study.
In the current scenario, nanomedicine is one of the leading appli­
cations of nanotechnology, which committed to developing nanoscale
medicinal tools to provide an effective health care system. This approach
allows us to understand human physiology in a better way to fight
against several deadly diseases such as cancer and cardiovascular dis­
eases. The significance of nanomedicine is mainly applied for imaging,
diagnosis of diseases, tissue engineering, and architecting more efficient,
cost-effective and safe drug delivery systems to precisely delivering
drugs to target sites which can accelerate treatment outcome via
reducing off-target effect and toxicities [8]. According to Bebo et al., to
date, approximately 51 nanomedicines have been approved by US-FDA,
followed by 77 products are in the pre-clinical stage, of which approx
40% are in the clinical trial phase. Most of these approved nanomaterials
are polymeric liposomal and nanocrystal formulations. However, the
scientist thinks to develop more efficient material including micelles,
protein-based nanoparticles (NPs) as well as a variety of inorganic and
metallic particles in clinical trials [9].
Nanotechnology can hold promise to promote revolutionary ad­
vances in medicine, communications, genomics, and robotics in human
health, which can result in immense clinical benefits. It is very vast and
diverse to discuss and explore the whole nanotechnology application.
Still, in contrast to this, the most significant advantage of nanotech­
nology tools and products may have great values in human health in
global contexts [10] The history of Evolution Timeline of Nanotech­
nology in Medical science has been shown in Table 1.
This Review highlights the significance of nanotechnology in human
health with particular emphasis on its nano-medicinal application in
imaging, screening, diagnosis, targeted drug delivery systems, and
effective treatment strategies for human diseases. Here, we also depicted
the risk associated with this and its future advancement in medicinal
sciences.
2. Classification of nanotechnology (nanomaterial’s/
nanoparticles)
Nanoparticles are classified according to their dimensionality,
morphology, state, and chemical composition [11]. Nanoparticles are a
class of material under nanotechnology containing substances in the
form of particle size around 10–100 nm. These materials are broadly
divided into various dimensions such as 0D, 1D [12]. According to some
finding, these materials, size can influence the physiochemical visual­
isation (optical properties) of substances like gold (Au), platinum (Pt),
silver (Ag), and palladium (Pd) NPs have characteristic wine red colour,
yellowish-grey, black and dark black colours, respectively. NPs are
constructed of three structural parts First, surface layer, which may be
functionalized with a variety of small molecules, metal ions, surfactants,
and polymers. Second, the shell layer, unlike core, this structure is a
chemically diverse material, and the third is the core, which is essen­
tially the central part of the NP and is usually termed as NP itself [13].
The NPs can be used in the biomedical system for several health pur­
poses including drug delivery chemical and biological sensing gas
sensing, CO2 capturing and other related applications [14–17].
Based on nanoparticles’ chemical properties, they are typically
classified in the following material-based categories, namely organic,
inorganic, and carbon-based.
2
Journal of Drug Delivery Science and Technology 63 (2021) 102487
Table 1
Evolution Timeline of Nanotechnology in Medical science.
Year Development of Nanotechnology
1857 Michael Faraday (Synthesis of colloidal ruby gold nanoparticles).
1905 Einstein estimate size of sugar molecule/compound to 1 nm
1928 The near field microscope is highly used in diagnosis (Invention of field-ion
microscope)
1931 Max knoll and Ernest Ruska (Transmission electron microscope)
1953 James Watson and Francis cric (Discovery of DNA)
1959 Richer funman first lecture on Nanotechnology “There plenty of room at the
bottom”
1963 Stephen Papell Invention of Ferrofluids
1974 Mark A. Ratner and Arieh Aviram (Invention of Molecular electronics).
1974 The term of “Nanotechnology” first used by Norio Tanguchi
1977 Richard P. Van Duyne (Discovery of Surface Enhanced Raman Spectroscopy
(SERS)).
1981 Eric Drexler (Molecular Engineering).
1981 Invention of IBM Scanning turning microscope
1982 Nadrian Seeman (Development of the concept of DNA Nanotechnology)
1991 Sumio Iijima (Invention of Carbon nanoparticle)
1993 Sumio Iijima and Donald Bethune (Discovery of Single-wall Carbon
nanotubes).
1996 Chad Mirkin and Robert Letsinger (SAM of DNA + gold colloids)
1997 Zyvex (First nanotechnology company founded)
1999 Chad Mirkin (Development of Dip-pen Nanolithography (DPN)).
2000 Mark Hersam and Joseph Lyding (Feedback-Controlled Lithography (FCL)).
2000 The National nanotechnology initiative was made in the USA
2001 Carlo Montemagno (Molecular nanomachines: molecular motor (rotor) with
nanoscale silicon devices).
2002 Cees Dekker (Carbon nanotubes functionalized with DNA)
2004 Xu et al. (Discovery of Fluorescent Carbon dots).
2004 First Royal society report on the implication of Nanotechnology
2006 Paul Rothemund (DNA origami).
2007 J. Fraser Stoddart (artificial molecular machines: pH-triggered muscle-like).
2008 Osamu Shimomura, Martin Chalfie and Roger Y. Tsien (Nobel Prize in
Chemistry for the discovery and development of the green fluorescent
protein, GFP)
2009 Nadrian Seeman (DNA structures fold into 3D rhombohedral crystals)
2009 First time Nanoparticle was used for the target of drug delivery to cancer
tissue In vivo
2016 Studying the effect of nanoparticle on the organism
2.1. Organic matter based NPs
Classically, these types of NPs are mostly organic-based. Nano­
particles utilize noncovalent interaction for the self-assembly and design
of molecules which facilitate the transformation of organic NPs/nano­
materials (NMs) into the specific desired structures, including den­
drimers, micelles, liposomes, and ferritin or polymers. These NPs are
very specific due to their biodegradable and non-toxic effect. Some NPs
like micelles and liposomes containing hollow core, which are known as
nanocapsules and are sensitive to thermal and electromagnetic radiation
such as heat and light [18]. These exceptional presentation and char­
acteristics make them an ideal candidate for targeted drug delivery in
the biomedical system.
2.2. Inorganic matter based NPs
Inorganic NPs are not made up of carbon skeleton. Mainly, metal ions
(Al, Cd, Co, Cu, Au, Fe, Pb, Ag, and Zn) and metal oxide are involved in
the formulation of inorganic NPs. Of which, metal-based NPs are pro­
duced by nanometric size metals via two methods, namely destructive
and constructive [19]. These NPs are carrying various distinctive
properties such as sizes (10 nm–100nm), high surface area to volume
ratio, pore size, surface charge, and surface charge density, crystalline
and amorphous structures, spherical and cylindrical shapes. Inorganic
NPs are sensitive to atmospheric factors like air, moisture, heat, and
sunlight. Unlike metal-based, metal oxide-based inorganic NPs are
synthesised in the presence of oxygen via the oxidation of metals to
generate Aluminium oxide (Al2O3), Cerium oxide (CeO2), Iron oxide
(Fe2O3), Magnetite (Fe3O4), Silicon dioxide (SiO2), Titanium oxide
T. Sahu et al. Journal of Drug Delivery Science and Technology 63 (2021) 102487

(TiO2), Zinc oxide (ZnO). Metal oxide NPs are synthesised mainly due to Graphene is an allotrope of carbon atoms. It is not yet manufactured
their increased reactivity and efficiency [20]. The silent feature of these for utilization purposes and still in the development process. Some au­
NPs is their bioavailability which provides them highly active and more thors depicted their application, including reinforcement for polymer-
specific surface area, which can be simply altered by several chemical matrix composites, solar cells, organic LEDs, hydrogen storage for fuel
reactions like a polymer chain, coupling agent, or doping metal ions cells, electronic components with a higher electron speed than with
[21]. silicon, electron storage for supercapacitors; gas separation membranes,
sensors [23]. Graphene nano foil is utilized to synthesize carbon
Nanofiber as carbon nanotubes (CNT) and wound into a cone or cup
2.3. Carbon-based NPs
shape. They are used in field electron emission sources, as scanning
electron microscope tips, and as composite reinforcement. Unlike Gra­
Carbon-based NPs have unique features and play a key role in many
phene nano foil in CNT, carbon atoms are wound into hollow cylinders
interdisciplinary fields. These NPs are mainly made of carbon particles.
to form single and multilayered CNT of various lengths and self-aligned
Carbon-based NPs show several individual chemicals, physical and
under van der Waals force [24]. They have multiple applications such as
mechanical properties, including chemical stability, conductivity, and
reinforcement for composites, tips for atomic force microscopes, and
thermal properties. Hence, these NPs are grabbing much more attention
scaffolds for bone growth. Carbon black is generally spherical and made
and are known for their several applications [22]. Carbon-based NPs are
of amorphous carbon material. Carbon black is mixed with polymers
classified into the following categories, namely carbon nanotubes
elastomers as a mechanical reinforcement, heat, UV absorber, antistatic
(CNT), carbon nanofibers, fullerenes (C60), graphene, and carbon black.
agent, and electricity conductor. The overview and types of Nano­
Of which, fullerenes are spherical and made up of carbon material by
particle has been depicted in Fig. 1.
sp2 hybridization. They mainly used as a contrasting agent in medical
imaging, cosmetics science for antiaging, catalysts for water purifica­
tion, photovoltaics, methane conversion, electronics, and reinforcement
for composites.

Fig. 1. Types of Nano Drug molecules.

3
T. Sahu et al.
3. Application in medicine
The reason why nanotechnology is a promising area in the medicinal
field and health care system is merely based on its unique functional
characteristics and features to coordinate with our body’s natural sys­
tem. As we well understood that living cells are actually in nanoscale
ranges. Therefore it was hypothesized that the nanotechnology world is
an attractive field in biology and medicine. Nowadays, the application of
nanotechnology in medicine is continually growing day by day due to
their targeted delivery and nature. To date, various nanoscale material
has been invented with the diverse clinical application including disease
diagnosis, drug delivery, and molecular medical imaging followed by
some products which have been under clinical trials [25,26]. Nano­
technology is a filed with multiple opportunities in disease diagnosis,
prevention, treatment and cure. The scope of nanotechnology in health
care setup and medicine is not yet explored fully and need further
investigation and advancement to help people with severe medical
conditions like cancer, cardiovascular diseases [27]. Nano-medicine has
emerged as one of the major interdisciplinary areas which aggregate
biology, chemistry medicine and engineering in a single platform to
promote and develop more effective tools for bio-medicinal purposes.
These approaches are opening new windows and dimensions in clinical
practice, surgery to strategic treatment of various diseases. According to
some authors, nano-medicine have a remarkable impact on drug de­
livery systems, tissue regeneration strategies, medical imaging, diag­
nosis, and implantable materials [28]. Nano-medicines broadly divided
into various types including liposomes, proteins, polymers, micelles,
emulsions, nanocapsules, dendrimers, and nanoparticles. Currently,
some nano-medicinal products have been commercially available after
the approval by US-FDA. In a recent update, according to Bobo et al. to
date, 51 nano-medicines have FDA approved and 77 are in the
pre-clinical/clinical stage [29]. A great deal on numerous possible
application of nanotechnology in medicine aid efforts to understand and
cure the severe medical condition in a better way.
3.1. Drug delivery
In the current scenario, there has been a profound interest in the drug
delivery research to successfully applying drug molecules/therapeutic
agents to their target location for the treatment of various diseases [30].
In recent time, various drug delivery tools have been employed in
medical system. However, certain challenges still arise that need to be
further addressee and explore the successful delivery of drugs to a tar­
geted site. Nowadays, nanotechnology oriented drug delivery system is a
field of interest for scientists and health care professionals.
The specific drug-targeting system’s formulation is based on suitable
concentration, therapeutic efficacy, and a longer circulation time. This
appropriate drug targeting approach is derived by utilising the patho­
physiological modulation in the course of diseases. This targeted de­
livery can facilitate the binding and delivery of drugs to respective areas.
The primary application of nanotechnology in drug delivery has been
centralized into NPs which are mainly recommended to treat tumours
[31]. Organic, inorganic, metallic and polymer based NPs including li­
posomes, micelles and dendrimers, are routinely considered in designing
the target-specific drug delivery system. In drugs with poor solubility
with low absorption potential drug delivery is triggered by these NPs
[32]. However, the efficacy of these NPs as drug delivery vehicles varies
depending on the shape, size, and other inherent biophysical/chemical
factors. The term NP called by various other names including nano
constructs, nanospheres, nano vehicles, nanocarriers. The first invented
NPs for drug delivery system is liposome which invented by Gregory
Gregoriadis [33]. Later several NPs based drug carriers have developed
and some are under research for various diseases. Currently, various NP
based therapeutic drug delivery system has been designed with the
specific formulation as polymer micelles, emulsion, and solid particles
which are used in health care., Some nano-based drug such as Caelyx®,
4
Journal of Drug Delivery Science and Technology 63 (2021) 102487
Doxil®, Transdrug®, Abraxane® is commercially available for cancer
treatment. Conventionally, oral administration is the best route of drug
delivery because it is noninvasive. Peptide or protein drug delivery has
not yet been attained by oral route [34] due to the stomach’s acidic
environment. However, applying nanotechnology to encapsulate such
drugs in nanoparticles will modify the properties of the drug carrier to
overcome such barriers in drug delivery. It also increases site-specific
drug targeting to reduce the off-target effect by blocking the delivered
drug’s accumulation. Currently, NPs based drugs have mostly been used
in combination with natural products to reduce toxicological issues.
3.2. Drug development
The application of nanotechnology in drug development is decided
primarily based on the biophysical and biochemical properties and na­
ture of the targeted drugs. In recent years, pharmacokinetic and phar­
maceutical industries have been working to minimize drug development
cost. However, the competition in generic manufactures, increased
production cost and elevated failure rates are putting pressure on the
drug manufacturing industries. The use of nanotechnology in drug
development and lifestyle management can make drug development
more cost-effective. Nanotechnology-based drugs are particularity
developed to reduce toxicity and improve health outcomes. Besides,
solid NPs suggest profound advantages in drug development, which can
be attributed to their biophysical stability and the opportunity of
modifying the formulating drugs to achieve controlled drug release. The
solid potential to formulate NPs to achieve constant release provides a
possible opportunity for product life cycle management.
To date, there has been a variety of materials utilize to invent solid
NPs with and without surface functionality. Perhaps the most widely
used are the aliphatic polyesters such as poly (lactic acid), hydrophilic
poly (glycolic acid), and their copolymers poly (lactide-coglycolide). For
successful development, it’s very crucial that NPs in the dosage to
maintain their particle size throughout their whole self-life which can
help in improving the stability of drugs.
4. Application in disease
4.1. Cancer treatment
Cancer is the leading cause of deaths worldwide. Cancer is believed
to be a multi-stage carcinogenesis process involving various physiolog­
ical cell functions, such as cell signalling and apoptosis, making it the
most mysterious and complex disease. Numerous developments have
been made in traditional cancer treatment, such as chemotherapy and
radiotherapy, which appear to be far from successful. As it is hindered by
some disadvantages such as chemoresistance [35–37] and severe side
effects. Nanotechnology is developing as a new frontier for multidisci­
plinary research in genetics, engineering, chemistry and medicine. It is
likely to contribute significant advances in cancer identification, diag­
nosis and treatment. Nanomedicine has an enormous capacity to
transform cancer treatment and diagnosis by developing innovative
biocompatible nanoparticles that are the most crucial feature of nano­
particles for drug delivery purposes. The nanotechnologies that can be
used to treat cancer include nanoshells, nanocantilevers, nanoprobes,
nanocrystals, nano polymers, quantum dots, and dendrimers [38,39].
The development of nanomaterials for cancer therapy has two key
features: detecting the tumours and reaching the target tumour site
without affecting normal cells. Numerous nanoparticles are promising in
their ability to identify high-specific and sensitive cancer cells through
different mechanisms. These nanoparticles have unique properties that
distinguish them from other cancer therapies [40].
• The nanoparticles themselves may have therapeutic and investiga­
tive properties and may be engineered to hold a broad therapeutic
load.
T. Sahu et al.
• Nanoparticles may be bound to polyvalent targeting ligands with
high affinity and specificity for target cells.
• Nanoparticles may be designed to accept several drug molecules that
instantaneously allow combined therapy for cancer.
• Nanoparticles can circumvent conventional drug resistance
mechanisms
Doxil, daunorubicin (Daunoxome) and Abraxane are the most widely
used therapeutic nanoformulations approved by the FDA and currently
available for cancer chemotherapy. Abraxane (Abraxis) is an albumin-
bound nanoparticle for paclitaxel and Doxil, a liposome-mediated
drug delivery system for doxorubicin. Both of these nanoformulations
are commonly used in the treatment of metastatic breast cancer. Tar­
geted liposomes with folate receptors effectively supply in vivo doxo­
rubicin and have been shown to circumvent multidrug resistance in
tumour cells lines [38].
The interchange between chemotherapy and antiangiogenic agents
is a key consideration in tumour therapy. Sengupta et al. have found that
tumour dysfunction in the blood vessels may impair chemotherapy
drugs’ transport and increase the expression of drug resistance factors. A
drug delivery system was developed using nanoparticles containing two
layers: first, a core containing poly lactic-co-glycolic acid (PLGA) which
is coupled with doxorubicin and bound to PEG and combretastatin
conjugated liposome. Doxorubicin is a cancer therapeutic drug, while
combretastatin is an anti-angiogenic drug. When this nanoparticle
intravenously inserted into tumour-mediated (carcinoma or cell-derived
melanoma) mice, the nanoparticles were readily absorbed by the
tumour. They caused significant inhibition tumour growth. This nano­
particle formulation has shown efficacy in melanoma and lung carci­
noma in mouse models, and comparable efficacy is predicted in human
models [41]. Singh et al., compared nanoparticles with native drugs,
they found that higher cell penetration and increased synergistic effects
of dual-drug-loaded magnetic nanoparticles. It was developed by
encapsulating hydrophilic and hydrophobic anticancer drugs as a
double-drug delivery method and Her-2 was used as a target group for
breast cancer therapy [42].
The integration of diagnosis and treatment in a single step is devel­
oping a biomedical approach known as theranostics. With the help of
theranostics, the main phases of medical care, such as diagnosis and
therapy, will be put together to make treatment faster, easier and more
efficient. Biocompatible nanoparticles are currently being developed as
cancer screening agents that will allow for non-invasive and effective
cancer treatment. Shim et al. have achieved a collective diagnosis and
treatment for cancer (theranostics). They used small gold nanoparticles
in which Si RNA was encapsulated to discover the possibility of com­
bined stimulus-responsive optical imaging and stimulation-enhanced
gene silencing [43].
4.2. Ocular applications
Poor eye absorption is one of the main problems related to the topical
delivery of ophthalmic drugs, making it difficult to maintain an appro­
priate concentration of the drug in the precorneal region. Nanoparticles
are appealing alternatives to traditional ocular topical medicines, as
they show improved durability and longer half-life (t1/2) in tear fluids
(up to 20 min) compared to conventional drugs (t1/2 = 1–3 min). Nano-
particle drug delivery systems have shown a potential for increased
absorption of therapeutic agents, enhanced bioavailability, decreased
adverse effects and sustained intraocular dosage levels [44].
Commercially available Eudragit ® polymers have been used by
Pignatello et al. to administer non-steroidal and anti-inflammatory
drugs to the eyes of rabbits. Eudragit ® RS and RL are made up of
poly(ethyl acrylate), poly(methyl methacrylate) and poly
(chlorotrimethyl-aminoethyl-methacrylate). Drug and polymer mix­
tures have been dissolved in ethanol and emulsified to produce drug-
injected nanoparticles of approximately ~100 nm. These
5
Journal of Drug Delivery Science and Technology 63 (2021) 102487
nanoparticles were suspended in the conjunctivitis sac of the rabbit’s
eyes. Nanoparticles filled with flurbiprofen and ibuprofen successfully
blocked inflammatory reactions due to trauma following surgery. Be­
sides, the nanoparticle device produced higher amounts of drugs in
vitreous humour relative to traditional eye drop devices [45].
CMV infection (cytomegalovirus) can cause irreversible damage to
the retina, choroid, iris, and surrounding tissues. Bovine serum albumin
(BSA) nanoparticles have been used by Merodio et al., which contains
ganciclovir, a drug used to treat CMV infection. This medicine has been
incubated in an aqueous solution with BSA, and the emulsification
method has been used to make droplets by adding ethanol. The resulting
nanoparticles had a diameter of about 280 nm. These nanoparticles have
been resuspended in saline and administered by I.V. Researchers found
that nanoparticles remained in the thin layer of the retina for up to two
weeks after injection. The histological examination suggested no in­
flammatory reactions or improvements in tissue morphology compared
to standard eye controls [46].
Silva and colleagues have developed and tested the efficacy of 0.75%
w/w isotonic hydroxypropyl methylcellulose (HPMC) solution con­
taining chitosan/sodium tripolyphosphate/hyaluronic acid nano­
particles and antibiotic ceftazidime for eye treatment. These
nanoparticles also introduced mucoadhesion, which resulted in good
contact with ocular mucosa and extended-release antibiotics. Therefore
nanoparticles may increase the life expectancy of the medicine in the
eyes. Further, these nanoparticles were also able to maintain antibac­
terial action, making them ideal drug delivery systems to deliver
ophthalmic drugs with improved mucoadhesive properties [47]. Den­
drimers may also be used as ophthalmic drug delivery systems. A com­
plex of dendrimers of puerarin and poly(amidoamine) (PAMAM) was
prepared that developed longer ocular residence periods in rabbits
relative to eye drops of puerarin, thereby suggesting a possible ocular
drug delivery system to increase the effectiveness of a drug in treatment
[48].
4.3. Application in heart disease
Cardiovascular diseases (CVDs) are a group of disorders that include
atherosclerosis, myocardial infarction, stroke, hypertension, and heart
failure. These diseases are the leading cause of death for people all over
the world. Early diagnosis is vital for the prevention and effective
treatment of cardiovascular diseases. Plain X-ray, electrocardiography
(ECG), computed tomography (CT) and magnetic resonance imaging
(MRI) are some of the standard methods used to identify CVDs. How­
ever, these methods are inadequate due to low specificity and sensi­
tivity. Several new techniques have been introduced to overcome these
obstacles, such as cardiac immunoassays and molecular imaging.
Although it has various advantages over the above methods, the early-
stage diagnosis of CVDs is still challenging due to its complex patho­
physiology. Hence, rapid, accurate, and susceptible and specific strate­
gies are needed to detect CVDs [49,50].
Nanotechnology has enormous advantages over conventional diag­
nostic processes. A combination of nanotechnology and cardiac immu­
noassay can be used to diagnose early-stage CVDs. Using
nanotechnology in various immunoassays such as Electro­
chemiluminescence (ECL) Immunoassay, Fluorescence Immunoassay,
and Enzyme-Linked Immunosorbent Assay (ELISA), specific biomarkers
of CVDs may be detected at an early stage. Nanotechnologies may
minimize non-specific binding sites, have high binding cardiac targets,
have reasonable bioavailability, have significant signal amplification,
and have many functions. These properties of nanoparticles allow them
to circulate across low-restriction human bodies and to create functional
imaging vehicles and contributing to a dramatic improvement in diag­
nostic quality. Injected or ingested nanoparticles functionalized with
visible MOI molecules will spread throughout the human body and
target different RNAs for diagnosis [49].
Fluorescent materials are a common choice for nanoparticle
T. Sahu et al.
conjugation. For instance, fluorescence-labelled quantum dots (QDs)
have a good output for atherosclerotic plaque imaging. Also, radio­
labelled nanoparticles play an essential role for atherosclerotic plaques
when a PET/CT scan is used. The MRI can detect thrombus and plaque
composition, including fibrous caps necrotic base, macrophage material,
intraplaque haemorrhage and plaque neovascularization. Super­
paramagnetic nanoparticles, such as iron oxide nanoparticles, may in­
crease the MRI’s sensitivity by providing dark contrast to improve the
signal [51,52]. To assess the inflammatory response of atherosclerotic
plaques, Aikawa et al. used cross-linked iron oxide fluorescent nano­
particles to instantly capture macrophages [53]. Radionuclides like 18F,
124I, 64Cu, 86Y, 68Ga, are conjugated with QDs, UCNPs, AuNPs, and
NCs for the diagnosis purpose of CVDs [54].
Atherosclerosis is the most prevalent form of CVD that causes a heart
attack or stroke. It is characterised by the thickening of the arterial wall,
which swollen by plaque formation. Nanotechnology-based treatment
approaches for atherosclerosis include regulation of lipoprotein level,
reduction of the level of inflammation, prevention of coagulation and
inhibition of neovascularization. Inflammatory macrophages/mono­
cytes cause atherogenesis and atherosclerotic plaque rupture. Nakashiro
et al. used bioabsorbable nanoparticles to deliver pioglitazone (Inflam­
matory Reaction Inhibitor) to circulating monocytes to prevent athero­
sclerotic plaque rupture [55]. Hirulog (a natural hirudin-derived
thrombin inhibitor) was coupled with micellar nanoparticles to suppress
fibrin clots formed after thrombosis-induced coronary artery occlusion
due to plaque degeneration and rupture [56]. Iron oxide super magnetic
nanoparticles can be used because of their unique magnetic properties
and their desirable biocompatibility to control and monitor the thera­
peutic impact of stem cells on myocardial infarction [57]. Binsalamah
et al. used chitosan alginate nanoparticles comprising a placental
growth factor (PlGF) to improve cardiac function at the myocardial
infarction site. Nanoparticles provide continuous release of PlGF and
enhance the beneficial effects of growth factors on acute myocardial
ischemia [58]. Nakano and colleagues suggested combining PLGA
nanoparticles and irbesartan (angiotensin II receptor blockers) to sup­
press inflammatory monocytes that lead to myocardial
ischemia-reperfusion injury [59].
Nanoemulsion, liposomes, polymeric nanoparticles, solid lipid
nanoparticles (SLNs) and nanostructured lipid carriers are most
commonly used to treat hypertension. Olmesartan medoxomil (an
angiotensin II-AT1 receptor inhibitor), a drug used to lower blood
pressure, exhibits poor oral bio-absorption and accessibility due to lack
of water solubility and permeability. When incorporated with nano­
emulsion and after oral administration, the plasma concentration of
active olmesartan in rats showed a 2.8-fold improvement compared to
the standard dosage. Besides, the antihypertension benefit of the drug
has been shown to enhance and increase with a three-fold decrease in
the regular dosage [60]. Shah et al. have demonstrated that
phelodipine-charged poly-(lactic-co-glycolic) acid (PLGA) nanoparticles
can regulate BP and alter ECG for a longer period, avoiding pro-phase
metabolism and providing a continuous release of drugs [61]. Nano­
wire has excellent encapsulation performance and can thus be used as a
new antihypertensive drug with high stability [62]. Pharmacodynamic
studies of nanostructured lipid carriers have shown that they have
released antihypertensive drugs such as lercanidipine hydrochloride in a
sustained form for longer than regular medicines [63].
Heart transplantation is the only treatment available for patients
with heart failure. However, very few patients are fortunate enough to
undergo transplantation therapy because there is a shortage of cardiac
donors and immune rejection is also a major problem. Cell-based
treatment and tissue engineering have gradually become a promising
research direction to overcome this, but there are also some drawbacks.
Synthetic biology tissue engineering is a promising solution to these
problems. One study found that carbon nanofibers incorporated into
PLGA made cardiac muscle growth more resilient, and the 50:50 ratio of
PLGA and carbon nanofiber composite improved cardiac muscle
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Journal of Drug Delivery Science and Technology 63 (2021) 102487
function by copying cardiac tissue tensile strength and conductivity and
enhancing the adsorption of proteins believed to help cardiac muscle
function [64].
4.4. Application in respiratory disease
The use of nanoparticle-based drug delivery approaches has been
relatively minimal in respiratory diseases. Allergic conditions (such as
asthma) are understood to cause a decrease in the growth of interferon-γ
(IFN-γ) in patients, making them susceptible to airway irritation and
hyperresponsiveness. Kumar et al. have identified how chitosan/inter­
feron-αpDNA nanoparticles, a polymer-drug conjugate, can minimize
allergic inflammation of the airways. The approach was to overcome the
IFN-γ deficiency by providing polymer-drug conjugate via the intranasal
route. The therapy results showed increased expression of IFN-γ by
epithelial cells and facilitated the reduction of inflammation and lung
morphology in allergen-related mice within 3–6 h [65].
John et al. described using a liposome-based nanoparticle drug de­
livery system to suppress inflammation in the murine allergic asthma
model. The strategy was to block P-selectin receptors on circulating
endothelial activated cells, which reduces the development of peri­
bronchial inflammation by minimizing interactions between endothelial
cells and leukocytes. For this purpose, fucose and sulfate ester groups
were incorporated on the liposomes’ surface, which mimics the physi­
ological P-selectin super ligand (PSGL-1). When these liposomal nano­
particles have been administered to mice in lung inflammation and
airway hyperreactivity, selectins on activated endothelial cells are
preferred. It shows a significant decrease in peribronchial inflammation
and airway hyperreactivity compared to controls [66].
Primary research focused on the use of nanotechnologies in the
treatment of tuberculosis. Pandey and colleagues described the effec­
tiveness of direct nanoparticle delivery of anti-tuberculosis drugs in
numerous experiments. They incorporated multi-emulsion and vacuum-
dried antituberculosis drugs. The prepared formulation directly neb­
ulised into the lungs of guinea pigs. The drug administered remained
high in the bloodstream for 6–8 days and in the lungs and half-life of the
drug for up to 11 days, and its bioavailability was better than that of oral
administration or injection. In this study, guinea pigs become free of TB
bacilli after applying poly (DL, lactide-co-glycolide) (PLG) to the drug
inhalation carrier at an interval of 10 days. The same outcome could be
achieved after 46 times oral administration [66]. Bhardwaj et al.
established a ligand attached to Dry Powder Inhaler (DPI) and used it in
various in vitro and in vivo parameters and reported effective treatment
of TB [67]. Recently, for the novel coronavirus (SARS-CoV-2), the first
vaccine candidate to be introduced in clinical trials is the mRNA vaccine
administered via lipid nanoparticles, which has already been in phase II
and phase III clinical trials [68,69].
In recent years, researchers have focused on using gene therapy in
the treatment of lung cancer. Nanotechnology has been documented to
target and administer in situ drugs to kill cancer cells selectively, elim­
inating exposure to healthy organs and tissues, as well as side effects.
Researchers are now combining gene therapy with nanotechnology for
cancer treatment. Gopalan et al. used a non-viral nanoparticle carrier
DOTAP/cholesterol that could carry tumour suppression genes with a
controlled release program directly to the tumour site [70]. In breast
cancer treatment, Prabha et al. performed a related analysis and used
PLGA nanoparticle and P53 anti-proliferative genes [71].
4.5. Application in dermatology
The main barrier to drug penetration in dermatology is the skin due
to the epidermis structure. Before the drug enters the bloodstream and
exhibits its action, it must first be absorbed through the skin, followed by
crossing through the successive epidermis layers to reach the dermis
[72]. Liposomes, cyclodextrins, microparticles such as microcapsules
and microspheres, and nanoparticles are some of the drug delivery
T. Sahu et al.
components used to transport active substances in topical administra­
tion. All nanoparticles are the most effective system because they have
no scientific restrictions, have high physicochemical stability, and can
be incorporated in different formulations [73].
Emulsions with active ingredients are currently used to trap or
convert allergens to skin disorders. The mechanism of the skin barrier
against irritants is intolerance, such as atopic eczema [74]. Nano­
particles are currently used as an antioxidant carrier that protects the
skin from excretion of doxorubicin by sweat glands. Similarly, nano­
particle barrier creams are more effective in protecting the skin from
water loss and attenuating the potential risk of contact dermatitis in the
hands than high lipid content moisturisers, often showing more robust
occlusive results and antioxidant action [75].
Aseptic formulations are the primary application of nanotechnology
in dermatology. Due to its accelerated absorption from the capsule wall,
one formulation of nanoparticles containing chlorhexidine gluconate
(Nanochlorex ®) has an immediate antibacterial effect. It has a long-
lasting effect due to continuous release from the particle nucleus [76,
77]. Other nanoparticles, such as TiO2, show substantial antibacterial
properties after absorbing ultraviolet radiation. Bare TiO2 acts as a
photocatalyst that promotes the peroxidation of the polyunsaturated
phospholipid portion of the prokaryotic lipid membrane after exposure
to UV radiation [78]. Nanosilver is the most effective and commonly
available antibacterial nanomaterial to date, not only used in wounds
and burns, but also as a water disinfectant and a room spray. It shows its
antibacterial effect by causing mitochondrial toxicity by interacting
with internal membrane protein thiol groups, which causes oxidative
stress [79].
Schaefer and colleagues incorporated adapalene particles with
polymerised nanoparticles (PLA and PLGA) which shows beneficial re­
sults in drug distribution for intrafollicular drug delivery and for much
better success in treating sebaceous gland disorders such as acne and
other pilosebaceous diseases [80]. Castro and colleagues revealed that
solid lipid nanoparticles containing all-trans-retinoic acid (ATRA) are
slightly less irritating than common retinoid cream. These new
nanoparticle-based formulations are a promising substitute for topical
treatment of acne with retinoids [81,82].
Long-term research in recent years has led to the commercialisation
of such nanoparticles as the basis for anti-acne products such as benzoyl
peroxide (BP) such as BP microsphere cream 5.5% (NeoBenz Micro ®,
SkinMedica, Inc.) and BP microsphere wash 7% (NeoBenz Micro Wash
Plus Pack ®, SkinMedica, Inc.).
As nanoparticles enhance drug penetration in hair follicle openings,
nanoparticle delivery mechanisms have demonstrated a critical function
in treating hair disorders and acting as a reservoir for the prolonged
release of the drug within them. Nanoparticle formulations are also
considered to be more effective than aqueous solutions and alcohol used
to date to treat hair conditions such as androgenic alopecia and alopecia
areata. Hair growth ingredients, when encapsulated in nanoparticles,
showed 2.0 to 2.5 times longer durability in hair follicle regions than
aqueous control solutions [74]. Jain et al. described that when minoxidil
is encapsulated in liposomes, it shows increased penetration of pilose­
baceous units compared to the same drug’s conventional formulations
[83].
The integration of immunomodulation agents into nanoparticles or
nanoparticle delivery systems may replace more selective and reliable
topical therapy with oral administration of drugs. Therefore it is useful
in treating autoimmune hair follicle disorders such as alopecia areata
[74].
4.6. Application in dentistry
There are some developments in dentistry nanotechnology. In recent
years, the growing interest in esthetic restorations has contributed to the
further production of products of the same colour as teeth. One field of
nanotechnology often used in dentistry is that of composite
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Journal of Drug Delivery Science and Technology 63 (2021) 102487
nanoparticles. Research has shown that artificial nanocomposite teeth
are more stable than acrylic teeth and composite microfill teeth and are
more resistant to abrasion. After the polishing phase, nanoparticles
allow the production of composites with a smooth surface and impart
superior esthetic characteristics to the content. The reason for the use of
nanoparticles is to strengthen aesthetics by making surfaces more
transparent and enhancing durability rate.
Nanomedicine may improve the quality and efficacy of diagnostics in
the field of dentistry. Very few research and therapeutic strategy have
been reported in nanotechnology on the diagnosis of dental disorders.
AFM (Atomic Force Microscopy) can detect the genomic and proteomic
markers of oral cancer. In addition, AFM cantilever (nanomechanical
biosensors) was made possible to perform a real-time scan of a live
bacterial cell with high sensitivity. AFM can interact directly with live
cells and take pictures of them without affecting their morphology and
properties. With this ability, AFM is used to characterise bacteria that
are attached to dental surfaces or implants. AFM also provides reliable
evidence of biomechanical interactions between antibacterial drugs and
bacterial cells. Vancomycin binds bacterial cell wall peptidoglycan
precursors to the D-Ala-D-Ala terminal, which may help to develop
antibacterial therapy against drug-resistant bacteria.
The surface of the nanoscale implant is essential for cellular reactions
in the tissues. Rabbit tibias have been implanted with titanium implants
coated with a nanostructured calcium surface. Effects on osteogenesis
were investigated; the nanostructured calcium coat improved bone
sustainability around the implant. In addition, the surface morphology
of the nanoscale increases the surface area and thus provides an
enhanced surface area for an implant that can react to the biological
environment.
PLGA and poly(lactic acid) nanoparticles showed higher trapping
efficiencies of up to 63.8%. Their implantation in dogs showed that
triclosan-loaded nanoparticles were able to penetrate the epithelium
junction. A more osteoconductive vehicle for transporting tetracycline
was developed using calcium-deficient HA nanoparticles. Over five
days, the drug-loaded showed sustained release of up to 88% and strong
antibacterial activity. Growth factors in dental tissues have also been
used for their therapeutic action. Nanodiamonds, which are 4–5 nm
carbon nanoparticles, have also been used for alveolar ridge increase as
a growth factor carrier [84–86].
4.7. Application in neurological disorders
The human brain is the most sensitive and complex organ of the body
covered by the Blood-Brain Barrier (BBB) membrane. Since BBB is a
major barrier to treatment, CNS diseases are a severe threat to human
health. Only lipophilic molecules or molecules with a molecular weight
below 400–600 Da are permeable to BBB and therefore, there are limited
options for specific future therapeutic and diagnostic methods. Potential
macromolecular drugs administered are unable to cross the capillary of
brain endothelial cells, preventing the drug from reaching the CNS
target. Nanoparticles in conjunction with polymer coatings may, how­
ever, resolve BBB and allow the delivery of drugs to CNS. In addition, the
ability of NPs to cross the BBB creates more significant opportunities for
early detection of CNS disease.
The majority of drug delivery systems used for the treatment of
neurological diseases are polymeric nanoparticles, as they have been
found to cross tight cell junctions, bypass BBB, encapsulate higher drug
content and can be combined with ligands to achieve site-specific drug
release. Polymeric nanoparticles such as (butyl cyanoacrylate) (PBCA)
or poly(isohexylcyanoacrylate) (PIHCA), poly(lactic acid) (PLA) or
copolymer (lactide-co-glycolide) (PLGA) and human serum albumin
(HSA) appear to be the most effective choice for brain drug delivery. To
make effective drug delivery with nanoparticles to the CNS, nonspecific
binding must also be accomplished. Nanoparticles functionalisation by
surface modification and BBB transporter conjugation, such as vascular
endothelial growth factor, epidermal growth factor, insulin-like growth
T. Sahu et al.
factor, insulin, albumin, transferrin, lactoferrin, and angiopep-2, will
substantially increase the kinetics of nanoparticles. Such as Lactoferrin-
nanoparticle conjugation results in higher BBB absorption of Lf-
conjugated nanoparticles than non-conjugated nanoparticles due to
the presence of the Lf receptor on the BBB surface.
In brain cancer, NPs filled with anti-cancer drugs, such as taxols may
have improved brain endothelial cells aggregation when conjugated
with transferrin. Doxorubicin is one of the most effective cancer medi­
cines, but it does not reach the BBB and has not been approved for the
treatment of brain tumours. However, doxorubicin was found in the
brain when it was loaded onto NPs coated with a polysorbate-80 sur­
factant. Polysorbate is an absorbent for apolipoprotein B and E on the
surface of NPs. The results showed that it was transferred to endocytosis
via receptor-mediated brain capillary endothelial cells. One study shows
that magnetic nanoparticles (MNPs) are also very effective at delivering
anticancer drugs to tumour sites. MNPs can be magnetised in the pres­
ence of a magnetic field. Distribution can be influenced and directed to
the relevant area with increased absorption at the target site, resulting in
successful treatment with reduced off-target effects at minimal dosing.
When the magnetic carrier was bound to cytotoxic drugs and a magnetic
field was introduced to absorb drugs at the tumour site, the drugs were
released from the carrier by an enzymatic method or by changes in
physiological conditions, resulting in improved absorption of the drug
by the tumour cells at the target sites [87–89].
Fan et al. prepared doxorubicin (DOX)-Multi-functional Micro Bub­
bles (MBs) combined with MNPs acting as a dual MRI and ultrasound
contrast agent for magnetic targeting improved drug delivery. Nano­
particles, mainly iron oxide, have been used as super magnetic particles
for precise tissue targeting during MRI. In one study, Iron oxide nano­
particles were injected intravenously into the blood and collected by
RES. Once inside these cells, such as macrophages, iron oxide NPs can be
monitored using MRI. This can be very effective in the monitoring of
macrophages in the determination of the composition of BBB in different
diseases characterized by inflammation [90]. Ferumoxtran-10, a
dextran-coated iron oxide nanoparticle, provides a stable imaging
marker to eliminate brain tumours during surgery and stays in the brain
long enough for postoperative MRI, even after surgical manipulation
[91].
Alzheimer’s disease (AD) can be detected by the presence of beta-
amyloid peptide (Ab) of 40 or 42 amino acids (Ab40 or Ab42) in the
walls of the brain and cerebral blood vessels. Wadghiri et al. used
magnetic nanoparticles that were chemically combined with Ab1-42
peptide (for identification of amyloid plaque deposition) and poly­
ethene glycol (for improvement of brain permeability). When an
advanced contrast agent was injected in vivo into AD transgenic mice,
the MRI calculation showed a significant imaging capability compared
to wild-type mice.
Loss of dopaminergic neurons in the substantia nigra, and accumu­
lation of a-synuclein in the brain stem are characteristic features of
Parkinson’s disease (PD). Nanotube arrays incorporated with gold and
titanium dioxide detect a-synuclein by using photoelectrochemical
immunosensors. Furthermore, poly butyl cyanoacrylate nanoparticles
when conjugated with anti–α-synuclein, helped in neuronal a-synuclein
clearance [92].
Gene transfer causes gene expression to changes in neurological
disorders, primarily in degenerative diseases such as Alzheimer’s disease
and Parkinson’s disease, which generally increase the ability of neuronal
cells to regenerate and survive naturally. Nanoparticles can be used as
an alternative to viral vectors in the gene transfer method. They trigger a
less immune response; they are more effective and easier to synthesize
and use. Organically modified silica nanoparticles and nanoparticles
conjugated with chitosan and green fluorescent protein (pGFP) may be
used as gene expression vectors and protein expression vectors [88].
Like the peripheral nervous system, the CNS is not easy to repair. ZnO
nanoparticles have been used by Seil and Webster as a tissue rejuvena­
tion for CNS neurons because an electrical charge can be executed and
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Journal of Drug Delivery Science and Technology 63 (2021) 102487
tolerated by ZnO nanoparticles, which have been shown to direct and
stimulate neural development; this unique form of nanoparticles has
been helpful [93].
4.8. Application in gastroenterology
The gastrointestinal (GI) tract is a desirable target system for the
application of nanotechnology. It is the site of medicinal absorption.
Under certain conditions, such as varying pH, transit time, heat and
bacterial content, nanoparticles’ action may be controlled throughout
the transit of the digestive tract. Bergin et al. have shown that with sizes
below 100 nm, the absorption of nanoparticles by gastrointestinal cells
is significantly greater than that of micrometre-scale units [94].
For nano-vehicles to enter the target location, disruptive natural
barriers such as low gastric pH and enzymatic digestion of intestinal
excrements must be overcome. Nanocarriers are degraded not only by
local flora bacterial enzymes but also by the mechanical forces in the
colon requiring intestinal motility. 5-FU is a proven DNA inhibitor and is
commonly used as a chemotherapeutic medicine for gastrointestinal
tumours. Zhang et al. developed 5-FU-containing chitosan poly aspartic
acid nanoparticles by ionic gelation and demonstrated the slower release
of 5-FU in vitro and in vivo, longer duration of drug concentration and
higher growth rate of tumour inhibition relative to the control group.
Colorectal cancer is a common cancer that has spread throughout the
world and, in the future, nanotechnology can only provide hope for
better care for the disease. Several active targeting methods have been
proposed for the prevention of colorectal cancer. Transferrin receptors
are usually overexpressed in tumour cells. Liposomes with transferrin on
the surface showed improved antitumour efficacy. Kirui et al. used gold
nanoparticles with carboxy-terminal phospholipids, conjugated with a
single-chain antibody (scFv). On the surface of colorectal cancer cells,
the A33 antigen is overexpressed so that the nanoparticles are selec­
tively immobilised on cancer cell surfaces. The nanoparticles are then
occupied by the cancer cells preferentially. The cancer tissue was
selectively damaged after 808 nm light absorption, indicating that this
technique is appropriate for cancer detection and treatment.
Inflammatory bowel disease (IBD) involves Crohn’s disease and ul­
cerative colitis. It is a long-lasting, painful inflammatory disease, and
there are currently no successful and targeted drugs available due to
serious side effects. Anti-inflammatory drugs (5-aminosalicylic acid,
steroids) or immunosuppressants are the only treatment options avail­
able to date. Despite these pharmaceutical drugs’ potency, their use has
been limited by their non-specific impact on the immune system,
resulting in devastating short-term and long-term side effects. Pre­
liminary experiments have successfully attacked swollen tissue in an
experimental model of colitis with micro drug delivery systems based on
the presumption that immune-related cells are the target for selective
oral drug delivery in IBD. Oral microparticles made of poly-DL-lactic acid
filled with dexamethasone have been used to treat colitis-induced DSS-
induced mice.
A significant factor in the pathogenesis of IBD is the abnormal for­
mation of Reactive Oxygen Species (ROS) at sites of intestinal inflam­
mation. Wilson et al. formulated a new type of nanoparticles that
degrades in the presence of reactive oxygen species (ROS). It has been
observed that TNF α gene play a vital role in the ROS [95]. Further,
when these nanoparticles conjugated with TNF- α-siRNA and adminis­
tered orally, these nanoparticles targeted the sites of intestinal swelling,
reduce TNF- α -mRNA in swollen intestinal tissues reduce intestinal
inflammation [96–98].
Globally, liver disease has risen as a significant contributor to the
public health burden. The 14th most frequent cause of death is liver
disease worldwide. The primary causes of liver disease are hepatic
fibrosis, viral infections, and hepatocellular carcinoma. Nanotechnology
opens up new drug delivery prospects in the treatment of liver disease.
There are several potential causes of liver fibrosis; more than one con­
dition may also be found in a single person. The pathogenesis of hepatic
T. Sahu et al. Journal of Drug Delivery Science and Technology 63 (2021) 102487

fibrosis in chronic liver damage, frequent alcohol use, viral infections
such as hepatitis B, C, genetic defects, etc. Different types of cells are
activated in fibrotic tissue compared to other normal tissue, such as
activated hepatic stellate cells and myofibroblasts, that encourage the
secretion of varying matrix metalloproteinases which causes alteration
of the standard matrix which is swapped with fibrillar collagen
structure.
Insulin-like growth factor 2 receptor is overexpressed on hepatic
stellate cells, mannose 6-phosphate, when bounded to nanoparticle
loaded with drug directly, targets the receptor and the drug is released
for its action. Type VI collagen (a matrix protein involved in cell adhe­
sion), broadly spread in hepatic stellate cells, which expresses integrins.
RGD (Arginine-Glycine-Aspartate) sequence has been used to target
collagen VI and the hepatic stellate cells in the fibrotic liver. Liposomes
loaded with interferon (IFN)a-1b when incorporated with RGD, directly
targets the integrins and thus shows anti-fibrotic activity. Another study
shows the use of silymarin-coated gold particles in the treatment of liver
fibrosis. Gold particles downregulate the hepatic stellate cells. There is a
decrease in numerous inflammatory markers in animal models following
treatment with silymarin-coated gold nanoparticles, which are expected
to be the primary markers for fibrosis induction. Reduced levels of
alpha-smooth actin muscle (α-SMA) give the precise outcome of reduced
fibrogenesis and liver fibrosis. Liposome loaded with dexamethasone
(corticosteroid) is prepared to show anti-inflammatory activity and is
thus used to treat liver fibrosis.
To prepare nanoparticles, Berberine was conjugated with bovine
serum albumin, Berberine BSA nanoparticle target hepatic stellate cells
in the liver, thereby preventing further fibrogenesis by inhibiting the
activation of hepatic stellate cells.
The most common primary liver malignancy in adults is hepatocel­
lular carcinoma (HCC). It is the third most common reason for death
worldwide, related to the incidence of hepatitis B virus infection, alcohol
intake, and other causes of hepatic cirrhosis. One of the critical causes of
HCC’s chemotherapy failure is its chemoresistance to multiple anti­
tumour agents. Nanotherapeutics may enhance the drug delivery to liver
tissue, decrease its supply elsewhere and improve the therapy’s effec­
tiveness. Doxorubicin transdrug (DT) is a doxorubicin-loaded poly
(isohexyl cyanoacrylate) nanoparticle preparation that has demon­
strated significant anti-tumour action against multidrug-resistant pro­
tein-overexpressing in hepatocellular carcinoma in vivo. One study
suggests using silver/silica nanoparticles to target folic acid in the case
of radiation-induced liver Cancer. Indocyanine green when incorporated
with silver/silica nanoparticles, released silver as well as indocyanine
green which has the potential properties against folic acid, thus pre­
venting liver cancer.
Superparamagnetic iron oxide nanoparticles (SPIONs) have played a
significant role in the detection of HCC by liver imaging in pre-treatment
via intravenous injection. Although the process SPIONs with a mean
particle diameter of 150 nm are rapidly sequestered by the Kupffer cells
of the liver, resulting in improved tumour and liver comparison since the
tumour does not contain Kupffer cells. Ferumoxide is the two scientifi­
cally approved SPIONS for liver cancer imaging (Dextran-coated SPION,

Fig. 2. Application of nanoparticle in medicine.

A: Modified nanoparticle with a different surface peptide that inhaled in the nose and it goes to direct transmission in the brain to reduced or help in several
neurological disorders B: Nanoparticle direct use as drug carriers to stimulate mesenchyme stem cell induction, bone cell regeneration, stem cell formation and bone
tissue engineering C: Nanoparticle injected in blood and it goes to direct in liver/hepatic cell and kill the microorganism D: Nanoparticle used as drug carriers to
reduced tumour size in different types of cancer therapy. Nanomaterial can improve the enhanced permeability and retention effect, increase bioavailability, and
reduce chemotherapy drugs’ toxicity.

9
T. Sahu et al.
Endorem, Ferridex) and Ferucarbotran (Carboxydextran-coated SPION,
Resovist) [98–100]. Detailed Application of nanoparticle in medicine
has been depicted in Fig. 2.
5. Application in biomedical engineering
5.1. Surgical equipments
5.1.1. Surgical blades
Surgical blades are being used since the awareness of several diseases
from the ancient time itself. However, the advancement of surgical
equipment is gaining attention due to the modification of the conven­
tional surgical tool. For the progress of the surgical blades, these blades
are being coated with a hard metal diamond and gold and other metal
and being used. Furthermore, due to metal-coated diamond nanolayer,
its properties change to low physical adhesion concerning its tissue,
material, chemical, and biological inertness. Diamonds are used as
nanolayers because of the low friction coefficient, which decreases the
penetration force coefficient [101]. These blades are thin and sharp due
to plasma polishing which leads to a decrease in the coating thickness
around 5–25 μm–0.5 μm, which results in diminishing surface roughness
approximately 20–40 nm. These types of nano-layered blades are used in
the field of neurosurgery and ophthalmic surgery [102].
5.1.2. Invasive surgery
The use of catheters had influenced the advancement of minimally
invasive surgery. MWCNTs had been integrated as a filter in nylon-12
(matrix bed), which leads to the fabrication of a nanotube-based poly­
mer-reinforcement catheter. This device had been tested in-vitro and in-
vivo both, which results in improvement with significant mechanical
property and reduction in thrombogenicity, shows maximum resistance
to fracture, improves electrostatic property [103]. Optical tweezers:
Optical tweezers are other surgical tools with a single gradient optical
trap used for non-invasive manipulation of nano-sized or micron-sized
objects such as viruses, DNA, etc. However, instead of using forces
and tweezers, light is being used to check the dynamics of partials. Be­
sides, this technique is often said to be non-intrusive. It has been found
that in nematodes(c.elegance), optical tweezers can generate stress due
to continues-waves of infrared light [104].
5.2. Tissue engineering
The advancement of tissue engineering had improved tissue func­
tioning. This technique provided an alternative to missing body tissue
and injured or damaged tissues [105]. Tissue engineering became a
boon to medical science because of its application which has given them
hope to humankind for survival. Tissues engineering have been occupied
as the central core of science in term of organ transplantation, bone
replacement, skin grafting, nerve tissue repair, etc. In this section, the
advancement of tissue engineering was discussed in brief.
5.2.1. Bone tissue engineering
Bones can regenerate or repair due to the presence of collagen. In
case of any large bone defect or skeletal abnormalities, 3D porous
scaffolds with their similar composition like bone and bio-ceramics
scaffolds are being used for theircompatibility [106]. These osteo­
conductive scaffolds use signalling and progenitor cells of biomolecule
for the new bone formation. Furthermore, for releasing of osteogenic
factor nanoparticles are designed invitro for enhancement in new bone
formation and maintains of the 3-dimensional structure [107].
5.2.2. Nerve tissue engineering
In neural tissue engineering, regeneration and repair can directly
affect human life. It has given a new perspective to neural therapy.
Generally, nerve cells can fill the gap up to 6 mm. Thus, beyond these
larger gaps are medically challenging to fulfil. Nanofibers have the most
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Journal of Drug Delivery Science and Technology 63 (2021) 102487
promising signs in tissue engineering, Due to their similarity with scaf­
fold [108]. Nanofibers are less than 1 μm in size and consist of a fibrous
3- dimensional structure. Nanofiber consists of a broad surface area to
volume ratio, which makes it more compatible and stimulates the
growth of inner cells in tissue engineering. PPLA nanofibrous scaffolds
have been developed through electrospinning which is the most efficient
technique to produce polymeric nanofiber and supports adhesion of
neural stem cell, differentiation, and outgrowth [109].
5.3. Antibody
Antibody conjugated Nanoparticle: Antibody is generally known to
target the specifically targeted antigens in the body, whereas nano­
particle shows high binding efficiency due to their larger surface area to
volume ratio. Antibody conjugated nanoparticle had proven its signifi­
cance in biomedical engineering. Together they offer the ability towards
specific and selective recognition of antigens, improvement in central
intracellular stability [110].
5.3.1. Photodynamic therapy
Using anti-carcinoembryonic antibodies of human cells, LoVo had
been joined to TiO2 nanoparticle. Electron present in the valance bond
of TiO2 gets excited in exposure to irradiation of UV light to the con­
duction band, which results in the formation of a pair of photoinduced
electrons and holes [111]. The presence of holes and photoinduced
electron have redox(reduction, oxidation) reaction properties, which
leads to the destruction of malignant cells due to the formation of
reactive oxygen species while exposing to UV irradiation [112]. For
improvement in optical detection, these antibodies are used to label with
(FITC) Fluorescein isothiocyanate, analyzed in confocal laser micro­
scopy. The electroporation technique is applied to accelerate the
incorporation of conjugated nanoparticle in malignant cells. The in-vitro
analysis shows the maximum number of malignant cells was photo killed
within 90min. Application of photodynamic therapy is also used in
external tumours present in the body by using gold-coated silica nano­
particle, which results in irreversible thermal damage of cancerous cells
present in the human breast while exposing to NMR rays invitro [113].
5.3.2. Neuro therapy
In neuroscience, several approaches were failed to treat disorders of
the central nervous system due to the presence of two physiological
barriers in the brain. The blood-brain barrier (BBB) is monolayer and
composed of endothelial tissue. This barrier does not allow any thera­
peutic drug from the periphery into the brain. The other barrier is blood-
cerebrospinal fluid, which separates the mixing of blood and cerebro­
spinal fluid. It shows low resistivity and allows diffusion of the smaller
particle [114]. While specific targeting BBB by using long-circular
nanoparticles shows promising results for improving non-invasive
drugs into the brain. Nanoparticles have shown suitable adaptability
due to several properties like size, high surface area, which comfortably
allows crossing BBB. It has been reported that different size of nano­
particle below 100 nm there is no significant differences observed while
crossing BBB [115]. Nanoparticles surface are being coated with some
active agents like poloxamer-188, which enhances many drug delivery
processes. This mechanism is associated with the receptor-mediated
process by capillary endothelial cells of the brain [116]. An antibody
can recognise the various influx transport carried in cerebral endothe­
lium which includes receptor-mediated endocytosis (RME) and
absorptive-mediated endocytosis (AME) which may use as targeting
biomolecules. The research reported that treating intracranial U-87 MG
brain tumours present in nude mice encapsulated with DOX. Long
circulating nanoparticles conjugated with monoclonal antibody 2C5
shows promising therapeutic to reduce the size of the tumour as well as
increase the survival time [117].
T. Sahu et al. Journal of Drug Delivery Science and Technology 63 (2021) 102487

5.3.3. Encapsulation
Monoclonal antibody can be encapsulated to avoid circumstances
like half-life (in-vitro) and less physiochemical stability. Nanoparticles
can be used to encapsulate drugs, which will not alter its coupling re­
action, which concise it to a higher capacity of loading drugs [118]. The
main advantage of encapsulating antibodies within nanoparticles can be
used as biosensors. To encapsulate antigens for vaccination, nano­
particles can be used, which intensify the solubility into the blood­
stream. For the nasal delivery system, cationic nanoparticles are used
with recombinant proteins like Hbs-Ag and β-galactosidase require an
in-vivo humoral, mucosal and cellular response due to their electrostatic
attraction concerning their negative charge present in the mucosal layer
[119].

5.4. Visualisation

5.4.1. Quantum dots imaging

Application in in-vivo quantum dots had been practised for cell sur­
face antigen labelling with covalent conjugation of mercapto-acetic acid
loaded quantum dot to transferrin protein. Endocytosis of cancerous
cells takes place with a hold on to its bright fluorescent [120]. This
technique can be further explored toward the intracellular labelling of
Fig. 3. Recent advances in the development of nanoparticles in biomedical
the intracellular cell. The little work has already been explored using the
engineering.
cdsc/ZnS quantum dots coated with polyethene glycol which were used
to insert into Xenopus laevis embryo. Furthermore, by analyzing with
6.2. Different shape may lead to toxic impacts
microscopic fluorescence imaging, their differentiation and cell lineage
were observed and found that there was normal development of embryo
Characterization of nanoparticles has shown that these nanoparticles
exhibited and no substantiation of toxicity was found even after inject­
possess different shape and this variation of shape of same nanoparticles
ing quantum dots particle multiple time [121].
have a hazardous effect on the same target such as rod-shaped ZnO
nanoparticles are more toxic to the lungs epithelium than the spherical
5.4.2. Tumour targeting imaging
ZnO nanoparticles.
This technique was first demonstrated in nude mice by using quan­
tum dots—in-vivo targeting to a therapeutic human cancerous cell.
6.3. Rate of movement
Interestingly subdermal tumour requires small penetration depth for
imaging. Nude mice were injected with polyethene glycol conjugated
Correlation between size and mobility states that the size of any
with quantum dots, functionalized with an antibody against the mem­
particle is inversely proportional to its mobility; hence nanoparticles
brane antigen (prostate-specific). Conjugation was firstly due to antigen-
have an immense mobility rate thus it can invade various internal tissues
antibody binding along with the retention effect and permeability of
or cells and its accumulation/aggregation over there leads to toxic ef­
vascular tumours. This effect is shielded by the inherent vasculature
fects and may block many efficient pathways.
permeability of cancer tissue devoid of lymphatic drainage. Poly­
ethelynglycol containing quantum dots were non-conjugated with
6.4. Property of aggregation
antibody and impact and permeability were observed to the induced
tumour of mice. However, it has been found that this method is less
To attain stability the nanoparticles, have a property to aggregate in
efficient than the active targeting of probes [122]. The advances in the
the form of clusters, and this property sometimes leads to physiological
development of nanoparticles in biomedical engineering have been
abnormalities. Several other properties, such as high conductivity,
sown in Fig. 3.
magnetic properties, modified thermal properties, may lead to minor
abnormalities in cells [123]. These tiny particles have many sources of
6. The risk associated with nanotechnology invasion in humans/animals and plants such as through the nasal
channels, pores on the epidermis.
Nanotechnology is an emerging field of research with a broad
spectrum of applications, including human welfare, health care, medi­ 7. Risk associated with human health
cine, etc. Together with these applications, concerns regarding the
hazardous effect of these nanoparticles also drew the attention of many 7.1. Lungs damage
researchers and several works was done to analyses the toxicity of these
nanoparticles. The conclusion of these researches suggests that nano­ Inhalation of nanoparticles in any form leads to the passage of these
particles’ following properties can lead to toxic effects of these particles. nanoparticles to various organs such as the lungs, brain, liver, spleen,
accumulation to the mucosal layers of the epidermis and this invasion
results in toxic effects on physiology, for example-TiO2 nanoparticles
6.1. Reduced size of nanoparticles
when exposed to rat model system inferred that the nanoforms of these
compound are comparatively more toxic than the bulk material and lead
To increase the efficiency, these nanoparticles are reduced to their
to pulmonary inflammations [124].
most pleasing forms but at this small diameter, these nanoparticles
become almost impossible to further process upon hence if these nano­
particles invade undesired cells or tissues and its accumulation can lead
to toxic effects.

11
T. Sahu et al.
7.2. Skin damage
Pores present on the skin are another potent entry site of these
nanoparticles; the best example to show the toxic effect of nanoparticle
invaded through the skin is the use of sunscreen because new technol­
ogies have made it possible to use nanoparticles in sunscreen to provide
efficient protection against excess UV exposure, but overuse or more
extended use of these sunscreens have shown adverse effects on the skin
such patching, sunburn, several other skin disorders, severe cases may
lead to skin cancer as well; hence the activity of Zn nanoparticles was
accessed for adverse effects [125].
7.3. Immunosuppressant
Nanoparticles have essential application in the area of immunolog­
ical research; it has been proved as a potent substance to deal with
various drug targeting and delivering issues, but studies have facts that
these nanoparticles first counter with phagocytic cells(macrophages) of
the immune system and if the encounter is not efficient enough then this
event can lead to triggered inflammatory response or autoimmune dis­
eases [126].
7.4. Cancer therapy
Quantum dots have played a significant role in enhancing the pro­
cedure of bio-imaging, especially in the case of cancer patients where
clarity in tumour imaging is an essential step of treatment in which
patients are administered with nanoparticles for clear visualisation but
in many cases, it has been seen that these nanoparticles invade the
tumour and causes cytotoxicity.
8. Limitation of nanomedicine
Nanomedicine is an entirely new genre and very little evidence exists
on this genre. We still want to see the useful application of nanomedicine
to be on the safe side; we should say it is always at the experimental
phase. Due to less information about the disadvantages of nano­
medicine, we can not confidently say what the health risks of nano­
technology are. Still, we can conform to the fact that nanoparticles can
enter our bodies in many ways, which may give rise to much concern.
Although Nanomedicine has several applications and many advan­
tages, it cannot be described as perfect. A relatively coherent reason for
this assessment is that as they transition from micro-particles to nano-
particles, the size range is significantly reduced.
In the organs, nanoparticles are trapped by the mononuclear
phagocytic system (MPS). However, the same property could have
become challenging for nanostructures intended for drug activity in the
other part of the body. The increased surface area of nanoparticles in­
creases such particles’ chemical reactivity, leading to critical instability
as to how these particles behave in different situations and whether they
cross the plasma membrane and enter the cells. Increasing the chemical
reactivity of nanoparticles results in the production of reactive oxygen
species (ROS) that can cause oxidative stress, inflammation and damage
to DNA, proteins and membranes, leading directly to adverse reactions.
The main drawback to nanomedicine is that nanoparticles do not have a
common object except their size. Each particle must therefore be
assessed individually.
In addition, changes in form and structure may lead to different
chemical and physical substances that are non-hazardous at 100 nm and
may become toxic at 1 nm or vice versa. A further limitation is that such
molecules are highly dependent on environmental particles that may
disintegrate or aggregate, resulting in toxicity. Unforeseen interactions
between these particles can occur within the body and lead to unpre­
dicted reactions.
Once nanoparticles are administered into the body, entering the
capillaries, moving from the injection site to other parts of the body,
12
Journal of Drug Delivery Science and Technology 63 (2021) 102487
passing through the cell membranes, and anomalously enter in the BBB.
Nanoparticles may cause effects that have not been observed with
conventional medicine. Such as damage to various cellular organelles,
including the nucleus or mitochondria. They may also activate blood
clotting mechanisms and enhance platelet aggregation. Although
intended to reduce systemic adverse drug reactions, carrier systems
themselves can cause toxicity.
Nanomedicine has a promising future, especially for diseases such as
cancer. Scientists hope that nanomedicine will improve the efficacy of
drug delivery in target tissues and regulate drug release at a specific
location, increasing the therapeutic index. As a result, the ethical, social
and legal aspects of nanomaterials need to be addressed effectively in
order to benefit from community support. Although efforts are being
made to increase awareness of the use of nanomedicine in humans, there
is uncertainty about the risk factors that people may be exposed to while
using nanomedicine. For clear validation, more medical trials involving
nanomedicine are needed. Major ethical issues include risk assessment,
management and communication in clinical studies. In order to avoid
the possibility of public criticism, it is essential to inform people about
the benefits and risks of nanomedicine.
9. Future perspective
The global nanomedicine market size is estimated at $53 billion in
2009 and is projected to increase by 13.5% at the Compound Annual
Growth Rate (CAGR) to more than $100 billion in 2014. The vision of
creating a more efficient system for the development of nano-products is
limited. Understanding the biodistribution of nanomaterials within the
body is a crucial step. This is linked to a second constraint, which re­
quires imaging methods to investigate nanomedicine’s biodistribution
over time.
While nanomedicine standards are high and potential benefits are
continually identified, nanomedicine’s safety is not yet fully defined. As
nanotechnology develops simultaneously in other fields, its use is likely
to extend to diagnostics, molecular research techniques and tools.
Although Instead of investing in new and advanced nanotechnology
applications, it should focus on fixing existing issues, such as the
availability of medicines to the poor, easy and cost-effective diagnostic
solutions. It will cater to the needs of the majority in need of primary
healthcare facilities.
In addition, further investigations are needed with more focus on
mechanisms of transport, endocytosis, biological barriers, degradation
pathways and control over its possible adverse effects in order to
develop nanotechnology-based treatment strategies.
10. Concluding remarks
At the more visionary end of the scale are the plans for “thera­
nostics,” a fusion of therapy and diagnostics. Nanotechnology has
emerged as a new revolution in the field of medical and health sciences.
It is an innovative technique used for drug discovery and drug delivery.
Applications of nanoparticles are simplistic and successful. Though, the
toxicity of nanomaterials is still not well known. A wide variety of
nanoparticles and number of contraindications represents one of the
major challenges in the field of health and medicine. Despite this, in
medicine, several necessary studies were carried out to resolve the
profoundly different properties of nanoparticles. Here, we have delib­
erated the current status of numerous types of nanoparticles and there
diagnostic and therapeutic roles in various health-related complications.
The field of nanotechnology is multidisciplinary, touches numerous
fields of science, including physiology, biotechnology, chemistry, elec­
trical engineering, and materials science. Besides, it is difficult for one
investigator to obtain mastery in all fields. Therefore, nanotechnology
developers should work together with collaboration to ensure that de­
velopments can lead to beneficial products.
T. Sahu et al. Journal of Drug Delivery Science and Technology 63 (2021) 102487

Declaration of competing interest Ethics approval and consent to participate

The authors declare no conflict of interest. Not applicable.

Abbreviations Consent for publication

NPs/NMs Nanoparticles/Nanomaterials All the authors have read the manuscript and have approved this
CNT Carbon Nanotubes submission.
PLGA Poly lactic-co-glycolic acid
PLA Poly lactic acid Availability of data and materials
PBCA Poly butyl cyanoacrylate
PIHCA Poly-isohexylcyanoacrylate Not applicable.
PEG Polyethylene Glycol
CMV Cytomegalovirus
Funding
BSA Bovine Serum Albumin
HSA Human Serum Albumin
Not applicable.
HPMC Hydroxypropyl Methylcellulose
PAMAM Puerarin and Poly amidoamine
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