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CHAPTER 8
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Phytoconstituent-Loaded Nanomedicines
for Arthritis Management
SYED SALMAN ALI1*, SNIGDHA BHARDWAJ2, NAJAM ALI KHAN1,
3
SYED SARIM IMAM
1
, and CHANDRA KALA
2
and Allied Sciences, Sam Higginbottom University of Agriculture,
3
4
4
ABSTRACT
Arthritis is still a questionable for medical research in terms of effective
treatment. A better knowledge of the pathophysiology of chronic inflammatory conditions, such as arthritis, nanomedicines are supposed to have
improved penetration and prolonged retention mechanism and a ligand
conjugation on a surface for active binding to the cell receptors, through
which they can passively accumulate into inflammatory tissues resulting in
increased efficacy and lesser systemic adverse effects. Currently available
anti-arthritic synthetic treatment for the management of arthritis are found to
have multiple disadvantages like serious side effects, high costs of treatment,
requirement of parenteral administration and incomplete relief to patient in
respect to pain intensity and joint movements. These problems encourage
more research to provide a convenient, cost-effective therapy with minimum
or no side effects.
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Biomarkers as Targeted Herbal Drug Discovery
Traditional herbal medicines are now extensively studied as a potential
therapy of choice for arthritis patients because of their anti-inammatory and
immunomodulatory properties. Despite of the known fact, development of
herbal drugs as novel drug delivery systems is not efciently implemented by
the scientists due to insufcient regulatory framework. The incorporation of
herbal bioactives into nanocarriers like nanoparticles, metallic nanoparticles,
liposomes, and phytosomes may overcome the existing problems of available treatment for arthritis in terms of improved bioavailability, stability,
site-specicity, and fewer side effects. On the patient side, improved patient
compliance may be achieved with the thought of lower side effects of
natural’s agents based medicines. Thus, the herbal nanomedicines can be
an effective alternative medication for arthritis. This chapter highlights the
research conducted, in recent years, using nanomedicines in combination
with herbal drugs as an effective therapy in arthritis and concludes several
important investigations with promising results for the treatment of chronic
disease in an efcient way.
Inflammation can be defined as a response generated towards infection or
any injury. Under the extreme circumstances, the defensive mechanism of
inflammation reverses and acts harmful with increasing response in respect
to intensity and duration. Anaphylaxis and septic shock are conditions that
lead to excessive and potentially chronic inflammatory responses. One of
the main purposes of inflammation is to eradicate foreign pathogens such
as bacteria. Through well-coordinated signaling, inflammation is involved
in eliminating the initial cause of cell injury, clearing out damaged tissues
while stimulating tissue repair. Although excessive inflammation can clearly
be pathogenic. In chronic conditions of inflammation, like Crohn’s disease
and ulcerative colitis (collectively defined inflammatory bowel disease,
IBD), rheumatoid arthritis (RA), ankylosing spondylitis, psoriatic arthritis
and psoriasis, the coordination among cell is lost resulting in an unwanted
inflammatory response, often distinguished by relapse-remission cycles with
flares of increased activity (Philip et al., 2014).
Arthritis is not a single disease. It is joint inammation. A joint may be
referred as a point or junction where two bones join together. The edge of
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the bone is protected with a layer of tissue generally called cartilage (Harris
et al., 1990; Semerano et al., 2016). This disease involves the breakdown
of cartilage. Cartilage protects the joint and allows it move smoothly.
Symptoms of this disease are joint pain, redness, swelling, stiffness.
Arthritis occurs when the body’s immune system attacks healthy tissue
and cause inammation. It leads to painful swelling in joints (Yarwood
et al., 2016; Ruiz-Esquide et al., 2012; Okada et al., 2014). Osteoarthritis
called degenerative joint disease as the shedding of the cartilage occurs
at bone joints when rub together, resulting in pain, stiffness, and other
symptoms (Majithia et al., 2007; Siddiqui et al., 2011). RA is a chronic
disease it can affect many parts of body. RA is marked by symmetrical,
peripheral polyarthritis, due to an inammatory response that affects
joints in the hands, feet, and wrists in particular (Erin et al., 2008; Pham
et al., 2011). Similarly, ankylosing spondylitis refers to inammation of
the spinal joints. Psoriasis is an inammatory skin disease, commonly
indicative with plaque-type lesions on elbows, knees, and scalp. Generally, patients with psoriasis, (up to 30%) also develop psoriatic arthritis,
in which, in addition to skin lesions, inammation predominantly affects
joints in the hands and in the spine (Firestein et al., 2003; Rathore et
al., 2007). The pathogenesis of RA, ankylosing spondylitis, psoriasis, and
psoriatic arthritis seem to be as multifactorial and involves causes such as
genetic predisposition, reactivity to external pathogens and inappropriate
activation of the immune system in the process (Afeltra et al., 2001; Alexandros et al., 2011) (Figure 8.1).
Inammation is an immune system response that involves immune cells
and small signaling proteins called cytokines. Of the inammatory cytokines
that mediate the inammatory response, TNF is a central mediator to chronic
inammatory disease. The response mechanism of inammatory may be
subcategorized further into four general elements that indulge systemically
in the inammatory pathway (Daniel et al., 2012):
1. Inflammatory Inducers: These are generated signals that specifically work in stress, injury, and malfunction of tissues. The signals
may be either exogenous (such as toxin, pathogens, etc.), or endogenous (such as urate crystals, ATP, etc.).
2. Sensors: Produce inflammatory mediators in response to inducer
identification with their particular receptors, such as tissue-resident
macrophages and mast cells. Production of mediators’ combinations
and amount may vary depending on the nature of the inducers, with
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respect to the development of unique mediator impression for their
specific inducer.
3. Inflammatory Mediators: They work on targeted tissue resulting in
the alteration their functional states. Apart from this, these mediators
are also responsible for encouraging banishing of the inflammatory
inducer, adjustment to the noxious condition, maintaining tissue
homeostasis.
4. Target Tissues: Functio laesa (disturbance of function) refers to
potential of the inflammatory response in diseased conditions. With
increasing alteration in target tissue due to inflammatory response,
the endothelial adhesiveness and penetration of inflammatory
cytokines like tumor necrosis factor (TNF) and interleukins are also
increased which results in an increase in exudate and mucus produc
tion, promote host defense from infection.
In response to any inammatory reaction, the change in the functional
state of tissue represents the cost and pathological capacity of inammation
regardless of the intensity and duration of response generated. Thus, damage
caused by extreme response to inammatory site is considered to be the most
common negative outcome observed during the process (Georg et al., 2018).
-
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Nanotechnology is a branch of technology that represents the field with
fabrication of devices and tools of size less than 100 nanometers (nm)
with modification at the atomic as well as molecular levels. After being
in nanosize range, these particles possess distinctive structural, electronic,
magnetic, and optical properties within the system which cannot be
attained with large size molecules. The concept of nanotechnology using
in clinical practice and medical investigation is referred as nanomedicines
(Selvarajan et al., 2009).
Initially, a nanomedicine was described by European Science Foundation (ESF), as the technology designed to treat, diagnose, and prevent any
disease, pain, or injury for achieving the improved human health provided
with the proper understanding of these carrier performances within the
human body. Further revision is done in the denition by the US NIH that
explained nanomedicines as highly specic nano-carriers that intervene at
the molecular level to cure the disease symptoms and repair tissue damage.
The ESF mentioned ve sub-areas of nanomedicines that are given below
(Raj et al., 2009):
1. Investigative or analytical tools;
2. Imaging tools at nano level;
3. Properties and applications of nanomaterials (NMs) and nanodevices;
4. Clinical investigation and toxicity considerations clinical and toxi-
cological issues;
5. Novel nano-drug carrier systems.
Nanomedicines present the medical use of nano-sized particles, nano-
ber, and nanodevices for delivering the active drug in the diagnosis and
treatment of disease to the target cells in the human body thereby offers less
damage to a healthy cell in the body. Nanomedicines are being assumed to
have a great impact in medical research (public health) and offer several
advantages such as nanoscale devices in medicine are of great use because
of their prompt interaction at the molecular level on the cell surface of cells
as well as penetration into and within cell. This approach offers noninvasive
fabrication of devices that facilitate the entry of these devices to the interior
of a target cell without damaging the normal one, which needs a better understanding of concepts like cell’s biology and chemistry. Nano-carrier systems
offer multiple advantages like improved bioavailability, dosing uniformity;
speed up onset of action, and reduction in fasting and feeding variability as
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Biomarkers as Targeted Herbal Drug Discovery
compared with traditional microparticulate systems. Nanomedicines represent advancement in drug delivery and types of delivery systems as well as
the designing of miniaturized diagnostic and analytical methods (Moustafa
et al., 2006).
Nanomedicines include often hybrid multicomponent, nano-sized structures,
and can be made using either both top-down or bottom-up manufacturing
techniques. On the other hand, rising level of synthesizing those ‘ultrafine’
nanoparticles in the environment and/or workplace has been proved to be
particularly hazardous during prolonged accidental human exposure. Thus
using these NMs in a broad range of applications (from construction to aerospace materials, from environmental applications and electronic components
to cosmetics and consumer products, etc.), has led to the birth of the field
now termed ‘nanotoxicology’ (Ruth et al., 2012).
Drug designing using herbals at the nanoscale has been investigated
and they offer several advantages to modify properties (solubility, release
prole, penetration, bioavailability, etc.), that facilitates the development
of suitable administration route with minimal toxicity, less side effects and
improved biodistribution pattern of drug candidate to target site (receptor
present on cell surface, lipid components of cell, proteins on cell, etc.). The
nanostructures system consists of self-assembly, micellar structure which
are formed from building blocks. Drug targeting is divided into active and
passive targeting. In active targeting the moieties (such as protein, peptide,
and antibody) serves as an anchor between delivery system and receptor at
specic site, after being adhered to drug delivery system. Whereas in passive
targeting, formed drug carrier complex, circulating via bloodstream is taken
to target site by afnity (such as pH, temperature, site, etc.) (Jayanta et al.,
2018).
Herbal remedies, after being an important research area and clinical
practice in orthopedics and rheumatology, it is a key priority of physicians and their patients to understand the balance ratio of risk and benefits
associated with herbal therapy for the proper management of arthritis,
rheumatic conditions, and musculoskeletal pains. With increasing cases
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of various arthritic conditions (such as Osteoarthritis and other forms),
recent studies suggest that available pharmacotherapy is not effective in
terms of capability to retain the originality of bone structure and function in diseased conditions. Several problems like less relief of symptom,
side-effects with prolonged treatment leads to chronic illness, makes less
attractive approach towards conventional medical therapy for the proper
treatment of arthritis, and other arthritic conditions indicate a straightforward approach for novel, innovative, safe, and effective alternative
treatment for arthritic patients. Natural products may be an answer to the
current problem in therapy as most of them have faith that herbals are a
natural gift and moreover is a safer option as compared with synthetic
drugs. Ethnopharmacology is a new and rapidly developing discipline and
involves the study of the use of herbal and medicinal plants by particular
cultural groups (Ali et al., 2012).
Herbal products belong to the ancient system of medicines such as traditional Chinese medicines, Indian Ayurveda medicines, Japanese traditional
medicines Egyptian and other African traditional medicine; have a great
collection of natural products for medical use. Medicinally active bioactives,
extracted, and isolated from plants, have been developed as drug products as
well as a delivery system and are consumed worldwide for treating diverse
disorders (autoimmune disease, infectious disease, inammatory conditions,
and cancer) (Shivaprasad et al., 2016).
Some treatments and strategies for arthritis are fully satisfactory to
patients because of the narrow safety window and less effective. So, it is
required to design and develop new drug delivery systems that are specially
targeted in amed joints. The use of nanoparticles possible to increase
bioavailability and enables selective targeting joints damaged (Ulbrich et al.,
2010; Mitragotri et al., 2011).
Globally, many cases with age-related diseases associated with bone, joints,
and muscles are gradually increasing day by day and affecting the physical
and mental health of millions of people. According to United Nations (UN)
and World Health Organization (WHO) reports that all types of arthritic
condition is the leading cause of the disability and morbidity across the world
and also affecting the people’s work efficiency and healthcare expenses
(Original Source: The Arthritis Foundation and WHO). Field of herbals and
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