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Biomarkers as Targeted Herbal Drug Discovery
nutraceuticals are of great challenges at central as well as state government
regulations (Mahfoozur et al., 2017).
Various challenges are to analyze the under dispute parameters like herbal
toxicity and epidemiology. The key issues in using herbals in the formulations are as follows (Thillaivanan et al., 2014):
• Lack of planning in assessing risk management, improper communication on herbal developments as direct therapy.
• Non-availability of pharmacological, toxicity, and clinical data.
• In-effective pharmacovigilance;
• Poor availability of data on drug interaction;
• Improper measurement and constraints with clinical trials;
• Deficiency of standardization procedures;
• In-sufficient data on safety and efficacy parameters;
• Lack of information on developmental approach of high yielding
plant species and their cultivation, etc.;
• Improper quality control measures;
• Poor GMP guidelines;
• Poor research and developmental standards establishment.
There are various medicines such as steroids, nonsteroidal anti-inamma-
tory drugs (NSAIDs), and immunosuppressant and widely used for control-
ling and suppressing inammatory response but are associated with adverse
effects. So, Herbal therapy is best suited as an alternate or complementary
therapy to achieve increased pharmacological response with no or minimal
side effects (Mona et al., 2016).
Nanotechnology is the science and technology that have the ability to
measure, design material at atomic, molecular, and supermolecular
level. Development of NMs focuses on the treatment at cellular level in
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specific disease condition; reduce the toxicity and enhancing effectiveness. Targeted Release of bioactive from nanoparticles may follow active
targeting and passive targeting process. These nanocarrier systems are
biocompatible and degradable (Butoescu et al., 2009; Brennan et al., 2008).
Nanocarrier systems such as vesicles, liquid crystal nanoparticles,
micelles as well as polymeric nanoparticles dispersions made up of very ne
particles ranging in nano-scale (10–400 nm, depending upon type), offers
wide scope for drug delivery and other applications like imaging, diagnosis,
etc., (Figure 8.1). During the development of these nanoformulations, the
ultimate aim remains is to formulate the drug delivery system with opti-
mized drug entrapment, modied release proles, low toxicity proles, and
prolonged shelf life (Sakuta et al., 2010) (Figure 8.2).
The active principle remains entangled within the core of the micellar
structure and transported at concentrations with an increase in the intrinsic
water-solubility prole. In the micellar structure, the hydrogen bonding
generally takes place with the aqueous surroundings in the hydrophilic
blocks which develops an intact covering layer around the micellar core.
This provides nice protection to the hydrophobic contents of the core against
chemical reactions such as hydrolysis and enzymatic degradation. Amphiphilic block copolymers can be easily changed their chemical composition
of compounds, structural block length ration and molecular weight (total)
which allows monitoring of surface morphology 9 (size, shape, and surface
charge, etc.), of the micelles, represent extraordinary feature for drug delivery
applications. Surface charge modication facilitates the functionalization
of block copolymers with crosslinking groups (ligands), during micellar
formation, resulting in high stability and site-selectivity of formed structure
(Costas et al., 2006).
General classifications of pharmaceutical drug carriers.
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Biomarkers as Targeted Herbal Drug Discovery
By standard description, nanoparticles are nano-range sized polymeric
colloids in which active medicament entrapped or dispersed (core) within
the polymeric matrix or adsorbed or conjugate onto the surface (shell) and
are considered to have at least one specific dimension of less than 100 nm.
Depending on their respective micro and macro-scale counterparts, nanoparticles show different properties with the same chemical compositions.
The more the surface energy of nanoparticles more will be the cohesion
between nanoparticles. In addition, the progressive improvement in energy
on nanoparticles surface may lead to alteration in crystal arrangement of
nanoparticles, reactive nature at interface and intrinsic properties may be
affected (Lee et al., 2012).
The polymers used to synthetically formulate the nanoparticles consist
of biodegradable and nonbiodegradable. Currently, biodegradable polymers
are often considered to be a more attracted approach towards the synthesis of
nanoparticles. Nanoparticles may also be designed using different materials
like silica, silver, gold, copper, zinc oxides, therapeutics, quantum dots,
Nanotubes, and various contrast agents. Major improvements through these
nanocarrier systems has been investigated in respect of their effectiveness in
escaping multidrug resistance and targeted delivery via active targeting of
drug (Biswajit et al., 2014).
There are different methods through which nanoparticles can be synthesized. The following aspects are involved in formulating nanoparticles
are neutral pH, low cost, and environmental friendly approach (nontoxic).
Nanoparticles production by plants is considered as more acceptable mode in
terms of more stability and faster rate of synthesis as compared to other cases
of organisms. Thus, suitable methods for synthesizing nanoparticles using
herbs need to be developed in upcoming days, considering cost-effectiveness
and maintenance issues. NMs are further classied into sub-groups which
are depicted in Figure 8.3 (Heera et al., 2015).
Generally, multiple mechanisms that contribute to drug release from
nanocarriers such as diffusion-controlled, degradation controlled, stimuli
controlled and solvent controlled, though each and every mechanism has
its own inuence on drug release. For example, in polymeric nanogels,
drug release is controlled by two mechanisms, i.e., swelling, and diffusion
through the membrane. Nanoparticles are further designed and modied
in several other ways to attain patterned monitoring on the drug release
kinetics as given in Table 8.1 (Jinhyun et al., 2015).
Types of nanomaterials for drug delivery.
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Drug release from nanocarriers, with respect to its temporal control; focuses
on maintaining drug levels in systemic circulation and target tissue effectively.
Different mathematical models has been developed and can be used to analyze
release kinetics (such as zero order, first order, Huguchi model, Hixson-Crowell,
Korsmeyer-Peppas model, and regression model) from delivery systems. Several
mechanisms involved in drug release from the carriers can control or modify
system kinetics. For instance, release kinetics can be modified and is controlled
by drug diffusion across the carrier matrix or a barrier. Different approaches like
swelling of matrix and breakdown of drug-polymer linkage also are of concern
in terms of controlling rate of drug release (Jinhyun et al., 2015).
Nanomedicine is an interdisciplinary technology which has become field of
great importance worldwide, in respect to advancement in multiple branches
TABLE 8.1 Types of Nanomaterials Used in Drug Delivery of Pharmaceuticals
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Nanoparticles Polymeric 10–100 (nm) Spherical colloidal particles with Useful in encapsulating water- Costas et
micelles hydrophobic interior (core) and soluble pharmaceuticals al., 2006
hydrophilic body (shell) amphiphilic
copolymer micelles, high drug
entrapment, and biostability
Polymeric 10–1000 (nm) These are biocompatible and Surface modified nano-carriers Bhatia et
nanoparticles biodegradable systems and can be used for active and passive al., 2016
efficiently protect the drug from the delivery of bioactive as well as
surrounding environment. carriers for controlled drug delivery.
Metallic <100 (nm) Different metals used in the Metallic nanoparticles are Biswajit et
nanoparticles fabrication of these tiny particles biosensors and excellent carriers al., 2014
(such as Gold, silver, and other for therapeutics delivery in cancer
heavy metals), Highly stable and treatment.
functionalized in nature due to the
availability of high surface area.
Liposomes 50–200 (nm) Bilayer vesicles consisting of Carrier for controlled delivery and Lee et al.,
phospholipids. also used for active and passive 2012
Offers good drug entrapment and are
biocompatible
Dendrimers <10 (nm) Three dimensional, branched Used as contrast agents, drug Rye et al.,
structures contain three moieties delivery for anti-cancerous drugs, 2013
such as core part branched part and and gene vectors.
tight-packed surface.
delivery of proteins, peptide, and
genes.
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Biomarkers as Targeted Herbal Drug Discovery
Solid lipid 50–1000 (nm) Prepared by phospholipids (such Adjuvant for vaccines, targeted Ekambaram
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nanoparticles as mono-di-tri-glycerides and fatty carrier for anticancer drug, lung et al., 2012
acids) dispersed in an aqueous infection, brain delivery, ultrasonic
medium containing surfactants. drug, and gene delivery, cosmetic,
and dermatological preparations
and agricultural purpose.
Liquid 2–9.5 (nm) The ordered self-organization of Applications in Photonic crystal Camila et
crystals rod-shaped structures, and are paper or advanced composites. al., 2018
nanoparticles electrically charged.
They exhibit both liquid and solidstate properties.
Carbon nanotubes (CNT) Diameter: Two dimensional, made up of Biosensors for Proteins and DNA, Anna et al.,
0.5–3 (nm) the third allotrope of carbon as Ion channel blocking agents, 2015
Length:
20–1000 (nm) Coating for prosthetics and surgical
Quantum dots 10–100 (Å) Three dimensional, semiconductors, Disease diagnosis and screening Biswajit et
crystalline carbon sheets and divided bioseparators, and biocatalysts.
into single-walled or multi-walled
types.
Electrically charged, great
mechanical strength but lightweight.
formulated with II, III-V, and VI technologies like cellular imaging, al., 2014;
column element. Offers intense real-time tracking of molecules and Rye et al.,
fluorescence, fine emission, and high cells in sustained profiles and tumor 2013
photostability. targeting
implants (e.g., vascular stents)
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Biomarkers as Targeted Herbal Drug Discovery
of treatment towards high-level disorders due to advantages such as efficacy
and efficiency. It is assumed that in the coming 10–15 years, the Indian
market of nanomedicines is believed to expand the growth of USD 1.6 billion
values and after that India would be able to be a ranker among the top three
healthcare markets by 2020. The government of India is also supporting the
research and development activities in the field of nanomedicines to fulfill
the current societal needs.
Government departments involved in research activities also focus on
the drug delivery advancement by setting new standards for these nanomedicines and their implementation in research organizations working on it. Few
examples are the Department of Science and Technology (DST), in 2007,
started a mission namely “nanomission” to boost fundamental research,
designing of research infrastructure, to make better international collaborations, strengthen the platform for developing nano-based technologies.
Other organizations such as the Council of Scientic and Industrial Research
(CSIR), Defense Research and Development Organization (DRDO), Department of Biotechnology (DBT) and Indian Council of Medical Research
(ICMR), also promoting and providing funds for the research-based related
to nanomedicines associated with herbals.
Although with this progression in nanomedicines research in India, the
involvement of Indian departments in the area of nanomedicines and innova-
tions is currently not up to the level that may be difcult to provide a proper
landscape on nanomedicines (Pooja et al., 2018). Another reason is that these
nanomedicines affected by individual biological variation because of diseased
conditions offer a restricted landscape as scale-up production as additional
steps in the process may be required for surface conjugation of ligand moieties
which makes the manufacturing process more complex (Bruno et al., 2017).
The production of nanostructured system may be a serious issue with respect to
toxicology as the high reactivity increases from the large surface-to-volume ratio
of these nanosystems compared to bulk systems, which is a matter of concern.
Any newly developed nanostructures system needs to be tested carefully with
respect to its potential side effects within the human body and the environment.
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Nanotechnology concepts for its clinical application also require for strict regulatory guidelines to ensure the safe and proper use of new nano-medical devices
and drugs originating from nanoscience (Kristina et al., 2009).
Anti-inammatory mechanism is an important wound healing mechanism
responsible for the production of immune responsive agents like cytokines
and interleukins, lymphocytes, and macrophages which are secreted from
primary immune organs. These anti-inammatory mediators induce the
healing process and control the expansion of diseases after being involved in
biochemical pathways. Some other inammatory mediators (enzymes, antibodies, etc.), are secreted by endocrine system. Various studies on synthesis
of gold nanoparticles attract the researcher to think over it as future therapy
because these systems are compatible and have wide scope in drug delivery. It
has also been studies that gold nanoparticles have been explored as effective
therapy in wound repair and tissue generation in inammatory conditions.
Hence, this evidence strongly supports the fact that gold and other metal
nanoparticles can be explored as an alternative therapy for the treatment of
inammatory conditions (Palaniselvam et al., 2016).
Green synthesis refers the process which uses natural source agents (plant,
bacteria, fungi, etc.). As well, all know that plants are sustainable resources in
nature and hence may be explored in the green synthesis of nanoparticles and
other nanosystems along with these factors like wide distribution, easy availability and reproducibility make them a better candidate for nanomedicines.
The green chemistry is an alternative approach to formulate biocompatible
nanoparticles by a chemical process and represents the anchor between two
emerging specializations such as material science and biotechnology (Nanobiotechnology). Green synthesis is the method of synthesizing nanoparticles
from herbal resources. Several metallic nanoparticles using herbal bioactives
have been synthesized by this process (Table 8.2). The metal nanoparticle-herb
combination may show better efcacy against different inammatory conditions.
Several herbal bioactive has been explored for their therapeutic efficiency
against the pathological conditions of arthritis. Incorporating these herbal
compounds in the systems for synthesizing different nanostructured systems
for biomedical applications has been produced in recent times. Several
benefits attract herbals for the synthesis of nanosystems is availability, easy,
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Biomarkers as Targeted Herbal Drug Discovery
and harmless handling as well as to the environment. Few plants are listed
in Table 8.3 which has been used to formulate the different nanomedicines
(Jayanta et al., 2014).
TABLE 8.2 Metal Nanoparticles Using Herbal Compounds for the Management of Arthritis
Sl. Nanoparticles Plant used Part used Treatment References
No.
1. Ag-NP Night Jasmine Aqueous Extract Rheumatoid Arumugam
(Nyctanthes Arthritis et al., 2013
arbor-tristis)
2. Ag-NP
3. CD Conjugated Curcumin Rhizomes Osteoarthritis Murali et
Au-NP extract al., 2015
4. Ag-NP
5. Ag-NP
6. Ag-NP
7. Au-NP
8. ZnO-NP
Tylophora
ovata
Cardiospermum
halicacabum
Morinda
tinctoria Roxb
Centratherum
punctatum
Cass.
Achyranthes
aspera Linn
Moringa
oleifera
The leaves and Arthritis Joy et al.,
roots 2015
The leaves Rheumatism Mahipal et
extract and arthritis al., 2013
The leaves Arthritis Geetha et
extract al., 2017
The leaves Arthritis Krithika et
extract al., 2016
Seeds Arthritis Anand et
al., 2014
Immature pods Arthritis Monakari
and flowers et al., 2016
9. Ag-NP Caffeic acid The plant source Osteoarthritis Qingyan et
10. Cu-NP
* Ag: Silver, Au: Gold, ZnO: Zinc Oxide, Cu: Copper, CD: Cyclodextrin.
Site-specific delivery of drugs to target cells and tissues is considered to be
an important application of engineered nanoparticles as medicines. Recent
Delonix elata
al., 2017
Flower extract Arthritis Suganya et
al., 2016
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investigation for herbal drugs has been tested against various forms of
arthritic conditions and indicates a significant decrease in the levels of IL-6
and TNF-α in the synovial fluid. Active medicaments derived from herbals
exhibits a great impact in lowering amounts of cytokines in the Synovial
fluid resulting in the relief from the diseased condition that may lead to
better quality of life of patients. This aspect presents a promising approach
of developing nanostructures systems using active drugs which enables drug
release in surrounding environment at controlled rate, thereby, requires less
drug dosages and avoids the non-specific side effects of the drugs (Li et al.,
2010; Kowalski et al., 2013).
TABLE 8.3 Inclusion of Bioactive Compound in Different Forms of Nanomedicines
Sl.
Bioactive
No.
Group
1. Polyphenols Quercetin Nanoparticles Quercetin PLGA-NP
2. Phytocanna-
binoid
3. Stanols Phytosterols Nanodispersion Produced by
4. Carbohydrates Mannose-6-phosphate Nanocapsule Polyamide NC
5. Essential oil
(EO)
Bioactive Component Nano Carrier
System
Nanocapsule Lipid coated NC
Resveratrol Nanoparticles PLGA NP containing
Solid lipid
nanoparticles
Cyclodextrin CD-based nanosponge
nanosponge
Ellagic acid Nanoparticles Ellagic acid-loaded
∆-9-Tetrahydrocanna-
binol
Oregano and cassia EO Nanoparticle Corn zein NP
Thymol and Carvacrol Nanoparticle Corn zein NP
Lipid
nanoparticles
Nanoparticles PLGA-NP
Liposomes Liposome containing
Type of Delivery
System
Resveratrol
Resveratrol loaded
SLN
PLGA NP
NLC
emulsificationevaporation
Suspension of
submicron particles of
phytosterols
Aloe vera gel
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