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TABLE 8.3 (Continued)
Sl. Bioactive Bioactive Component Nano Carrier Type of Delivery
No. Group System System
Cinnamon and Thyme Cyclodextrins Inclusion in CD
EO
Lippiasidoides EO Nanoparticle Alginate/Cashew gum
Cumin and Basil EO Nanocapsules Polyamide NC
6. Terpenoids Squalene Nanocapsules Polyelectrolyte
Lycopene Nanoemulsion Aquos propolis and
p-Cymene Cyclodextrins Inclusion in CD
Linalool Cyclodextrins Inclusion in CD
Carvacrol Cyclodextrins Inclusion in CD
* NP: Nanoparticles; CD: Cyclodextrins; NC: Nanocarriers; SLN: Solid lipid nanoparticle;
NLC: Nanostructured lipid carriers; PLGA: Poly (lactic-co-glycolic acid).
Source:Raffaele et al. (2017).
Biomarkers as Targeted Herbal Drug Discovery
NP
multilayer NC
lycopene
Nanoparticles SLN
Cyclodextrins Inclusion in CD
In active targeting, the modification or functionalization of the drug carries is
done so that content can be delivered to the site corresponding to which the
carrier is designed. Ideal active targeting nanomedicines for arthritis need
suitable range between 10 to 100 nm and charge on their surface (Lee et al.,
2014; Kim et al., 2013).
Active targeting nanomedicines need to overcome three barriers to
achieve the optimal effects on arthritis:
1. Drug loaded nanocarriers were modified with PEG and active ligands
to for the active targeting nanomedicine.
2. PEGlyation prolonged the duration of nanomedicines in blood
circulation.
3. Modification at surface charge facilitated the active delivery of
nanomedicines to inflamed tissues and cells (Lee et al., 2013; Kim
et al., 2015).
195 Phytoconstituent-Loaded Nanomedicines for Arthritis Management
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Nanomedicines are multidisciplinary domains and have been used for
different purposes. Some of these applications are listed here (Rocco et al.,
2003; Bindhani et al., 2013):
• As potential platform for therapeutic application;
• As diagnostic purpose with improved fluorescent for screening
purpose;
• Delivery of antigens for vaccination;
• Drug delivery for targeted at specific sites in the body;
• Bioavailability issues improvisation with potential nanotechnology
solution;
• Provides protection for agent susceptible to degradation.
Some of the literature studies indicate observation of multiple mecha-
nisms in different types of arthritis. Some of the molecules has been identi-
ed and considered a potential targets by the upcoming therapies for arthritis
or several inammation conditions (Table 8.4).
TABLE 8.4 Molecular Targets for Nanomedicines in Arthritis and in Other Inflammatory
Conditions
Target
Group
Cytokines Interleukin-1β
Targets at
Molecular Level
(IL-1β)
Interleukin-6
(IL-6)
Interleukin-17 A
(IL-17A)
Tumor necrosis
Factor-α
Urokinase-type
plasminogen
(uPA)
Cathepsin-B During early degenerative
Occurrence Description
Knee joint and synovial
fluid
Synovial T-cells Divergence of T helper
Synovial fluids Activation and expression
Synovial fluids Secretion of
Synovial cells uPA/uPAR signaling
phase of Osteoarthritis in
synovial tissue
Prevent hyaline cartilage
production
cells as TH-1, TH-2, and
TH-17 cells
of interleukins-1, 6 and 8
interleukins and matrix
metalloproteinases
(MMPs)
provoke inflammation at
joints.
Promotes progression of
Osteoarthritis by splitting
aggrecan
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TABLE 8.4 (Continued)
Target Targets at Occurrence Description
Group Molecular Level
Matrix Synovial tissue Develops osteoarthritis
metalloproteinases pathogenesis
-3 (MMP-3)
Oncostatin M Synovial fibroblasts Promote cartilage damage
Proteins Type I collagen Bone Initiation of osteoblastic
Type II collagen Cartilage Support cartilage Strength
Aggrecan Synovium Support cartilage Strength
Inflam– Prostaglandin E1 Osteocytes Encourage bone
matory Cells resorption
Forkhead box Synovium Maintain equilibrium
T-cells among regulatory and
Extracellular Osteopontin Secreted by leukocytes, Trigger cell adhesion,
matrix present in extracellular movement, invasion,
glycoprotein fluids and at the sites of and controls signaling
Biomarkers as Targeted Herbal Drug Discovery
through synergistic effect
with IL-1
separation of cells in bone
marrow
helper (T-H-17) T-cells
inflammation. function
Source: Kislay et al. (2015).
PHARMACOTHERAPY
The concept of nanotechnology can be of great effectiveness for medicinal
plants as well as for its biological active constituents. Herbal compounds
(phytotherapeutics) delivery in form of nanoparticles likely to improve their
pharmacokinetic and pharmacodynamics profiles. The purpose to combine
the herbal medicine with nanotechnology is to design nanostructured systems
that provoke the action potential of plant extractives, minimization of effective dose, dosing frequency, and lowering side effects (Newman et al., 2007).
For instance, bioactive incorporate such as hesperidin, curcumin, celastrol,
resveratrol results in high efficacy for the treatment of arthritis which opens
up the door for new and effective drug delivery for arthritis as an alternate to
low effective conventional therapy. Phytocontituents have immense potential
in arthritis pharmacotherapy but hindrances associated with restricted use of
197 Phytoconstituent-Loaded Nanomedicines for Arthritis Management
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herbals in medical research might be overcome using nanocarriers based drug
delivery methods for their effective delivery (Allen et al., 2004).
In designing of a proper delivery system, the physicochemical parameters
of natural therapeutics and the system are of great importance to understand
drug absorption. These properties control the target site action and penetration
across the skin due to the presence of metabolic enzymes and skin fencing.
Currently, nanomedicines such as liposomes, microspheres, solid lipid
nanoparticles (SLNs), nanoemulsions, and microemulsions have been
developed to improve the absorption of such bioactive so as to avoid abovementioned issues (Kostarelos et al., 2003). These systems offer several merits
like controlled delivery of drugs (both hydrophobic and hydrophilic in nature),
high drug loading (DL) capability, and better suitability in systemic and topical
drug delivery. In addition, the nanostructured system provides higher surface
area-to-volume ratio, which provides in signicant improvement in the pharmacodynamic and pharmacokinetic properties of active drugs on the specic
site. A system consisting of small size particles favors better skin interaction
and permeation that contributes the extended circulation of drug molecule to
specic site via active targeting (Allemann et al., 1999).
Nowadays, researcher’s interest is mainly concerned with the medicinal therapeutics extracted and isolated from plants as because the currently available
therapy is considered to have some issues related to adverse effects as well
as high expense. Currently in India, more than 2500 traditional plant species
are using as herbal medicines for the treatment either as directly medication
or indirectly as an ingredient of pharmaceutical preparation. Hence, from
this perspective, thorough information of these potential herbals may help in
finding innovative and economic drugs as an alternative therapy (Manjusha
et al., 2015) (Table 8.5).
The science of nanomedicines is among the most interesting areas of
research. In the last two decades, the filling of 1500 patents and completion
of several dozens of clinical trials has already been conducted. In the nanomedicines approach, using an appropriate nano-delivery system facilitate
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Biomarkers as Targeted Herbal Drug Discovery
the delivery of the accurate amount of drug to the affected cells without
disturbing the physiology of the normal cells. The application of the nanodrug delivery system is currently the trend that will remain to be the future
arena of research and development for the near future. Research on NMs
has to be done on a higher level with more consistent uniformity and DL
and release capacity. The incorporation of metals such as gold, silver, and
copper within nanostructures systems provides advancement in diagnosis
and therapy in various inflammatory conditions that could potentially lead
to wider application of nanomedicines in the treatment of arthritis in coming
decades (Raffaele et al., 2017).
Biochemical observations of the experimental studies clearly demon-
strate the important role of herbals in the regulation of proinammatory
cytokines, although more clinical studies at large scales need to be
performed to conrm the analysis as well as to dissolve some conicts.
The word “natural anti-inammatory” refers to natural compounds, life-
style, exercise, and sleep, and eating habits. Various studies on natural
compounds and herbal medicines suggested variable outcomes and an
inconsistent result which might be based on the method of extraction
of chemical constituents because the pharmacological effect of each
medicinal herb is the result of plenty of metabolites combination and
their synergistic effects; perhaps, it is one of the reasons of contradictory
results. There are several synthetic anti-arthritic drugs that have been used
in arthritis therapy, but they suffer from several drawbacks which restrict
their efcacy.
Herbal treatment approach is of great concern with respect to have great
structural diversity, which has not usually seen with synthetic ones. Several
synthetic anti-arthritic compounds, employed in arthritis therapy, have
several limitations such as non-uniformity in dose and poor bioavailability
and higher metabolism. Recent studies revealed that phytotherapeutics have
been delivered by means of nanocarriers so as to achieve specic action
in arthritis therapy by minimizing dose, and higher drug localization at the
target site. For the effective delivery of bioactive, research data on nanocarriers needs to be established in vitro and in vivo along with safety data. In the
near future, nanomedicine may become a rst-line approach for an effective
delivery system for targeted delivery of bioactive for better management of
arthritis. To support the already available research data more investigations
need to be done for further materialistic approach in respect to clinical trials
and market approvals so as to reach to the desired population (Mona et al.,
2016).
TABLE 8.5 Some Reported Herbs Used in the Management of Arthritis
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Sl. Plant Name Biological Source Family Active Component References
No.
1. Aloe vera
2. Spicewood
3. Ginger
4. Ashwagandha
5. Barringtonia
6. Panicled Erycibe
7. Milk weed
8. Kalpanath
9. Thunder god vine
10. Day-blooming
Jasmine
11. Chhotahalkusa
12. Galangal
13. Ashoka
Aloe barbadensis
Lindera aggregata
Zingiber officinale
Withania somnifera
Barringtonia racemosa
Linn.
Erycibe obtusifolia
Calotropis procera Linn
Andrographis paniculata
Tripterygium wilfordii
Cestrum diurnum
Leucasaspera Linn.
Alpinia officinarum
Saraca asoca Roxb.
Liliaceae Anthraquinones Devis et al., 1986; Joshep
et al., 2010
Lauraceae Norisoboldine (NOR) Wei et al., 2012
Zingiberaceae Sesquiterpenoids, Rehman et al., 2011;
sesquiterpene lactones Zaker et al., 2011
Solanaceae Withanolides Grover et al., 2010
Lecythidaceae Bartogenic acid Sun et al., 2008
Convolvulaceae Scopoletin Pan et al., 2010
Asclepiadaceae Benzoyllineolone, Vaidya et al., 2006
Benzolisolineolone
Acanthaceae Andrographolide Burgos et al., 2009
Celastraceae Triptolide Kimura et al., 2011
Solanaceae Ursolic acid Ahmad et al., 2006
Lamiaceae Ethanolic extract Narendhirakannan et al.,
2005
Zingiberaceae Diarylheptanoids Lee et al., 2009
Caesalpiniaceae methanol extract Prajapati et al., 2010
Phytoconstituent-Loaded Nanomedicines for Arthritis Management
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TABLE 8.5 (Continued)
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Sl. Plant Name Biological Source Family Active Component References
No.
14. Chinese peony
15. Tinosporagulancha
16. Deodar cedar
17. Indian sarsaparilla
18. Black adusa
19. Indian white cedar,
20. Pink Arnebia
Paeonia lactiflora
Tinospora cordifolia Linn.
Cedrus deodara
Hemidusmus indicus Linn.
Gendarussa Linn.
Dysoxylum binectariferum
Arnebia euchroma
Paeoniaceae Gallic acid Jiang et al., 2011
Menispermaceae Tinosporine, tinosporide, Kumar et al., 2003
cordifolide, heptacosanol.
Pinaceae Polyphenols Rajan et al., 2011
Asciepiadaceae Coumarin Bajpai et al., 2009
Acanthaceae Ethanolic extract of leaves Sheihk et al., 2011; Paval
et al., 2009
Meliaceae Rohitukine Jain et al., 2012
Boraginaceae Hydroxy naphthaquinone Fan et al., 2012
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This chapter tried to highlight the potential of different herbs and herbal
constituents which have been active and traditionally used in the treatment
of arthritis as a main or supplementary medication. Though research on
animal studies put interesting facts and observations but not much clinical
and toxicological studies have been performed in this area to support the
efficacy and potency of the treatment by herbals. Future opportunities for
research in this area have a wide scope which may yield new drug candidates
against arthritis, a major socio-economical medical problem among senior
persons around the world. Nanotechnology has been already employed for
drug delivery and tissue engineering of various natural compounds, as it
offers the possibility to develop a therapy with improved therapeutic efficacy
of natural bioactive molecules, increased drug bioavailability, site-specific
targeted delivery and ultimately reducing toxic side effects. We are hopeful
that natural compounds will be a complementary treatment against arthritis
and bone-joint related disorder in the coming future.
• arthritis treatment
• carbon nanotubes
• essential oil
• matrix metalloproteinases
• nanomedicines
• pharmacotherapy
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