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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5365_Библиотеки_им_академика_М_И_Перельмана
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CHAPTER 4
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Ursolic Acid: A Pentacyclic Triterpene
from Plants in Nanomedicine
MONALISHA SEN GUPTA,1 MD. ADIL SHAHARYAR,
MAHFOOZUR RAHMAN,2 KUMAR ANAND,1 IMRAN KAZMI,
4
MUHAMMAD AFZAL,
1
Department of Pharmaceutical Technology, Jadavpur University,
and SANMOY KARMAKAR
1
3
1
2
Department of Pharmaceutical Sciences, SIHAS, SHUATS, Allahabad,
Uttar Pradesh, India
3
4
ABSTRACT
Ursolic acid (UA) is the most promising member of the triterpenoid
groups, is a naturally derived pentacyclic triterpenoid. The basic structure
is composed of ursane, lupane, and oleanane, which is leading to different
pharmacological activities of UA. Though having numerous physiological
properties like anti-inflammatory, anticancerous, bone regeneration, antifungal, hepatoprotective, antioxidant, it possesses one major drawback
is less solubility in water, followed by poor bioavailability in the drug
delivery system. Another drawback of UA is the off-target drug delivery
system which results in less use in the medical world. Having these major
side-effects, the use of UA is not restricted and overcome with the help
of nanotechnology, by developing different formulations like liposomes,
nanoemulsions, micelles, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), etc.
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Biomarkers as Targeted Herbal Drug Discovery
Ursolic acid (UA) is a naturally derived pentacyclic triterpenoid, an important
bioactive phytochemical. Ursolic acid is the most promising member of the
triterpenoid groups. Depending upon the quantities of different structural
isoprene units, families of triterpenoids are classified. By squalene cyclization,
these triterpenoids are synthesized which generally found in natural sources like
many plants and fruits (Jäger et al., 2009). Roots of Catharanthus trichophyllus,
leaves of Plumeria obtuse, Eriobotrya japonica, and Rosmarinus officinalis,
etc., are some source of UA (Shanmugam et al., 2013). Pentacyclic triterpenes,
exhibit numerous biological functions due to the presence of different functional groups. It also possesses activity like cytotoxicity on different cancer
cell lines. Having many potential benefits, some physical limitations restrict
the oral and systemic delivery of UA (Jeong et al., 2007; Jäger et al., 2008;
Yin et al., 2012). To increase the solubility and to improve the bioactivity of
UA, formulations like liposomes, nanoemulsions, nanoparticles (polymeric,
solid, and metallic, among others) and cyclodextrin drug complexes, among
other systems try to develop successfully (Jäger et al., 2015; Xie et al., 2016;
Li et al., 2015). The main focus of this chapter will be different evaluation
techniques (in-vitro and in-vivo) regarding the antitumor effects of pentacyclic
triterpene, i.e., UA. Not only that, but the contribution of nanotechnology to
facilitate the effective delivery of UA will be also concerned.
Ursolic acid (UA) (3-3-hydroxy-urs-12-ene-28-oic-acid) is a naturally derived
pentacyclic triterpenoid and a hydroxy monocarboxylic acid which derived by
substituting a beta-hydroxy group in urs-12-en-28-oic acid at position 3, from
a hydride of a ursane (Figure 4.1). It is an isomer of oleanolic acid (OA). It has
been isolated as an isomeric mixture of OA (Liu, 1995; Vasconcelos et al., 2006).
The basic framework of pentacyclic triterpenoids molecules is composed
of ursane, lupane, and oleanane. The presence of these functional groups is
leading to different pharmacological activities of UA.
UA a pentacyclic triterpenoid is widely distributed in plant kingdom like
fruits, medicinal herbs, and other plants. It exerts many major physiological
67 Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
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activities, among which chemopreventive and chemotherapeutic actions are
most important. Large, lustrous prisms shaped crystals of UA are obtained
from the absolute alcohol extract, whereas extract with dilute alcohol provides
fine hair-like needle-shaped crystals (O’Neil, 2006). A higher melting point
(284°C) of UA makes it more preferable among other phytochemicals (Lide,
2008). It is soluble in alcoholic NaOH solution as well as hot glacial acetic
acid but insoluble in petroleum ether (O’Neil, 2006). The toxicity of UA is
very low which also contributes to the more use in therapeutics. The solubility
of UA in water is very poor. Due to less solubility in water, UA becomes
poorly bioavailable in the drug delivery system. Another drawback of UA is
the off-target drug delivery system which results in less use in the medical
world. Having these major side-effects, the use of UA is not restricted. By
using the knowledge of nanotechnology, different formulations are developed
to overcome the limitations related to targeting and solubility of UA.
Chemical structure of ursolic acid (UA).
Different analytical methodologies have been developed for triterpenes,
with high selectivity, sensitivity, accuracy, and precision. Pharmacokinetic
studies constitute an important stage during the development of new medicines. Discerning the disposition process (i.e., absorption, distribution, and
elimination) of new drug candidates facilitates selecting the most appropriate
administration route and best dose regimen. The pharmacokinetic parameters
of UA in rats after an oral administration suggested rapid absorption, but plasmatic concentrations were extremely low (Liao et al., 2005). Additionally, a
lower dose like 10 mg/kg of UA presented rapid absorption with distribution
primarily through blood-supplied tissues, such as the lungs, spleen, and liver.
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Biomarkers as Targeted Herbal Drug Discovery
The half-life of UA in the plasma was less than 1 h, indicating rapid elimination (Chen et al., 2011). The study of safety and pharmacokinetic parameters
after administering an ascending oral dose of UA shows low and variable UA
bioavailability due to the poor water solubility of this compound. This trait
led to decreased intestinal absorption and rapid elimination through gut wall/
liver metabolism (Hirsh et al., 2014).
There is limited data to demonstrate the mechanism of pharmacokinetics
(PKs) especially absorption of UA which indicated the involved mechanism
of absorption was passive diffusion and P-glycoprotein transporter-mediated
active transport. It is established by conducting a study with the Caco-2
cell monolayer model. A previous PK study of UA in rats showed the rapid
absorption of UA at 1st hour along with the peak concentration after oral
administration though the concentrations were extremely low in plasma
(Liao et al., 2005). Recently, another PK study among rats demonstrated the
time of peak plasma concentration of UA was about half an hour, which ultimately indicating the rapid absorption of UA. Rapid elimination of UA was
determined by the lower half-life, i.e., less than 1 hour (Chen et al., 2011). As
a result, by enhancing the solubility of UA making it more bioavailable for
therapeutic development becomes really challenging. Table 4.1 summarizes
the pharmacokinetic properties of UA by using different animal models.
TABLE 4.1 Pharmacokinetic Parameters in Different Animal Models
Animal Route Dose C
Rats Oral 40 g
extract/
kg
Rats Oral 10 mg/
kg
Albino
rabbits
Oral 1 g
extract/
kg
UA posses numerous physiological properties in which anti-inflammatory, anticancerous, bone regeneration, antifungal, hepatoprotective, antioxidant, antimicrobial, antiallergic, antiviral activity, cytotoxic activities are most common
and are of great importance among others. It also works as a plant metabolite.
max
294.8
ng/mL
1.10 ±
0.3 μg/
mL
306.8
μg/mL
t
max
1.0 h 4.3 h 1175.3
0.42 ±
0.11 h
2.5 h 3.2 h 2245.4
T
1/2
0.71 ±
0.09 h
AUC References
ng h/mL
1.45 ±
0.21 μg
h/mL
μg h/mL
Liao et al.,
2005
Chen et al.,
2011
Shetty et al.,
2007
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In immunity, like innate and adaptive, the inflammation is critical for both
due to the quick and spontaneous response against infection or injury by
our body. The response can be reviewed as a segment of the complex
biological reaction of vascular tissues to detrimental stimuli alike infective agents, blemished or dead cells, and irritants. The exploring of
natural compounds and phytochemicals will be able to intrude into the
mechanisms which can be useful for the health of human by arresting the
prolonged inflammation.
Ocular inflammation prevalent complications after eye surgery. Due to the
complex structure of the eye, the major challenge in ocular medication is
the ability to maintain a therapeutic level of the medicament at the site of
action for an extended duration (Agnihotri andVavia, 2009) Generally ocular
efficacy is closely associated with the bioavailability of ocular drugs, which
may be increased by increasing corneal drug penetration (Gupta et al., 2010).
Ocular delivery of drugs is f the most challenging and fascinating venture
faced by the pharmaceutical scientist because the development of novel
delivery systems for ocular instillation is currently a demand (Araújo et al.,
2009; Holden et al., 2012; Karalezli et al., 2008). Several approaches have
been proposed but nanoparticles (NPs) represent itself as promising drug
transporter for ophthalmic use, by delivering ease of execution just like eye
drop having a lesser frequency of administration and extended the duration
on the extraocular part (Nagarwal et al., 2009).
UA acts by inhibiting enzymes like cyclooxygenase and phospholipase
A2 which involved in the production of eicosanoids. It also helps to avoid the
release of cytokines, histamine, serotonin. Not only that, the interaction between
serine/threonine kinases and ursolic acid is also avoided (Kwon et al., 2009).
Cancer is a sort of illness presuming unnatural cell growth with the
possibilities to occupy or spread to other portions of the body. Growing
cancer incidence and increased mortality trends implied that more efforts
should be made to overcome the challenges in the treatment of cancer.
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As adjuvant therapy, chemotherapeutic agents have been used independently or integrated with other or integrated with other treatments. Ursolic
acid shows a promising inhibitory effect in different cell lines. UA has
recently attracted great attraction for its potential as a chemotherapeutic as
well as chemopreventive factor. UA kills the fastly growing and dividing
cancerous cells as a solitary chemotherapeutic agent, and also destroys
the growing regular cells. It may cause adverse effects like congestive
heart failure (CHF) during clinical treatment. Limitations of solubility
and bioavailability can be solved by incorporating the convenient and safe
delivery system, which also helps to maximize the therapeutic activity and
minimize the side effects.
UA has its tasks at various phases of tumor enlargement. Still, the exact
mechanism of action of its anticancer activity is yet to uncover. But several
studies show the inhibitory activities of UA to proliferate and inuence
apoptosis of numerous tumor cell lines (Sultana, 2011).
Studies also show that apoptosis induced by UA happens due to the
involvement of multiple pathways like:
1. The inhibition of DNA replication (Kim et al., 2000).
2+
2. Induction of Ca
release (Baek et al., 1997).
3. Activation of caspases (Choi et al., 2000; Harmand et al., 2005).
4. C-Jun N-terminal kinase (Xavier et al., 2012; Zhang et al., 2010).
5. Phosphorylation of glycogen synthase kinase 3-, down-regulation of
antiapoptotic genes (Kassi et al., 2009).
6. Inhibition of cyclooxygenase-2 and inducible nitric oxide (NO)
synthase (Subbaramaiah et al., 2000; Suh et al., 1998).
7. Suppression of matrix metallopeptidase (Cha et al., 1998; Hollosy
et al., 2000).
8. The suppression of protein tyrosine kinase (Wu et al., 2012).
9. Phosphatidylinositol-3-kinase (Pathak et al., 2007).
10. Single transducer and activator of transcription (Kim et al., 2000;
Zheng et al., 2012).
11. Adenosine 5-monophosphate-activated protein kinase (Shishodia et
al., 2003).
12. Nuclear factor-light-chain-enhancer of activated B cell pathways
(Kanjoormana et al., 2010).
The abilities of UA to inhibit the different major activities like angiogenesis, invasion, differentiation, and metastasis of tumor cells has been demonstrated by different studies. Functions of numerous enzymes, responsible
71 Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
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for DNA synthesis and repair are also interfered by UA (Kim et al., 2000;
Novotny et al., 2001; Ovesna et al., 2004) (Table 4.2).
TABLE 4.2 In Vivo Potential Antitumor Effects of Ursolic Acid
Animal Mouse Treatment Route of No. of Effects References
Model Xenograft Admini– Animals
Model stration Per
Group
NOD/
SCID
mice
Kunming
mice,
male,
and
female
Athymic
nude
mice
Swiss
female
albino
mice
Balb/c
nude
female
mice
U937 (2 ×
106 cells/
animal),
SC
H22
cells of
exponential
growth
phase, SC
GBC-SD
(2 × 106
cells/
animal),
SC
Ehrlich
ascites
carcinoma
(15 ×
106 cells/
animal), IP
HCT15 (1
× 106 cells/
mice), SC
50 mg/kg IP 10 Induces
for 20 days tumor cell
apoptosis
2.53 mg/ O 10 Induces
mouse for tumor cell
10 days apoptosis
16 mg/kg IP 15 Antitumoral
and 32 mg/ effects by
kg suppressing
cell
proliferation
25, 50 and IP 10 Inhibits
100 mg/ tumor
kg/d/bw for angiogenesis
14 day and induces
apoptosis
75 mg/kg O 10 Cell death
bw for 14 induction
days and
autophagy
modulation
Zheng et
al., 2013
Wang et
al., 2011
Weng et
al., 2014
Saraswati
et al., 2013
Xavier et
al., 2013
GBC-SD: Cell line human; IP: Intraperitoneal; bw: Bodyweight; O: Oral; NOD/SCID: Nonobese diabetic/spontaneous mutant model; SC: Subcutaneous.
Hepatocellular cancer still remains one of the most threatening cancers,
accounts for almost 90% of major liver cancer cases worldwide (Siegel et
al., 2013; Parkin et al., 2001). Regardless of the advancement of recent treatments, the resistance to standard chemotherapy has led to less response rates
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Biomarkers as Targeted Herbal Drug Discovery
and poor overall survival. Due to the high frequency of recurrence along
with poor diagnosis, an immediate need to overcome the recent limitations
of chemotherapeutics is arise to improve the therapeutic efficacy. Existing
studies have already exhibited the restraining power of ursolic acid (UA), on
the progression of a series of cancer cells (Parkin et al., 2001; Shanmugam
et al., 2013). Recent works have also demonstrated the antitumor activity
of UA through the induction of apoptosis and retardation of angiogenesis
(Gao et al., 2012; Shanmugam et al., 2012). However, the restriction of UA
is accredited clinically mainly to the low solubility and deficiency of the
ability to target tumor areas. In one another study, the in vivo utilization of
UA was remarkably impaired by its poor solubility, which in consequence
leads to poor PKs (Limami et al., 2011). As a result, UA counts a serious and
unavoidable side effect, i.e., disability to the target tumor.
Ursolic acid (UA) has demonstrated having broad-spectrum anti-tumor
activities, but its limitations restrict its clinical application and efficiency. As
an in vitro model of using MCF-7 cells for anti-cancer mechanistic studies,
it is found that the internalization of UA by cancer cells through a folate
receptor-mediated endocytic pathway may become easy when it incorporated in a suitable matrix. A lysosomal product of UA shows a great activity
by destructing the permeability of the lysosomal membrane, and then got
released from lysosomes and localized into mitochondria but not nuclei. The
extended retention of UA from the suitable matrix in mitochondria induced
excess generation of ROS and demolition of mitochondrial membrane potential which ultimately results in the unrepairable apoptosis in carcinogenic
cells. In vivo experiments demonstrated that UA in the suitable matrix could
significantly reduce the burden of breast cancer particularly in the MCF-7
xenograft mouse model. These outcomes suggested that incorporated UA in
a suitable matrix, can be a future prospect as an anti-cancer drug candidate
against breast cancer and an upcoming perspective can provide a platform to
create a novel anti-drug delivery system against cancer.
Cervical cancer is f the most common cancers amongst the women which can
be concluded from the estimation of 528,000 new cases per year (Bast et al.,
73 Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
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2009), and the mortalities caused by cervical cancer in the world is approximately 266,000, which counts for almost 7.5% of all mortalities related to
women cancer (Phongsavan et al., 2010). Approximately 87% of the death
caused by cervical cancer, mainly in undeveloped nations and regions. Generally, the women, of 30 to 50 ages, are more prone to this cancer due to factors
like environment, gene mutation, job stress, and emotion (Agarwal et al., 2011).
Important novel strategies to diminish the cancer progression in therapeutically along with invasion of cervical tumor, metastasis were disclosed through
research works regarding molecular mechanisms (Kawase et al., 2010, p. 59).
Among the members of pentacyclic triterpenoids, the imberbic acid, betulinic acid, zeylasteral, and ursolic acid have been reported to show the anticancer activities. Ursolic acid is also familiar to increase apoptotic response in
different human cancer cell lines (Gong et al., 2014). However, there are nite
numbers of documents which reported the key role of ursolic acid in the ruling
of cervical cancer progression. ELISA, western blotting, ow cytometry, and
immunohistochemistry assays of ursolic acids were done to investigate the
molecular mechanism of modulating cervical cancer progression by ursolic
acid nanoparticles. Data indicated that cervical cancer cell proliferation can
be suppressed signicantly, invasion, and migration compared to the control
group, and also apoptosis was induced by ursolic acid nanoparticles through
activating caspases, p53, and inhibiting anti-apoptosis-related signals. Furthermore, in the in-vivo experiments, the size of the tumor was reduced by the
treatment of ursolic acid nanoparticles. In conclusion, ursolic acid can suppress
cell proliferation of cervical cancer via apoptosis induction, which can be a
potential approach in the future for clinical therapeutic strategy (Table 4.3).
Trauma, infectious, tumor resection, and other diseases cause bone defects.
These are the most challenging factors in orthopedics (Tansik et al., 2016; Xie
et al., 2017; Nabiyouni et al., 2018). The bone defects make bring unhappiness
and economic burden to the patient. Over the past several decades, a number
of bone grafts have been used in the sector of bone tissue regeneration like
autografts, allografts, and xenografts, which can significantly make a decent
result for the patients. An autologous graft is believed as a gold standard (Kim
et al., 2017), but it has some negative actions such as donor-site morbidity,
lack of availability (Lin et al., 2017). Allografts and xenografts have also their
disadvantages including disease transmission and immunogenicity (Duan et
al., 2017; Chen et al., 2017). Therefore, it is crucial to originate novel bone
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