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Basic structure of nanoparticles.
Biomarkers as Targeted Herbal Drug Discovery
Zhou et al. prepared powder of UA phospholipid nanoparticles using solvent
emulsification evaporation and ultrasonic dispersion. Specifically, soybean
phospholipids, UA, and poloxamer 188® were dissolved in an ethanol and
ethyl acetate as co-solvent. The UA nanoparticle suspension was added to
5% glucose and mannitol, which serve as cryoprotectants, and samples were
freeze-dried. The resulting nanoparticles had an average diameter of 273.8 ±
2.3 nm, a potential of –23.2 ± 1.5 mV, and encapsulation effectivity (EE) of
86.0 ± 0.4% (Sun et al., 2011).
To improve UA solubility, Sun et al. by using the supercritical antisolvent
process developed a nanoparticle, which resulted from 139.4 ± 19.4 nm to
1039.8 ± 65.2 nm. The processed UA dissolution rates were 4.4-fold higher
than unprocessed UA (Zhang et al., 2013).
In turn, Zhang et al. proposed a UA delivery system composed of poly-
meric nanoparticles prepared through a nano-precipitation method. This
method used mPEGPCL block copolymers and UA (ratio 2:1), which were
dissolved in acetone and then dialyzed in water. The obtained nanoparticles
had an average diameter of 144.0 ± 4.0 nm, a potential of –0.99 ± 0.3 mV,
and an EE of 87% ± 5.3% (Mandelli et al., 2013).
85 Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
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Furthermore, Mandelli et al. developed UA lipid nanoparticles for incor-
poration into a cosmetic formulation. Nanoparticles were produced through
high-pressure homogenization with 1% UA and cetyl-alcohol, methyl soyate,
tocopheryl acetate, and sorbitol, among others. Only stability of the UA was
evaluated (i.e., a variation of the viscosity and pH), with results revealing
that the nano-structured-lipid carrier provided better physical and chemical
stability than free-form UA (Singh et al., 2010).
Polymeric nanoparticles were studied by Alvarado et al. to develop an
ophthalmic delivery system. The polymeric nanoparticles were prepared
using the solvent displacement technique, which employed PLGA, poloxamer 188, and synthetic and natural OA/UA mixtures. The synthetic mixture
nanoparticles exhibited a Z-average of 222.75 ± 2.19 nm, a potential of
–27.30 ± 1.63 mV, and an EE of 76.55% ± 3.92%. In turn, natural mixture
OA/UA polymeric particles presented a size of 211.80 ± 1.83 nm, a potential
of –26.90 ± 0.27 mV, and an EE of 78.45% ± 2.40% (Zhou et al., 2009).
In-vitro and in-vivo effects related to Zang et al. study who worked on a polymeric delivery UA nanoparticle, had demonstrated that the UA-nanoparticle
significantly elicited more cell death by suppressing the expression of COX-2
and activation of caspase 3 with in-vitro cytotoxicity and apoptosis tests.
Notably, UA-nanoparticle doses were nearly equivalent to free-form UA. These
results showing its preference towards the superiority of the UA-nanoparticle
over the free-form UA in regard to cell membrane penetration, a requirement
for intracellular drug accumulation (Mandelli et al., 2013).
Cyclodextrins inclusion compound is a complex system where designs can
be incorporated either in which one component of complex (the host) forms
a cavity, or in the case of, spaces of crystal lattice in the shape of long tunnels
or channels where second chemical species (the guest) of the molecular entities are located. The guest and host are, attracted by the van der Waals forces,
but not by covalent bonding.
The cyclodextrin inclusion complex is one of the most studied pathways in
relation to the issue of solubility. For the formation of inclusion compounds,
the well-established hosts are cyclodextrins. The illustrative case of ferrocene is insertion under hydrothermal conditions, into the cyclodextrin at
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Biomarkers as Targeted Herbal Drug Discovery
100°C. Cyclodextrin also able to incorporate fragrances into the inclusion
compounds, which have reduced vapor pressure, and the stability in exposure to light and air is more. Due to the slow-release action, the fragrance of
these molecules lasts much longer when it incorporated into textiles (Cerga
et al., 2011), (Figure 4.6).
Formation of cyclodextrin-drug inclusion complex.
Cegal et al. evaluated the inclusion of OA and UA in two cyclodextrins (i.e.,
hydroxyl-propyl-cyclodextrin, and hydroxypropyl cyclodextrin), characterizing the complexation between the acids and cyclodextrins. Differential
scanning calorimetry (DSC) and x-ray characterization indicated that the
active compounds and cyclodextrin inclusion complexes remained unaltered
and could be used as drug delivery systems (Soica et al., 2014).
Soica et al. also developed an OA/UA cyclodextrin complex, which was
monitored using in vivo skin cancer models (SKH1 female mice were
exposed to UVB and 7,12-dimethylbenz (a)anthracene). The results showed
an increase in antitumor activity for the UA/OA mixture, both alone and in
complex with cyclodextrin (Zhang et al., 2015).
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Bioglass (BGs) was originally discovered in 1969 and now commonly used
in bone tissue engineering because of its good biocompatibility and osteoconductivity. After implanted in vivo, BGs can bond closely to host bones
via the formation of carbonated hydroxyapatite (CHA) layer between them,
however, their osteogenic capacity is not enough excellent to effectively heal
bone defects especially for the patients with bone diseases (Hench, 2006; Park
and Ha, 2018). Fortunately, empty mesoporous microspheres are mainly fit
for the restorative scaffolds in which the controlled delivery of osteogenic
drugs facilitates in vivo bone tissue formation (Kang et al., 2018). The empty
interiors in hollow microspheres facilitate drug storage, and the mesoporous
features provide the bigger surface areas for bone-like CHA deposition and
drug delivery (Kang et al., 2018; Moghaddam et al., 2018; Zhang et al., 2014;
Logith et al., 2016). Moreover, chitosan (CS) with 2-acetamido-2-deoxy-dglucan and 2-amino-2-deoxy-d-glucan units possesses so excellent biocompatibility, osteoconductivity, and biodegradability that it becomes a fascinating
bone repair material (Gupta et al., 2010). The functional groups such as -OH
and -NH2 in CS can up-regulate drug loading (DL)-release behaviors via
hydrogen-bonding interactions. Hence, it is inferred that hollow mesoporous
bioglass (MBG)/CS scaffolds can serve as ideal therapeutic carriers for bone
defect healing (Figure 4.7).
Basic structure and function of mesoporous bioactive glass scaffolds.
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Biomarkers as Targeted Herbal Drug Discovery
Generally, it is observed that Ursolic acid (UA) has an in-vivo effect on new
bone formation and BGs scaffolds have also shown its potential activities in
orthopedics. Therefore, Yu-Wei et al. developed the MBG/CS porous scaffolds for the first time, which are loaded with UA (MBG/CS/UA) to increase
d bone regeneration. The MBG microspheres were uniformly dispersed on
the CS films having particle sizes and pore sizes of ~300 nm and of ~3.9 nm,
respectively. The MBG microspheres having mesoporous structure and the
hydrogen bonding between the scaffolds and UA drugs, prepared the MBG/
CS/UA scaffolds having the controlled drug release activities.
The release of UA drugs from the scaffolds are remarkably increased the
activity of ALP, osteogenic differentiation-related gene type I collagen, runtrelated transcription factor 2 expression, and osteoblast-associated protein
expression. Moreover, the results of micro-CT images, and observations of
histomorphological demonstrated that the new bone formation ability can be
improved by MBG/CS/UA scaffolds. Therefore, the MBG/CS/UA porous
scaffolds can be used as novel bone tissue engineering materials. Hyperlink:
“https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347861/.”
Poly lactic-co-glycolic acid (PLGA) is one of the best-known classes
of biodegradable polymers for the sustained released drug. PLGA is a
biostable polymer, which is degraded into nontoxic oligomers and monomers, lactic acid, and glycolic acid hydrolytically (Araujo et al., 2009).
Amongst all these biomaterials, f the biodegradable polymer polylacticco-glycolic acid (PLGA) has shown immense potential as a carrier and
scaffolds for drug delivery and tissue engineering respectively. Amongst
the FDA-approved biodegradable polymers PLGA is one which is strong
physically and greatly biocompatible and also the use as delivery vehicles
for drugs have been extensively studied, proteins, and various other macromolecules like DNA, RNA, and peptides. Due to long clinical experience,
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favorable degradation properties and possibilities for sustained release
drug delivery. Current work has demonstrated that the deterioration of
PLGA can be employed for sustained drug release at desirable doses by
implantation without surgical procedures. Additionally, it is manageable
to tune the overall physical characteristics of the polymer-drug matrix by
supervising the relevant criterion of polymer such as molecular weight,
ratio of the lactide to glycolide, and drug concentration to execute the
desired dosage form and release gap depending upon the drug type
(Figure 4.8).
Basic structure of PLGA nanoparticles.
PLGA provides exact particle size and a narrow size range, ensuring less
irritation, requisite bioavailability, and stability mainly with ocular tissues
(Gonzalez-Mira et al., 2011). The main target of Helen et al. study was to
design and optimization of PLGA NPs into vehiculize this natural triterpene compounds in a controlled delivery system for ophthalmic delivery.
For this purpose, the response surface methodology (RSM) approach
was used to investigate the simple effect and the interaction of different
operating conditions, such as amount UA, amount of surfactant and pH of
the aqueous phase. Central composite rotatable design (CCRD) was used
because requires many few tests and has been shown to be sufficient to
describe the majority of the process responses (Uchegbu and Florence,
1995). Since the major drawback of those natural compounds is the limited
amount of availability in plants and the secondary objective was the
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Biomarkers as Targeted Herbal Drug Discovery
evolution of a synthetic mixture of UA. Moreover, accumulative release
operation and penetration capability, as well as, ocular tolerance of the
optimized NPs were assessed.
The evaluation of the ocular tolerability is a mandatory requirement.
The study showed that the ocular irritation index (OII) is 0.07 which
confirmed that nanoparticles (NPs) did not exert irritation. This was further
re-enforced by in vivo assay. The application of both types of NPs on the
rabbit eyes showed no sign of toxicity or irritation to the external ocular
tissues. NPs showed it’s best potential to use on damaged or inflamed
eyes due to based on biocompatible materials (Araujo et al., 2009). The
anti-inflammatory activity in rabbits of NPs exhibited a decrease in the
ocular inflammation caused by the installation of sodium arachidonate
a solution. In summary, to accomplish the demand for efficient ocular
drug delivery systems, this study states that an approach to the use of
a CCRD design for the optimization of PLGA NPs of UA elaborated
by the solvent displacement method. These formulations exhibited good
bioavailability properties due to low Z-ave and PI values, with negative
ZP, even upon storage after 6 months at both specified conditions. PLGA
NPs exhibited Newtonian behavior and low viscosity allowing sterile
filtration and easy administration. Concerning the corneal penetration
from NPs, the encapsulated drug was distributed at a constant rate with
enhanced accumulation into the ocular tissue creating a reservoir able to
prolong the ocular residence time and more powerful effect of the NM.
Eye-irritating effects were neither observed in vitro nor in vivo Draize
test. Finally, in vivo studies suggested that optimized UA loaded NPs can
be expected to gain considerable attention for ocular anti-inflammatory
treatment.
Niosomes are non-ionic surfactant vesicles having similar structures
and properties to liposomes (Jamal et al., 2015). A recent report on UA
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encapsulated in pseudo-niosomes prepared vesicles using the film hydration
technique which composed of Span 60, cholesterol, and phospholipids, the
diameter of the resulted product is 665.45 nm and entrapment efficiency
is 92.7%. Vesicles were then incorporated into a standard gel for use as a
potential arthritis treatment (Wang et al., 2015), (Figure 4.9).
Basic structure of niosomes.
In a search of other formulations based on nanotechnology, work by Wang
et al. was found. Specifically, this research group tailored the particle size of
UA nano-suspensions by using anti-solvent precipitation with a four-stream
multi-inlet vortex mixer. It was observed that an increased relative amount
of water to ethanol in the final mixture resulted in increased mean particle
size. Mean particle sizes of 90 nm (ethanol: water volume ratio of 1:7) and
300 nm (1:15 ratio) were obtained, and the p.i. of all nano-suspensions was
<0.3 (Gao et al., 2015).
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Biomarkers as Targeted Herbal Drug Discovery
The use of dendrimers as a targeted drug delivery system is also becoming
an attractive alternative due to the small size (115 nm) and high water
solubility of these polymers. By applying these properties Gao et al. developed a target for UA on poly-amido-amine (PAMAM; amine-terminated
PAMAM [G3-NH2, G5-NH2]), with folic acid used as the targeting
agent. Both folic acid and UA were covalently conjugated to the surface
of PAMAM through an acid-labile ester bond. The strong hydrophilic
properties of PAMAM help the UA to disperse in water very well. The
results of particle sizes and potentials of two different formulations (folic
acid-G3-UA and folic acid-G5-UA) were suggested that dendrimer-based
UA prodrugs have the potential for the targeted delivery of UA into cancer
cells (Zhao et al., 2015) (Table 4.4).
Naturally originating pentacyclic triterpenes UA, present significant therapeutic potentials. Notably, more than 30 reports on cancer treatment have
assessed the cytotoxic effects of these acids in human cell lines. Despite
treatment potential, the poor permeability and water solubility of pentacyclic
triterpenes hinder use as galenic agents, an issue starkly evidenced by the
limited number of reported clinical studies. Nevertheless, pharmaceutical
technologies could vastly improve solubility, stability, and bioavailability,
thus favoring the anticancer activities of pentacyclic triterpenes. Many
promising in vitro work reports have been currently published with the result
that the delivery of these compounds through different nanometric systems,
such as liposomes, nanoemulsions, nanoparticles, PLGA, BGs, niosomes,
and magnetic and polymeric nanoparticles, among others. This is particularly
relevant for nanoliposome-UA, which has shown high tolerances and low
toxicities in human studies involving healthy and ill individuals. Remaining
challenges for the nanopharmaceutical application of these systems include
assessing stability, determining elaboration costs, and ultimately, developing
the technology required for scaled production. Additionally, obtaining a
useful and viable alternative in the near future requires the design of vehicles
that employ biocompatible and biodegradable excipients that are approved
by regulatory authorities.
TABLE 4.4 In Vitro Anticancer Effects of UA Delivered Through Different Nanocarriers
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Nanosystem In Vitro (Cell
Line)
Cyclodextrin
complex
PEGylated
liposome folatereceptor-targeted
liposome
Dendrimer HeLa and HepG2
PEG-modified
liposomes
Liposome LNCaP cell lines
Polymeric
nanoparticle
Nanosuspensions MCF-7 breast
A2058 and A375
human melanoma
cell line
KB cell line
(human oral
cancer)
cells
EC-304 cancer
cells
(prostate cancer)
MDA-MB-231
(breast cancer)
SGC7901, gastric
cancer cell
cancer cells
Cytotoxicity
Evaluation
Method (Dose and
Incubation Time)
Alarma blue assay
(40–100 μM for
48 h)
MTT assay (6–200
μM for 24 h)
MTT assay (5–100
μM for 48 h)
MTT assay
(15.63–500 μg/mL
for 24 h)
MTT assay (1.2–40
μM for 24 h)
MTT assay (20–70
μM for 24, 48 and
48 h)
DAPI (20–40 μM
for 48 h)
Annexin V-FITC/PI
(5 μM for 24 h)
Effects References
Cytotoxic Cerga et al.,
2011
Antitumor Zhao et al.,
2015
Antitumor Qian et al.,
2015
Antitumor Zhang et al.,
2015
Inhibited
proliferation
Apoptotic Mandelli et
Anticancer Gao et al.,
Yang et al.,
2014
al., 2013
2015
93 Ursolic Acid: A Pentacyclic Triterpene from Plants in Nanomedicine
DAPI: 4′,6-Diamidino-2-phenylindole; FITC: Fluorescein isothiocyanate; UA: Ursolic acid.
• bioglass
• central composite rotatable design
• encapsulation effectivity
• ocular irritation index
• pharmacokinetics
• response surface methodology
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