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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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Sl. Therapeutic Use References
No.
13. Gastric ulcer Magdy et al., 2012
14. Streptozotocin-induced diabetes Abdelmeguid et al., 2010
Biomarkers as Targeted Herbal Drug Discovery
Thymoquinone, chemically named as 2-isopropyl-5-methylbenzo-
1,4-quinone, is a promising candidate with signicant potential for the
treatment of several diseases (Figure 13.2) including anti-inammation,
anti-oxidation, anti-bacterial, and anti-cancer (Ballout et al., 2018; Liou et
al., 2019). TQ has remarkable efcacy and selectivity against cancer cells
and has no toxicity against normal cells (Mohammadabadi et al., 2018).
The major therapeutic activity of thymoquinone (TQ).
TQ, despite being of so much therapeutic signicance is characterized
with hydrophobicity which leads to poor solubility in aqueous media and
hence limits its bioavailability. Moreover, the high index lipophilicity has
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been leading into poor formulation characteristics (Odeh et al., 2012). Most
of the therapeutic agents, especially the hydrophobic compounds, with
poor efcacy and safety measures have failed in the human clinical trials.
Additionally, these drawbacks may also be a consequence of the ineffectual
bioavailability associated with the compound’s hydrophobicity (Ravindran
et al., 2010). This has greatly hampered the development of the formulation
of several clinically used natural compounds.
There are many glitches in delivering therapeutic agents to tumor cells in
vivo, the major ones are enlisted as under (Brigger et al., 2002):
1. Drug resistance at the tumor level due to physiological barriers
(noncellular based mechanisms);
2. Drug resistance at the cellular level (cellular mechanisms);
3. Distribution, biotransformation, and clearance of anti-cancer drugs
in the body.
Nanoparticle drug delivery systems are now becoming one of the most
preferred technology for developing therapeutics as they enhance the pharmacokinetics (PKs) of the drugs and increased patient compliance by achieving
quicker recovery (Kumar et al., 2016, 2017; Chauhan et al., 2017). Several
natural polymers like albumin, alginate, chitosan (CS), dextran, starch, carboxymethyl cellulose, gelatin, and gums have been used widely for the development of nanoparticles. There have been multiple reports for the use of anionic
polymers namely gum Arabic (Rani et al., 2015), gum tragacanth (Ranjbar et
al., 2016), guar gum (Sarmah et al., 2014), gellan gum (Kumar et al., 2017;
Dahiya et al., 2017) and xanthan gum (Cai et al., 2016). Gum rosin has been
established as a novel material for target-specic and sustained release formulations, additionally it is a non-toxic, biodegradable, and inexpensive polymer.
All these properties make gum rosin a preferable and suitable nanocarrier for
the encapsulation and sustained release of drugs (Rani et al., 2018).
Development of TQ into suitable formulation has been rigorously
worked upon and several carrier systems have been engaged by now to
attain high therapeutic concentrations in human illnesses especially in case
of tumors. These formulations include microspheres (Chaurasia et al., 2006;
Cheung et al., 2006), niosomes (Uchegbu et al., 1998, 2000), nanoparticles
(Azarmi et al., 2006; Sun et al., 2008), dendrimers (Lin et al., 2018; Cai et
al., 2017), SLNs (Wong et al., 2007; Chirio et al., 2018), micelles (Parida
et al., 2017; Debele et al., 2017), liposomes (Shen et al., 2017; Cao et
al., 2017) and nanoliposomes (Razazan et al., 2017; Sharma et al., 2017;
Haghiralsadat et al., 2018).
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Biomarkers as Targeted Herbal Drug Discovery
The emergence of surface engineering of the nanoparticle carrier systems
has led to the development of folate-decorated nanoparticles or polymer-linked
vesicles like PEGylated liposomes. These carriers have enhanced circulation
time and hence carrier-drug complex has greater possibility in reaching the
target tissue (Figure 13.3). These surface-engineered micro- and nano-carriers
can be employed to target tumor antigens, cancer-specic receptors, and the
vasculatures of tumors with high afnity and precision, namely monoclonal
antibodies or tumor-specic ligands (Mozafari et al., 2009).
Advantages of TQ nanoformulations.
Many studies have been carried out to improve the bioavailability of
TQ, especially for the oral route administration, which includes micelle
nanoparticles, CS nanoparticles, and liposomes (Ganea et al., 2010; Alam
et al., 2012; Odeh et al., 2012). Nano-TQ has better photostability, and its
bioavailability is six times more than the free TQ solution and therefore
liquid formulations of TQ meant for oral administration has improved solubility and bioavailability and is protected from photodegradation (Salmani
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et al., 2014; Nihei et al., 2016). In addition, Tubesha et al. (2013), reported
in their study that nanoemulsion containing TQ has a stability of almost six
months. In this chapter, we have focused more on the effect of TQ containing
nanoformulations and their efcacy in different human diseases.
TQ has a great potential for anticancer activity through its regulation of
the diversity of cell signaling pathways and its interference with other cell
components (see Figure 13.4) (El-Far et al., 2015).
A brief summary of the TQ cellular and molecular activity; where ↑ means
upregulation and↓ means downregulation.
Source: Figure adapted from Majdalawieh et al. (2017).
Nanoformulation of TQ has been found to potentiate the anticancer
activity (see Table 13.2) signicantly, e.g., TQ, and Topotecan were loaded
together in poly (D,L-lactide-co-glycolide) (PLGA) nanomatrix where TQ
was loaded into the organic phase whereas the topotecan was dissolved in
the inner aqueous phase of the double emulsion. The resulting nanomatrix
enabled mutual drug delivery of both topotecan and TQ and enhanced the
anticancer effect of this nanomatrix formulation (Verma et al., 2017).
TABLE 13.2 Illustrating Preparation of TQ Nanoformulation Using Different Techniques and Their Outcomes
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Class of Materials Methods Pharmacological Effects References
Particle
Polymer PLGA Emulsification • Synergism between TQ and paclitaxel. Soni et al., 2015
carriers solvent evaporation
PHA-mPEG • Non-toxic to neuronal hippocampal and fibroblast cells of Shah et al., 2010
β-cyclodextrin Self-assembly • Enhances anticancer activity of TQ on MCF-7 breast Abu-Dahab et al.,
PEGylated Nanoprecipitation • Non-toxic to normal peripheral blood mononuclear cells.
Lipid- Nanostructured lipid High-pressure • Inhibits the formation of ethanol-induced ulcers.
based carriers homogenization
• Improves anticancer activity of TQ as compared to free
drugs against MCF-7 breast cancer cells.
• Antioxidant and antibacterial activity against E. coli, S.
aureus, and S. typhi.
prenatal rats.
cancer cell line. 2013
• Non-toxic to periodontal fibroblasts.
• Diminishes migration rate of MCF-7 and HBL-100 cells.
• Interrupts cytoskeletal actin polymerization through
upregulation of miR-34a.
• Heat shock protein 70 modulation.
• No toxicity to normal human liver cells.
Ilaiyaraja et al.,
2013
Bhattacharya et al.,
2015
Abdelwahab et al.,
2013
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Biomarkers as Targeted Herbal Drug Discovery
Class of Materials Methods Pharmacological Effects References
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Particle
• Lower toxicity than pure TQ administered orally to mice Ong et al., 2016
High speed • 2–3 times increased bioavailability of TQ. Elmowafy et al.,
homogenization 2016
followed by
ultrasonication
Liposomes Thin film hydration • Inhibits the cancerous growth of MCF-7 and T47D. Odeh et al., 2012
Gold niosomes Click chemistry • Inhibits the bioavailability of tamoxifen resistant and AKT Rajput et al., 2015
Solid-lipid Ultrasonication or • Improved bioavailability, and distribution of drug. Pathan et al., 2011;
nanoparticles solvent injection Singh et al., 2013
Chitosan Chitosan Ionic gelation • Enhanced drug targeting to brain cells. Alam et al., 2012
based
Myristic Self-assembly • Proliferation of MCF-7 breast cancer cells decreases. Dehghani et al.,
acid-chitosan 2015
• TQ-nanoformulation shows hepatoprotective and
antioxidant efficacy.
over proliferating breast cancer cells.
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Biomarkers as Targeted Herbal Drug Discovery
TQ loaded PLGA nanoparticles were found to be more efcacious than
free TQ in restricting the proliferation of MDA-MB-231 breast cancer cells
(Ganea et al., 2010). In another study, it was reported that the preparation
of dual drug (TQ and paclitaxel) loaded nanoparticles by emulsion solventevaporation method using PVA as the stabilizer showed better effect in breast
cancer cells even at lower doses (Soni et al., 2015). Similarly, there are many
other studies enlisted in Table 13.2, which are assertive of the enhance effectiveness of TQ when loaded into a nanoformulation. These also suggest the
possibility of using TQ-loaded PLGA nanoparticles in the clinical studies.
Diabetes, one of the rapidly growing metabolic disorders is mediated by
abnormal insulin secretion or action or both. It is characterized by hyperglycemia which ultimately causes oxidative stress and damages different
organs (American Diabetes Association, 2009). TQ is a potential antidiabetic
compound which alleviates almost every diabetic complication remarkably
(see Figure 13.5) (AbuKhader et al., 2012; Atta et al., 2017).
A study (Rani et al., 2018) investigated the antidiabetic potential of TQ
loaded nanoparticle in streptozotocin-nicotinamide induced type-2 diabetes
in rats and against metformin as the standard treatment. It was observed that
TQ- and metformin-loaded nanocapsules (NCs) possessed a sustained release
ability, and also decreased the blood glucose and glycated hemoglobin levels
signicantly in a dose-dependent manner accompanied with improvement in
the serum lipid prole. This study strongly asserted that nanoformulation of
TQ enhanced its antidiabetic activity remarkably. Further investigations are
mandatory to determine the molecular mechanisms of TQ nano preparation’s
anti-diabetic properties. Determination of the role of nanoformulations loaded
with TQ in pancreatic cell regeneration, insulin secretion and sensitivity will
provide more therapeutic indications for diabetes management in the future.
The presence of different kinds of pollutants and chemical molecules in the
environment increases the probability of inflammatory diseases in the CNS.
There are numerous reports on the CNS protective activity of TQ for conditions like Alzheimer’s, Parkinson’s diseases, and glioblastoma (Ebrahimi et
al., 2017; Abulfadl et al., 2018; Chowdhury et al., 2018). Effect of TQ-loaded
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solid lipid nanoparticles (TQ-SLN) on the brain of rats was evaluated in a
study using tail suspension test, modified forced swim test, and locomotor
activities (Alam et al., 2018). The study revealed that TQ-SLN enhanced the
delivery of TQ to brain cells and it was also faster than free TQ, as demonstrated by the determination of monoamine and SOD levels in the brain
(Figure 13.5). Thus, it was concluded that TQ-SLN is a potent formulation
that can be employed to improve the efficiency of TQ, enhance its delivery,
and mitigate the oxidative stress in CNS diseases.
Illustrates the biological activities of TQ nanoformulations. HDL-C: high-
density lipoprotein-cholesterol, HbA1c: glycated hemoglobin, IL: interleukin, LDL-C:
low-density lipoprotein-cholesterol, VLDL-C: very low-density lipoprotein-cholesterol,
SOD1: Copper, zinc-dependent superoxide dismutase (cytosolic), SOD2: manganesedependent superoxide dismutase (mitochondrial), SOD3: Copper, zinc-dependent superoxide
dismutase (extracellular), TAG: triacylglycerol, TNF-α:Tumor necrosisfactor-α, GPx:
Glutathione peroxidase.
TQ has been traditionally used as an anti-inflammatory agent and this has
been established by several studies in animal models (Rifaioglu et al., 2013;
Atta et al., 2017). In a study, TQ containing lipospheres were prepared and
used as an anti-psoriatic drug. RAW 264.7 murine macrophage cell lines was
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Biomarkers as Targeted Herbal Drug Discovery
used for testing the TQ lipospheres and it was found to decrease the levels
of nitric oxide (NO) and prostaglandins like IL-2, IL-6, IL-1β and TNF-α
(Figure 13.5). There are also other reports of TQ-nanoformulation when
used topically it elucidates better efficacy and it also has a better stability.
Liver is a vital organ and has a principal role in the physiological metabolism
and xenobiotic detoxifications. Generally, oxidative stress is the prime cause
of liver injuries. And, TQ has been found to possess hepatoprotective potential
against injuries induced by several mechanisms including free radical scavenging (Farkhondeh et al., 2018). In a study, different self-nanoemulsifying
drug delivery system (SNEDDS) formulations containing TQ were prepared for
assessing hepatoprotective activity in rats (Kalam et al., 2017). TQ-SNEDDS
formulations were found to have better absorption and enhanced bioavailability which protected the liver better than TQ suspension.
Similarly, TQ loaded in nanostructured lipid carriers (NLCs) also exhibited increased bioavailability in a male rat model when administered orally
(Elmowafy et al., 2015). In another report, TQ-SLN was prepared, characterized, and evaluated for the treatment of paracetamol-induced liver cirrhosis,
®
and compared with free TQ and SILYBON
. The investigators found that
TQ-SLN formulations showed more stability than free TQ-suspension, as
the serum glutamate oxaloacetate transaminase (SGOT), serum glutamate
pyruvate transaminase (SGPT), and alkaline phosphatase (ALP) were
signicantly reduced (Figure 13.6) (Singh et al., 2013). The antioxidant
potential of TQ was increased by the SLN formulation and hence remarkable
hepatoprotection was observed.
Multi-drug resistance is one of the most horrifying clinical health problems
in the upcoming time. It serves as an adamant challenge to the health professional and is a serious concern which if not dealt judiciously can create havoc.
Multi-drug resistance is the resultant of the irrational use of antibiotics in the
treatment of infectious diseases (Fernández et al., 2016). Hence, the investigators have started looking for the alternative herbal source of antimicrobial
drugs (El-Far et al., 2014). There have been multiple records emphasizing
on the antibacterial role of TQ, especially the nanoformulations, which may
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help in standing against the bacterial resistance (Bakal et al., 2017). Another
study intended to explore the antifungal activity of nanoparticles loaded with
amphotericin-B, ketoconazole, and TQ against Candida albicans yeasts and
Candida biofilm. The study revealed that the fungal strains were disinfected
2–4 times more effectively by the nanoparticles loaded with TQ, ketoconazole, and amphotericin-B (Randhawa et al., 2015) (Figure 13.6). Thus,
it can be deduced that TQ nanoformulations have better antibacterial and
antifungal activity than its free forms. However, further citations are needed.
The antimicrobial, hepatoprotective, and other health application of
TQ-nanoformulation.
Liposomes can retain the encapsulated nutrients safe from the environment
and are also capable of enhancing the solubility of hydrophobic nutrients
in semi-solid or liquid form; therefore, liposomes were one of the first
nanoformulations to be launched in the market. Moreover, liposomes also
have better topical bioavailability as they have good dermal permeation
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