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6
Impact of nanotechnology on herbal
bioactives: an overview
Atul Jain
1
, Jagpreet Kaur
2
, Kamal Shah
3
,
Nagendra Singh Chauhan
4
, M. Arockia Babu
5
and
Teenu Sharma
6
1
Department of Pharmaceutics, Delhi Pharmaceutial Sciences and Research University
(DPSRU), New Delhi, India;
2
Chandigarh College of Pharmacy, Chandigarh Group of
Colleges, Mohali, Punjab, India;
3
Institute of Pharmaceutical Research, GLA University,
Mathura, Uttar Pradesh, India;
4
Drugs Testing Laboratory, Avam Anusandhan Kendra (State
Government Lab of AYUSH), Raipur, Chhattisgarh, India;
5
School of Pharmacy, Sharda
University, Greater Noida, Uttar Pradesh, India;
6
Chitkara College of Pharmacy, Chitkara
University, Punjab, India
1. Introduction
Nature-based bioactives nowadays are being commonly used in the management of
various diseases, including cancer, CVS disorders, neurological disorders, and others. Indeed,
phytochemicals derived from natural sources have become a new ray of hope for prevention
and treatment of diseases because of their primary antioxidant characteristics [1]. These tend
to exert strong free radical scavenging and chelating activities. The structural variety and
pharmacological and molecular features of natural products and their derivatives show great
promise for the creation of novel treatment approaches. In fact, between 1981 and 2014, nat-
ural compounds or their derivatives accounted for 52% of the mo lecules registered [1e3].
These bioactives have been explored for a myriad of pharmacological activities. Box 6.1 un-
derscores the various reasons for the increasing demands of bioactives.
However, the potential use of most of the bioactives is impeded by their low and inconsis-
tent bioavailability which is primarily attributed to their poor aqueous solubility rapid first-
pass metabolism and rapid systemic elimination [4,5]. This calls for the fabrication of different
delivery carriers for overcoming challenges associated with the delivery of these potential
CHAPTER
139
Phytopharmaceuticals and Herbal Drugs
https://doi.org/10.1016/B978-0-323-99125-4.00007-X © 2023 Elsevier Inc. All rights reserved.
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bioactives [6,7]. Nanotechnology delivers medicines to tumor cells in a targeted manner,
reducing systemic toxicity and improving quality of life. Advances in molecular biology
and pharmacology have assisted in better comprehension of diverse diseases, thus allowing
the formulation of smarter therapies to target cancer, which could respond to its microenvi-
ronment [6e8].
2. Bioactivities of polyphenols
There is a growing interest in the pharmacological properties of polyphenols, such as anti-
oxidant, cardiovascular protection, cancer management, and nerve protection, as the benefits
of polyphenols continue to be discovered [1]. In the fields of medicine, nutrition, and health-
care products, polyphenols play an essential role.
2.1 Antioxidant activity
One of the most significant and well-studied biological functions of phenolic compounds is
antioxidant activity, which includes scavenging free radica ls, preventing lipid oxidation, and
lowering the production of hydrogen peroxide [9,10]. Presence of a number of hydroxyl
groups in the structure of phenols is responsible for their antioxidant properties, as this is
essentially required for recovering free radicals and chelated metal ions. By giving different
types of reactive oxygen species (ROS) electrons or hydrogen atoms, polyphenols can
neutralize free radicals [11]. Polyphenols can turn peroxides or metal oxides into stable mol-
ecules by chelating metal ions [12]. This tends to stop the growth stage of lipid autotrophic
chain reactions. Numerous flavonoids have been shown to recover peroxides either directly
or indirectly to prevent low-density lipop rotein (LDL) oxidation in previous studies [13].
Phenolic compounds are excellent antioxidants, but they can also operate as reducing agents
or lose electrons, which can cause the molecules to become free radicals or combine with
BOX 6.1
Bioactives as potential source of new drugs
> Need for relatively safer therapeutics.
> Diverse chemical structures and bio-
logical activities of naturally derived sec-
ondary metabolites.
> Competence of plant bioactive to func-
tion as biochemical as well as molecular
probe.
> Availability of newer techniques for
accurate detection, isolation, and character-
ization of the bioactives.
> Progress to meet the demand for supply
of complex natural products.
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transition metal ions to become prooxidants. Because of this, it ’ s critical to comprehend its
mechanism of action and set suitable dosage restrictions.
The enzyme redox system keeps the balance of the oxidative defense in cells. It is mostly
made up of catalase (CAT), hydrogen peroxide dismutase (SOD), glutathione peroxidase
(GPx), glutathione reductase (GR), and peroxidase (PRXs). But oxidative stress from reactive
oxygen will make it much harder for the body to defend itself [6]. Polyphenols have been
shown to restore equilibrium by enhancing the activity of SOD, CAT, GPx, GR, and PRXs
and by reducing systemic or local inflammation. Extensive research has been conducted on
the antioxidant properties of plant polyphenol extracts in different biological systems [6,14].
2.2 Cardioprotection activity
Polyphenols are known to promote the functioning of SOD, CAT, GPx, GR, and PRXs and
to suppress systemic or specificinflammation. Plant polyphenol extracts’ antioxidant activity
in various biological systems has been thoroughly investigated [15,16]. Although flavonol
consumption has been shown to reduce the incidence of CVD, the impact of flavonol intake
on lipid levels may vary by geographic location and health status. A study by Tang et al.
found that taking 100 mg of flavonoids on a daily basis reduced the risk of stroke by about
10% [17]. Thrombosis is a major contributor to many different diseases and conditions,
including but not limited to myocardial infarction, ischemic heart disease, and others. Num-
ber of studies show that dietary polyphenols can lower thrombus development [17]. Red wine
is recognized to protect the heart since it is high in polyphenols like resveratrol and proantho-
cyanidins, among others. Numerous studies have demonstrated that resveratrol can prevent
thrombosis by reducing oxidative stress and platelet aggregation in blood vessels [18].
2.3 Anticarcinogenic activities
A cell-proliferative disease called cancer is generated and controlled by genetic mutations
resulted by a variety of factors, including poor diet, radiation exposure, unhealthy lifestyle
preferences (like routine drinking and smoking), and infectious microorganism [19]. Many
studies have demonstrated that plant’s secondary metabolites called polyphenols have a vital
role as anticancer agents. These polyphenols mainly prevent cancer by blo cking the activa-
tion, promotion, and angiogenesis cascades in cancer cells as well as by enhancing the im-
mune system. Flavones signifi cantly decreased the risk of gastric, lung, breast, and
colorectal cancers by significantly limiting oxidative stress, oxidative damage, anti-
angiogenesis, and anti-metastasis, whereas total flavones had little effect on the incidence
of breast cancer. This was discovered as a result of an in-depth investigation into the function
of polyphenols in the prevention of cancer. Flavones can be found in a variety of plant-based
foods, including tea [20,21]. Another study is conducted to check the impact of flavonoids in
colon cancer risk, and it is discovered that prolonged utilization of flavonoids looked to be an
efficient supplemental therapy which lowers the colon cancer risk due to their cellular anti-
oxidant and antiinflammatory activities [22]. The research also showed that the subclasses
of flavonoid had a considerable synergistic impact on inhibiting carcinogen esis, tumor devel-
opment, and encouraging cancer cell death. Consumption of quercetin and other flavonoids
2. Bioactivities of polyphenols 141
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has been shown to reduce the risk of colon cancer, whereas apigenin and other flavonoids
have been found to reduce the risk of rectal cancer [23].
2.4 Neuroprotection
With the advancement in medical domains, humans live longer on average; but as a result
of an older population, the disorders related to brain have grown substantially, like cognitive
and neurodegenerative ailments [24]. Neurodegenerative problems happen when a lot of
neurons and neural stem cells lose their capacity to perform their functions. It develops
over time and is a sort of complic ated, deadly disease that causes sensory de ficiencies and
cognitive impairments. According to research, the majority of neurodegenerative disorders
display common cellular and molecular mechanisms, such as the buildup of oxidative stress,
inflammation, protein misfolding and aggregation, neurotoxicity. The excessive amount of
oxidative stress in cells is the primary cause of dementia in addition to hereditary and envi-
ronmental variables [25,26]. Numerous studies have shown that polyphenols have a variety
of methods via which they can reduce the rise in oxidative stress. For instance, polyphenols
can activate the Nrf2 pathway, increasing the activity of detoxifying and antioxidant enzymes
[27e29]. They can also alter the structural integrity and metabolic effectiveness of mitochon-
dria, as well as control the activity of enzymes that produce reactive oxygen. Such disorders
also include inflammation as a root cause. Nitric oxide, lipoxygenase, cyclooxygenase (COX),
and chemokines are examples of proinflammatory genes whose expression can be controlled
by polyphenols. The neuroprotective effects of polyphenols are also associated to decrease
the amyloid aggregation and/or precursor production [30]. It has been discovered that cur-
cumin has anti-amyloidosis action and can prevent the formation of new b-aggregates as well
as break down the previously produced aggregates [31]. The amyloid pentamer’s hydropho-
bic region was shared by the pomegranate flavonoids, myricetin, luteolin, and honokiol,
which had the strongest inhibitory effects on A1-42 aggregation [31,32].
3. Hiccups for the efficient delivery of phytoconstituents/bioactives
The potential use of most of the bioactives is impeded by some most common challenges
related to solubility, bioavailability, stability, and release [33]. These have been briefly dis-
cussed in the below sectio ns.
3.1 Solubility
The delivery of plant bioactive ingredients by incorporating in foodstuffs, beverages, cos-
metics, and pharmaceutical products is limited owing to their poor aqueous solubility. Phy-
tochemicals like curcumin, chrysin, quercetin, berberine exhibit low water solubility, and thus
cannot be readily incorporated into delivery systems or food stuffs for consumers [34,35].
Therefore, a lot of researchers are working on exploring numerous techniques and
6. Impact of nanotechnology on herbal bioactives: an overview142
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technologies to improve the solubility of phytochemicals exhibiting enormous potential in the
pharmaceutical world [35].
3.2 Bioavailability
The key parameter for delivery of any active constituent is its bioavailability. In this re-
gard, the inadequate and inconsistent bioavailability delivery of plant bioactives becomes a
major concern [36]. The solubility and bioavailability of phytoconstituents are outcomes of
factors like physicochemical characteristics of the phytoconstituents and its physical as
well as chemical compatibility with other ingredients and/or excipients, and its stability in
physiological environment; Owing to these multitudes of factors phytoconstituents demon-
strate poor bioavailability, variable pharmacokinetics, and lower therapeutic efficacy [35].
In this context, the novel nanotechnology-based delivery systems are the optimum solution
to overcome the aforementioned challenges and to augment the bioavailability. Further, tar-
getability of the delivery system can be achieved through surface modification of the carrier
system using apt ligands. Additionally, release of the encapsulated active constituent is
controlled by modifying surface properties.
3.3 Stability
Stability of the bioactives is one of the key challenges to be taken care for their effective
delivery as food, medicine, or cosmetics either as isolated individual compounds, extracts,
or essential oils. Naturally derived phytoconstituents are prone to undergo oxidative, hydro-
lysis, crystallization, enzymatic degradation either during processing or storage or in physi-
ological conditions. Numerous parameters, viz., presence of oxygen, additives, metal ions,
temperature, pH, tend to influence their stability [35]. In this regard, encapsulation of bioac-
tives in novel delivery systems like, SLNs, NLCs, phytosomes, etc., helps in protecting these
against the harsh condition.
3.4 Release
Release pattern of bioactive from prepared carrier systems should have site specificity and
controlled mann er. Release of API may initiate against any physicochemical response in a
particular environment inside the body (e.g., food, pH, temperature). In addition, biodegra-
dation of carrier systems is equally important for the development of an effective drug deliv-
ery system. In general, plant bioactive may get released from the dosages form via desorption
of bioactives, diffusion against the concentration gradients, decomposition of carrier matrix,
the combined effect of decomposition/diffusion. This strategy is crucial in these systems
because the various physicochemical properties of the plant metabolites allow their release
to be asynchronous and uncontrollable, which typic ally results in lower bioactivity. Drug de-
livery systems which are commonly used so far for the site specific and controlled release of
numerous bioactives include liposomes, nanoemulsions, polymeric nanoparticles, lipid-based
delivery systems, etc. [35].
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4. Nanotechnol ogy: Importance and application
The application of nanotechnology for the management and monitoring of the biochemical
processes in human systems has recently been incorporated and it is known as nanomedicine
[37]. It is the inception of providing a host for the new bioactive and help in revolutionizing
medical and biopharmaceutical in the management of various diseases. Besides, different
areas are already benefiting from the application of nanotechnology [38]. Nowadays, imple-
mentations of nanotechnology as nanocarriers systems are accepted in a very comfortable
manner. It represents the amalgamation of engineering and technology at the molecular scale
in deploying the matter at the atomic and molecular levels. Nanotechnology, in at least one
dimension, deals with molecular-sized particles in the range of 1e100 nm and encompasses
materials or devices within the specified size range. Research communities which are
engaged in biomedical and pharmaceutical research are exploiting the distinctive character-
istic properties of minuscule-size carrier systems for different biomedical applications [39].
The various advantages of the pharmaceutical nanocarriers systems are enlisted below.
1. Unique in their tiny size and high drug loading capacities make them capable of deliv-
ering medications to desired sites.
2. Small particle size and a high surface area contribute to rapid absorption by the blood.
3. A high degree of retention at the site of action as a result of the increased permeation
and retention (EPR) effect,
4. Can exhibit passive drug targeting to the desired site.
5. Have the capability to behave as an active drug targeting molecule.
6. Dose reduction and subsequent decrease in the side effects can also be obtained.
In recent decades, the utilization of nanotechnology has garnered a lot of interest in the
process of developing herbal medications [40]. Researchers are continuously working in
the field of development of advanced drug carriers like mouth-dissolving tablets; sustained,
prolonged and extended-release formulations; mucoadhesion-based systems, transdermal
formulations, microparticulate systems, microcapsules, implants, etc. Nanonization tech-
niques provide advantages, like enhancement of solubility, reduction of medicinal doses,
and improving the biopharmaceutical profile (ADME profile) of crude drugs. Besides, nano-
carriers systems after employing nanotechnology can resolve various inherent consequences
of the crude drug
1. Maintain a higher concentration of drug at the desired site via bypassing physiochemi-
cal barriers such as the harsh environment of the stomach.
2. Because of its diminutive size, the bioactive is more effectively and for a longer period
of time absorbed into the systemic circulatio n.
3. Lessening the dosage and adverse effects of presently available pharmaceuticals.
4. Increased target-site specificity and decreased noncompliance (from excessive dosing)
across a variety of chronic conditions.
Understanding the potential of newer technologies, researchers are also working in the
domain of development of drug delivery systems for herbal drugs like modified-release ve-
sicular and particulate formulations, and metallic and self-assembled delivery systems.
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5. Nanophytomedi cines: Nanostructured drug delivery systems for bioactive
Plant-based pharmacological active molecules coupled with nanocarriers are defined as
nanophytomedicines and are getting more importance in the current medical situation for
the management of different diseases with minimum side effects and toxic effects. However,
phytomedicines show different inherent hiccups like solubility, toxicity, stability, bioavail-
ability. Fig. 6.1 portrays the overall journey of photoactive within the biological system
following the ADME pathway. To overcome the problems associated with phytomedicines
nanotechnologies play an important role in minimizing the inherent hiccups, via size reduc-
tion, surface modification, altering the aqueous solubility, complexation and encapsulation of
bioactive by some natural, semi-synthetic, and or synthetic polymer. Some of the leading
herbal drugs which are highly explored as nanophytomedicines include curcumin, paclitaxel,
mangiferin, quercetin, and catechins, with different drug delivery systems have been re-
ported. Fig. 6.2 depicts the overall schematic presentation of a general source of bioactives,
method of preparation, type, effect/response, and application of nano drug delivery systems
as nanophytomedicines. Besides Table 6.1 enlists some recent scientific reports related to
bioactive and various drug delivery systems.
5.1 Nanoparticles: Drug delivery systems
A nanoparticle (NP), as per the PAS71 document, is defined as “A particle having one or
more dimensions of the order of 100 nm or less.” NPs are colloidal systems with particles
ranging in size from 10 to 1000 nm [66]. Nanospheres and nanocapsules are also referred
to as NPs. In contrast to nanocapsules, which contain an active ingredient core and a poly-
meric membrane, nanospheres have a matrixlike structure with the active ingredient spread
throughout (the particles). NPs are superior to traditional colloidal carrier s in that they are
more stable when exposed to biological fluids, have high drug loading capacities, and are
shielded from degradation by the incorporated drug’s solid matrix, increasing the drug’s
intracellular concentration. NPs can be functionalized or changed to alter their biodistribution
and enhance medi cation targeting. Some of the commonly used advanced nanocarrier sys-
tems are discussed below.
Journey of Phytoactives
BCS Class II and IV Drugs
A
Biotransformation
DM
Clearance
E
FIGURE 6.1 Journey of phytoactives.
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5.1.1 Polymeric nanoparticles
Considering their potential for drug delivery to specific organs and tissues, and their ca-
pacity to transport proteins and peptides, via the oral route of administration, biodegradable
polymeric nanoparticles have received a lot of attenti on nowadays [8]. Biological fluid inter-
action increases the durability of biodegradable polymeric nanoparticles [67]. A polymer that
FIGURE 6.2 Holisitic presentation of general sources and applications of bioactives, along with role of nano-
carriers for their efficient delivery.
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TABLE 6.1 Literature instances pertaining to use of nanocarriers for efficient delivery of bioactives.
S. No
Name of the active
component Drug delivery system Inference Reference
1. Paclitaxel Chitosan-ceramide
nanoparticle
Extensively enhanced efficacy to
cure solid
Tumors
[41]
2. Curcumin Polymeric nanoparticles Anticancer and
antiinflammatory via increased
bioavailability
[42]
3. Piperine Polymeric nanoparticles Anticancer activity via increased
cellular uptake
[43]
4. Pterostilbene Polymeric nanoparticles Anticandida biofilm activity [44]
5. Solanum lycopersicum L. leaf
Aq. Ext.
Silver nanoparticles Used to control bacterial wilt,
decreased the severity of soil
pathogen
[45]
6. Andrographolide Solid lipid nanoparticles Increased antitumoractivity [46]
7. Curcumin Lipid-based nanoparticles Antimicrobial, activity
employing sustained release
drug delivery systems
[47]
8. Curcumin and resveratrol Solid lipid nanoparticles Improved bioavailability and
anticancer activity
[48]
9. Gingerol Phytosome complexed with
chitosan
Improved bioavailability and
anticancer activity
[49]
10. Carica papaya Aq. Ext. Phytosome Improved bioavailability and
anticancer activity
[50]
11. Berberine Nanomicelles Enhancement of curative effect
on liver
[51]
12. Silymarin (SM) Block polymeric nanomicelles Considerably enhanced activity
as compared to native drug
[52]
13. Baicalin Self-nanoemulsifying drug
delivery system
Improved bioavailability and
anticancer activity
[53]
14. Pandanus conoideus lamk oil Self-nano-emulsifying drug
delivery system
Increased bioavailability and
cytotoxic activity of the
Pandanus
Conoideus Lamk oil
[54]
15. Curcumin and Lithospermi
radix extrac
Nanofibrous scaffolds Improve wound healing
property
[55]
16. Gymnema sylvestre Enhanced antibacterial activity [56]
17. Vincristine Glucuronide-modified long-
circulating liposomes
Enhancement of therapeutic
efficacy and reduced
neurotoxicity
[57]
18. Gambogenic acid from
garcinia hanburyi
PEGylated liposomal Increased expression of efflux
transporters
[58]
(Continued)
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