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248
Polyphenols: Food, Nutraceutical, and Nanotherapeutic Applications, First Edition. Edited by Mithun Rudrapal.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
12
Nanodelivery of Polyphenols as Nutraceuticals for Neurological
Disorders
Arpita Paul, Madhusmita Gogoi, and Kamaruz Zaman*
Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India
*Corresponding author
Neurological disorders (NDs) affect not only the brain and spinal cord but also all the nerves con-
necting them. NDs are one of the leading causes of death and disability worldwide [1]. The preva-
lence of NDs is greater in low- and middle-income countries than in high income countries [2].
Every year approximately 10 million people across the globe suffer from NDs, and this number is
expected to increase in the near future [3]. In NDs, damage to the neurons occur either by injury,
accumulation of abnormal proteins, gene mutation, or an increase in reactive oxygen species
(ROS). The most prevalent NDs include Alzheimer’s disease (AD), Parkinson’s disease (PD), mul-
tiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), ischemic
stroke, epilepsy, and neuropathic pain (NP). These neurological conditions share the same struc-
tural and mechanical abnormalities at the cellular, molecular, and functional levels, such as oxi-
dative damage, inflammation, synaptic loss, and neuronal apoptosis, eventually leading to
disruption of neuronal signal transduction pathways [4–6]. These disorders can manifest with
symptoms such as motor dysfunction, cognitive impairment, difficulty in speech, and pain [7].
NDs are heterogeneous; therefore, a single therapy is inefficient for treating the pathological con-
dition, which explains the failure of current monotherapeutic treatments and encourages multi-
target approach [8]. Moreover, clinical trials on drugs for CNS disorders are challenging because
of the complexity of the nervous system and impermeability of the blood–brain barrier (BBB) [9].
Polyphenols can provide greater therapeutic effect than monotherapy with synthetic drugs
because of their pleiotropic mechanism of action. Furthermore, in vitro and preclinical studies
demonstrated polyphenols were effective in epidemiology. However, poor solubility, low bioa-
vailability, and restricted entry of polyphenols across the BBB limits their application in the man-
agement of NDs.
Recently, nanodelivery systems can encapsulate polyphenols, thereby protecting them from
enzymatic degradation, enhancing their absorption, bioavailability, and transportation to target
organs, and altering cell signaling pathways [10]. Most of the nanodelivery systems comprise bio-
degradable and biocompatible polymers, and then they are formulated into different nanostruc-
tures. The nanodelivery systems, such as nanospheres, nanocapsules, nanoemulsions, solid lipid
nanoparticles, cyclodextrins, liposomes, and micelles, have revolutionized the delivery of thera-
peutic substances across the nervous system [11].
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12.1 Polyphenols and Their Role in Neurological Disorders (NDs) 249
12.1 Polyphenols and Their Role in Neurological Disorders (NDs)
Polyphenols are a large group of natural compounds biosynthesized by plants as secondary metab-
olites with chemical characteristics related to phenolic substances. In particular, the well-known
class of phenolic systems, “polyphenols”, is characterized by the presence of at least two phenyl
rings and one or more hydroxyl groups, resulting in a large number of heterogeneous compounds.
Consequently, polyphenols can be divided into numerous subclasses or simply classified as flavo-
noids and non-flavonoids depending on the number of phenol units in their molecular structure,
substituent groups, and/or the type of linkage between the phenol units [12].
NDs are a heterogeneous group of disorders characterized by the dysfunction and/or progressive
loss of post-mitotic neuronal cells in the CNS or PNS that represent a critical problem regarding
human suffering and the economic burden on the healthcare system. Cognitive decline, dementia,
motor irregularities, sleep difficulties, behavioral, and psychosocial disorders are the main clinical
symptoms of neurodegeneration [5]. Common neurodegenerative diseases include AD, PD, and
HD, and the illnesses share similar cellular and molecular mechanisms, such as the buildup of
abnormal, misfolded, and aggregated proteins, mitochondrial dysfunction, inflammation, the
accumulation of oxidative stress, impaired neuronal transport, impairment of the autophagic pro-
cess, and changes in proteasome activity. The imbalance between the generation of ROS and anti-
oxidant defenses leads to oxidative stress. It causes mitochondrial dysfunction, genomic instability,
and oxidative damage to DNA, proteins, and lipids, in addition to impairing DNA repair pathways.
The high oxygen consumption needed to meet the brain’s high energy requirements specifically
leads to excessive ROS production, high levels of polyunsaturated fatty acids in neuronal mem-
branes that make them more susceptible to oxidation, and insufficient antioxidant defense mecha-
nisms. These factors make the brain more vulnerable to ROS injury than other organs [7].
A diet rich in polyphenols lowers the cellular oxidative stress and is a successful technique for
preventing NDs. Several different mechanisms, including interaction with the hypoxia-inducible fac-
tor 1-alpha (HIF-1 alpha) pathway, modulation of the expression of genes that protect against oxida-
tive stress, regulation of ROS by interacting with oxidative pathways, and scavenging metal ions to
prevent free radical damage, are used by polyphenols to exert their antioxidant activity. Numerous
polyphenols have the capacity to chelate metal ions (Fe
2+
, Zn
2+
, and Cu
2+
) that accumulate in spe-
cific brain regions of ND patients and lead to oxidative stress. For instance, these compounds seem to
function by reducing the amount of iron and its accumulation by complexing transition divalent
metal ions. One of the ways that polyphenol compounds have neuroprotective effects is by reducing
the formation of beta amyloid aggregates and/or fibrils [13]. Numerous in vitro studies have revealed
that curcumin, resveratrol, and epigallocatechin gallate (EGCG) are beneficial in the direct disrup-
tion of β-pleated sheets [14]. Particularly, polyphenols seem to bind to different surface areas of the
β-sheet structure, leading to a variety of outcomes, including the formation of quick and non-toxic
oligomers. The anti-inflammatory property of polyphenols exerts protective action against neurode-
generation. These compounds predominantly influence the expression of pro-inflammatory genes,
such as nitric oxide synthase, lipoxygenase, cyclooxygenase, chemokines, and numerous cytokines,
by the nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein
kinase signaling [13]. Table 12.1 represents a list of polyphenols used in NDs.
Polyphenols also interact with other pathways that are either directly or indirectly connected to the
neurodegenerative process. They play an important role in the signaling pathways that control cell
growth, survival, apoptosis, and autophagy. The phosphorylation state and expression levels of proteins
involved in the signaling pathways for phosphoinositide 3-kinase, Akt/protein kinase B, tyrosine kinases,
and protein kinase C are altered by polyphenols, which in this case, affect cellular function [34].
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12 Nanodelivery of Polyphenols as Nutraceuticals for Neurological Disorders
250
Some studies reported that in PD, hesperidin and naringenin act by decreasing the ROS level and
increasing the level and activity of GSH; additionally, ferulic acid and pelargonidin act by decreas-
ing the oxidative stress. In vitro studies reported that silymarin in MS acts by increasing the expres-
sions of STAT5, JAK3, and FOXP3, as well as the levels of TGF-β. Many studies have shown that
gallic acid, quercetin, apigenin, and naringenin act by various mechanisms in AD [35].
The major limitation of polyphenols is their poor bioavailability. Polyphenols have a relatively
low bioavailability because of extrinsic factors (such as limited stability in the gastrointestinal sys-
tem, substantial phase I and phase II metabolism, and quick elimination) and intrinsic factors
(such as chemical structure, molecular weight, and low hydrosolubility). The cell membrane per-
meability of polyphenols is another factor that influences their bioavailability [36].
12.2 Nanocarriers for Brain Targeting
Nanotechnology offers a promising approach to treat CNS disorders through drug delivery, lever-
aging the small size of biodegradable and biocompatible nanoparticles that can cross the BBB. The
surface of these nanoparticles can also be tailored to enhance the compatibility with the drug being
loaded. Nanoparticles feature a two-fold composition with the first part safeguarding the drug
from degradation and targeting specific brain cells, crossing the BBB and releasing the drug at a
Table 12.1 Polyphenols used in the prevention and treatment of NDs.
Nds Active Polyphenol Study Model References
AD Resveratrol Neuro-2a (N2a) cells [15]
Rosmarinic acid C57Bl/6
J mice [16]
Rutin Tau-P301S mic [17]
Luteolin Sprague–Dawley rats [18]
PD Resveratrol SN4741 cells [19]
Myricetin Drosophila model [20]
Chrysin C57BL/6 mice [21]
Ellagic acid 6-hydroxydopamine (6-OHDA)-
induced rat
[22]
HD Quercetin Wistar rats [23]
Resveratrol and fisetin Drosophila expressing mutant Httex1
and the R6/2 mouse model
[24]
Naringin Wistar rats [25]
Hesperidin Wistar rats [26]
ALS Wedelolactone and gallic acid Wistar rats [27]
Resveratrol SOD1- G93A mice [28]
Epigallocatechin-3-gallate SOD1- G93A mice [29]
7,8-dihydroxyflavone SOD1- G93A mice [30]
MS Resveratrol C57/Bl6 mice [31]
Naringenin C57/Bl6 mice [32]
Curcumin C57BL/6 mice [33]
.
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12.2 Nanocarriers for Brain Targeting 251
specific pH. The second part constitutes the nano-engineered complex. With the ability to deliver
drugs to specific sites, the BBB crossing mechanism is a major advantage of nanoparticles. Example
nanodelivery strategies adopted for delivering drugs across the CNS are shown in Figure 12.1,
including the nanodelivery of polyphenols across the BBB through major pathways.
12.2.1 Solid Lipid Nanoparticles (SLNs)
Solid lipid nanoparticles (SLNs) are a desirable colloidal drug carrier system that comprises spheri-
cal solid lipid particles in the nanometer range, dispersed in water or an aqueous surfactant solu-
tion. SLNs have a solid hydrophobic core with a phospholipid coating, and the solid core can hold
the drug in a solid high-melting fat matrix with the hydrophobic end of the phospholipid chains
embedded. SLNs have the potential to transport either lipophilic and hydrophilic drugs or diagnos-
tics [37]. SLNs delivery offers a novel approach to delivering drugs into the brain by addressing
solubility, permeability, and toxicity issues, and has benefits over traditional invasive methods.
Their high physical stability is another advantage. However, the use of polymeric micro/nanopar-
ticles for drug delivery is limited because of the cytotoxicity of the polymers and difficulty in large-
scale production. In contrast, solid lipids are a well-known matrix material for drug delivery and
can be produced inexpensively and simply through high pressure homogenization or microemul-
sion technologies [38].
12.2.2 Polymeric Nanoparticles
Polymeric nanoparticles are a promising option for CNS drug delivery because of their controlled
release, programmable size (10–1000 nm), biocompatibility, and non-toxicity. They can also be
modified with ligands to increase binding to endothelial cell receptors and enhance transcytosis.
Polymeric nanoparticles have a longer circulation duration, biodegradability, and the potential for
Figure 12.1 Delivery of polyphenols with the help of nanocarriers across the BBB into the CNS. BBB:
Blood Brain Barrier; CNS: Central Nervous System.
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12 Nanodelivery of Polyphenols as Nutraceuticals for Neurological Disorders
252
sustained, targeted, and protected drug delivery via cellular absorption and activation of the poly-
meric lattice. They have the versatility to deliver a wide range of medications through hydropho-
bic, hydrophilic, electrostatic, and covalent interactions [39]. Natural polysaccharides (hyaluronic
acid, chondroitin sulfate, and chitosan) and synthetic polymers (polylactic acid (PLA), polyglycolic
acid (PGA), and poly lactic-co-glycolic acid (PLGA)) are extensively used in the formulation of
polymeric nanoparticles [40].
12.2.3 Liposomes
Liposomes are spherical vesicles made of lipid bilayers that can entrap both hydrophilic and
hydrophobic compounds. They are widely used as drug delivery systems to improve the safety and
efficacy of therapeutics. They also have potential in neurological applications as they can cross the
BBB and deliver therapeutic and diagnostic agents to the brain. Liposomes can reach the brain
through various paths such as adsorption-mediated transcytosis, receptor-mediated endocytosis,
and disruption of the BBB [41].
12.2.4 Micelles
Micelles are nanocarriers with a size of 5–50 nm that form spontaneously from self-assembling
amphiphilic molecules. They have a hydrophobic core and a hydrophilic surface, making them
useful for delivering poorly water soluble and lipophilic compounds. Micelles can penetrate the
BBB through endocytosis and/or transcytosis, and their penetration can be enhanced by attaching
specific ligands or through external forces [42].
12.2.5 Dendrimers
Dendrimers are nanoscale artificial macromolecules with a highly branched, globular structure
comprising an initiator core, branched repeat units, and functional terminal groups. Commonly
used dendrimer materials include polyamidoamine, polypropylenimine, and polyaryl ether.
Dendrimers can encapsulate both hydrophilic and hydrophobic molecules, and they are used as
nanocarriers for various therapeutic and imaging agents. They can overcome the BBB and are used
in the treatment of CNS disorders. The cellular uptake is facilitated by modulation of tight junction
proteins, and specific ligands can be conjugated to the surface for enhanced brain targeting and
transport across the BBB [43].
12.2.6 Carbon Nanotubes
Carbon nanotubes are a type of carbon-based nanomaterial made by rolling graphite sheets into
tubes with nanoscale diameters. They can be single-walled or multi-walled with open or closed
ends. Carbon nanotubes have unique properties such as high electrical conductivity, mechanical
strength, and thermal resistance, making them attractive for various applications in medicine and
biotechnology. These include drug delivery, gene therapy, tissue engineering, and biosensing.
Carbon nanotubes can be functionalized with specific chemical compounds to modify their physi-
cal and biological properties, making them useful as nanocarriers. However, they cannot cross the
BBB via passive diffusion and they require conjugation with compounds to enable active transport
to the brain for use in neuro-nanomedicine [44].
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12.3 Nanodelivery of Polyphenols in Neurological Disorders (NDs) 253
12.2.7 Inorganic Nanoparticles
Inorganic NPs, including metals, semiconductors, and metal oxides, have unique properties that
make them attractive for biomedical applications. Their performance and functionality can be
improved by adjusting the size, shape, composition, structure, and porosity. Silver NPs (AgNPs),
iron oxide NPs (IONPs), and titanium dioxide NPs (TiO
2
NPs) are mainly used in disease diagnosis
through bioimaging. Gold NPs (AuNPs) and SiO
2
NPs have been used as nanocarriers to target the
CNS [45].
12.2.8 Quantum Dots
Quantum dots are zero-dimensional nanomaterials known for their exceptional optical and elec-
trical properties. They are used in medicine and biology for drug delivery, targeted cancer therapy,
bioimaging, cell labeling, and cell tracking. To target the brain and cross the BBB, quantum dots
need to be functionalized, and the main mechanism for reaching the brain parenchyma is through
carrier-mediated transport [46].
12.3 Nanodelivery of Polyphenols in Neurological
Disorders (NDs)
Nanotechnology provides a new method to address the problems associated with NDs. Table 12.2
lists various treatment strategies for NDs using nanotechnology.
12.3.1 Solid Lipid Nanoparticles (SLNs)
Puerarin, an isoflavone from the roots of Pueraria lobata (Willd.), is beneficial in PD and AD; how-
ever, it has poor water aqueous solubility (0.46 mg/mL) that hinders its use. However, SLN-
puerarin has better absorption, shorter Tmax and three fold higher bioavailability when compared
with a puerarin suspension [58].
12.3.2 Polymeric Nanoparticles
The ability of resveratrol (Res) to protect against PD in mice was investigated using Res-loaded
polysorbate 80 (PS80)-coated poly (lactide) nanoparticles. The effects were compared with those of
bulk Res in C57BL/6 mice. The Res-loaded nanoparticles showed significant neuroprotective
effects against the harmful effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), unlike
bulk Res [51].
12.3.3 Liposomes
A study investigated the effectiveness of using phosphatidic acid (PA) and apolipoprotein E (ApoE)
to modify the surface of quercetin (QT) and rosmarinic acid (RA)-loaded liposomes to penetrate
the BBB and treat β-amyloid (Aβ1-42)-induced neurotoxicity in an AD model. The results showed
that incorporating ApoE or Tween 80 into the liposomes improved their ability to target the BBB,
Aβ1-42, neurons, and reduced oxidative toxicity. However, Tween 80 had slightly higher cytotoxic-
ity than ApoE. It was further observed that increasing the proportion of PA in the liposomes
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12 Nanodelivery of Polyphenols as Nutraceuticals for Neurological Disorders
254
increased the particle size and improved Aβ1-42 targeting. The addition of ApoE or Tween 80 also
slowed the drug release and increased drug activity by reducing AchE activity and lipid peroxida-
tion in rats with AD [47].
12.3.4 Micelles
To increase bioavailability and enhance delivery of curcumin in the brain of patients with AD, a
group of researchers formulated cocrystals of curcumin and incorporated them in a micellar
Table 12.2 Treatment strategies for NDs using polyphenol-based nanoformulations.
Nds Nanocarrier Type Active Polyphenol Study Model Outcomes References
AD Liposomes Quercetin and
rosmarinic acid
Sprague–Dawley
rats
Improved drug
delivery, release
and activity
[47]
Micelles Curcumin Sprague–Dawley
rats
Better antioxidant
activity, enhanced
bioavailability,
distribution, and
retention
[48]
Carbon nanotube Berberine Wistar rats Improved drug
absorption and
better performance
[49]
Carbon dot Curcumin PC12 cells Enhanced cellular
uptake
[50]
PD Polymeric nanoparticle Resveratrol C57BL/6 mice Enhanced
neuroprotection
against MPTP
[51]
Nanocrystal Quercetin 6-OHDA-
induced rat
Greater
bioavailability
[52]
Liposomes Gallic acid,
catechin, and
epicatechin
SH-SY5Y-
derived neurons
Excellent
distribution
[53]
HD Selenium
nanoparticles
———— Caenorhabditis
elegans
transgenic
model
Reduced neuronal
death and relieved
behavioral
dysfunction,
protecting from
damage in stress
conditions
[54]
Solid lipid
nanoparticles
Curcumin Wistar rats Reduced ROS,
improved
neuromotor
coordination
[55]
MS Polymeric
nanoparticles
Curcumin Lewis rat Efficient
therapeutic effect
[56]
ALS Micelles Curcumin Adipose tissue
sample
Reduced toxicity [57]
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12.4 Conclusions and Future Perspectives 255
nanocarrier system for efficient delivery directly to the brain via the nose. The results of the study
showed that curcumin cocrystals and their micelles had a much lower IC
50
than regular curcumin,
leading to improved antioxidant performance. Furthermore, in animal studies, the bioavailability
of curcumin cocrystal micelles was 1.7 times greater, with increased brain distribution and longer
retention [48].
12.3.5 Dendrimers
Res is effective in several NDs. However, the limitations of Res, such as low oral bioavailability,
poor solubility, and instability, can be overcome by encapsulating it in water-soluble
poly(amidoamine) dendrimers, which improves its solubility, stability, and overall effectiveness.
Dendrimers not only enhance the properties of Res, they also have the potential to promote the
solubility, stability, and controlled delivery for improved bioavailability and efficacy [59].
12.3.6 Carbon Nanotubes
A study investigated the use of berberine-loaded multiwalled carbon nanotubes (BRB-MWCNTs)
coated with polysorbate and phospholipid as a potential treatment for AD. Results showed
improved drug absorption in rats and better performance in memory tests compared with pure
berberine. The coated MWCNTs also showed potential in reducing AD symptoms by maintaining
normal biochemical levels in the brain tissue [49].
12.3.7 Inorganic Nanoparticles
A study combined the Aβ absorption property of selenium nanoparticles with Res to form Res@
SeNPs. The in vitro evaluation showed that Res@SeNPs provide a synergistic effect on Cu
2+
-
induced Aβ42 aggregation and ROS generation, and effectively protect neuron cells (PC-12) from
Aβ42-Cu
2+
induced cell death. Therefore, the results suggest that the combination of Res and
SeNPs is more effective in reducing Aβ42 toxicity than Res alone, making it a promising approach
for long-term AD treatment [60].
12.3.8 Quantum Dots
A new delivery system, a Fe
3
O
4
carbon dot (CD) nanocomposite, was used to load curcumin (CUR-
Fe
3
O
4
@CDs) for the treatment of AD. The CDs have a natural fluorescence and are biocompatible
with low toxicity. In vitro studies have shown that CUR-Fe
3
O
4
@CDs are highly specific towards
Aβ42, thereby preventing aggregation and countering toxic effects on neuronal cells (PC-12).
These findings suggest that CUR-Fe
3
O
4
@CDs could be a promising candidate for the treatment of
AD [50].
12.4 Conclusions and Future Perspectives
The improvement in lifespan has led to a rise in the prevalence of NDs that require new treatment
methods to improve a patient’s symptoms and quality of life. The CNS is protected by various bar-
riers, so drugs must pass the BBB for successful treatment. Phytochemical-based nanocarriers offer
advantages such as safety, eco-friendliness, low toxicity, affordability, and the ability to control
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12 Nanodelivery of Polyphenols as Nutraceuticals for Neurological Disorders
256
particle size and morphology. These nanocarriers can improve the delivery of phytotherapeutic
compounds to the CNS, increase drug penetration into the brain, and prevent drug aggregation in
the brain. Although many preclinical studies have shown the therapeutic effects of these nanocar-
riers in NDs, more research is needed to address safety concerns. The long-term clinical efficacy of
these nanocarriers in neurological medicine also needs to be evaluated. Designing nanocarriers
with specific targeting to different brain cells and for each type of ND is important to maximize
their effectiveness.
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