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International Journal of
Molecular Sciences
Review
Recent Advances in Nanoparticle-Mediated Delivery
of Anti-Inflammatory Phytocompounds
Raffaele Conte 1,† , Valentina Marturano 2,3,† , Gianfranco Peluso 1 , Anna Calarco 1, *
and Pierfrancesco Cerruti 2
1
2
3
*
†
Institute of Agro-Environmental and Forest Biology (IBAF-CNR), Via Pietro Castellino 111, 80131 Napoli,
Italy; [email protected] (R.C.); [email protected] (G.P.)
Institute for Polymers, Composites, and Biomaterials (IPCB-CNR), Via Campi Flegrei 34,
80078 Pozzuoli (NA), Italy; [email protected] (V.M.); [email protected] (P.C.)
Department of Chemical Sciences, University of Naples “Federico II”, Via Cynthia 4, 80125 Napoli, Italy
Correspondence: [email protected]; Tel.: +39-081-6132569
These authors contributed equally to this work.
Academic Editors: Paula Andrade and Patrícia Valentão
Received: 1 February 2017; Accepted: 23 March 2017; Published: 28 March 2017
Abstract: Phytocompounds have been used in medicine for decades owing to their potential in
anti-inflammatory applications. However, major difficulties in achieving sustained delivery of
phyto-based drugs are related to their low solubility and cell penetration, and high instability.
To overcome these disadvantages, nanosized delivery technologies are currently in use for sustained
and enhanced delivery of phyto-derived bioactive compounds in the pharmaceutical sector.
This review focuses on the recent advances in nanocarrier-mediated drug delivery of bioactive
molecules of plant origin in the field of anti-inflammatory research. In particular, special attention
is paid to the relationship between structure and properties of the nanocarrier and phytodrug
release behavior.
Keywords: inflammation; phytochemicals; nanosized delivery systems; polyphenols; carbohydrates;
cannabinoids; terpenoids; essential oils; nanoparticles; nanocapsules
1. Introduction
Inflammation represents the physiological response of the body to tissue injury (e.g., stress,
irritants, and radiations), infections (microbial and viral) or genetic changes and may be distinguished
into two phases: acute and chronic. The acute is the early nonspecific phase characterized by
local vasodilatation, increased capillary permeability, accumulation of fluid and blood proteins into
the interstitial spaces, migration of neutrophils out of the capillaries, and release of inflammatory
mediators (e.g., cytokines, lymphokines, and histamine) [1–6]. Clinically, acute inflammation is
characterized by five cardinal signs: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain),
and functio laesa (loss of function). Under normal conditions, neutrophils undergo apoptosis
after performing their action at the inflamed site and macrophages ingest apoptotic neutrophils.
Clearance of apoptotic neutrophils prompts a switch from a pro- to an anti-inflammatory macrophage
phenotype, which enable macrophage egress favoring tissue repair and regain of physiological function
(Figure 1A) [7–12].
Int. J. Mol. Sci. 2017, 18, 709; doi:10.3390/ijms18040709
www.mdpi.com/journal/ijms
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Figure 1.1.Schematic
representation
of the main
characteristics
of: acute (A) of:
and chronic
(B) inflammation.
Figure
Schematic
representation
of the
main characteristics
acute (A)
and chronic
(B) inflammation.
However, if the condition causing the damage is not resolved, the inflammatory process
evolves
toward if
subacute/chronic
inflammation
characterized
immunopathological
changes
such
However,
the condition causing
the damage
is not by
resolved,
the inflammatory
process
as
infiltration
inflammatory cells,
overexpression
of pro-inflammatory
genes, dysregulation
of
evolves
towardofsubacute/chronic
inflammation
characterized
by immunopathological
changes such
cellular
signaling
and
loss
of
barrier
function.
The
chronic
state
of
inflammation
has
important
roles
as infiltration of inflammatory cells, overexpression of pro-inflammatory genes, dysregulation of
in
the onset
of various
diseases,
including
cardiovascular
neurodegenerative
diseases,
cellular
signaling
and loss
of barrier
function.
The chronic disease,
state of inflammation
has important
diabetes,
cancer,
obesity,
asthma,
as
well
as
classic
inflammatory
diseases
(e.g.,
arthritis
and
roles in the onset of various diseases, including cardiovascular disease, neurodegenerative diseases,
periodontal
diseases)
(Figure
1B)
[13–23].
In
the
last
decade,
a
new
family
of
clinical
disorders,
diabetes, cancer, obesity, asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal
namely
auto-inflammatory
diseases,
Auto-inflammatory
disorders
are systemic
a group
diseases)systemic
(Figure 1B)
[13–23]. In the last
decade,emerged.
a new family
of clinical disorders,
namely
of
heterogeneous
disorders
characterized
by
apparently
inexplicable
recurrence
of
local
auto-inflammatory diseases, emerged. Auto-inflammatory disorders are a group of heterogeneous
inflammation,
with
an
increased
production
of
inflammatory
cytokines
that
can
occur
without
disorders characterized by apparently inexplicable recurrence of local inflammation, with an increased
detectable autoantibodies
auto-reactive
T cells.
thesedetectable
diseases are
caused by overproduction
production
of inflammatoryorcytokines
that can
occur All
without
autoantibodies
or auto-reactive
of
pro-inflammatory
cytokines,
such
as
interleukin
(IL)-1β
and
tumor
necrosis
factor
T cells. All these diseases are caused by overproduction of pro-inflammatory cytokines,(TNF)-α,
such as
abnormal
sensing
in inflammatory
bowel
disease),
and tissue
micro-damage
leading
interleukinmicrobial
(IL)-1β and
tumor(as
necrosis
factor (TNF)-α,
abnormal
microbial
sensing
(as in inflammatory
to
a
pathological
delay
in
the
turning
off
of
inflammatory
responses
[24–26].
bowel disease), and tissue micro-damage leading to a pathological delay in the turning off of
Several evidences
inflammatory
responsessuggest
[24–26].that the regulation of inflammation is tightly controlled by an array
of epigenetic
mechanisms
and that
cannot
confinedofto
a simple model
in which
the expression
ofof
a
Several evidences
suggest
the be
regulation
inflammation
is tightly
controlled
by an array
distinct
set
of
genes
depends
exclusively
on
a
single
or
a
defined
set
of
transcription
factors
[27,28].
epigenetic mechanisms and cannot be confined to a simple model in which the expression of a distinct
or inhibition
mediators
using
synthetic antiset ofSuppression
genes depends
exclusivelyofoninflammatory/pro-inflammatory
a single or a defined set of transcription
factors
[27,28].
inflammatory
compounds
(e.g., of
steroidal
and nonsteroidal) is one ofmediators
the majorusing
routessynthetic
for the
Suppression
or inhibition
inflammatory/pro-inflammatory
treatment
of
inflammatory
disorders.
However,
the
use
of
synthetic
anti-inflammatory
molecules
is
anti-inflammatory compounds (e.g., steroidal and nonsteroidal) is one of the major routes for the
associated
with
some common
side effects
including
gastric
irritation,
ulceration, bleeding,
renal
treatment of
inflammatory
disorders.
However,
the use
of synthetic
anti-inflammatory
molecules
failure,
hepatic
failure,
headache,
hemolytic
anemia,
asthma
exacerbation,
skin
rashes,
angioedema,
is associated with some common side effects including gastric irritation, ulceration, bleeding,
and
recent years,
phytochemicals
derived from
plants
have gained
increased
renalpruritus
failure, [29,30].
hepaticInfailure,
headache,
hemolytic anemia,
asthma
exacerbation,
skin
rashes,
attention
dueand
to their
safe [29,30].
toxicological
profiles
to allopathic
the treatment
of
angioedema,
pruritus
In recent
years,compared
phytochemicals
deriveddrugs
from in
plants
have gained
inflammatory
disease
[31–34],
and
their
protective
action
has
been
demonstrated
in
obesityincreased attention due to their safe toxicological profiles compared to allopathic drugs in the treatment
mediated
inflammation
[35,36],and
inflammatory
bowel
disease
[37–40],
Alzheimer
disease [41,42],
of inflammatory
disease [31–34],
their protective
action
has been
demonstrated
in obesity-mediated
diabetes
[43], skin
inflammation
[44,45].
However,
despite Alzheimer
promising disease
biological
activities
of plant
inflammation
[35,36],
inflammatory
bowel
disease [37–40],
[41,42],
diabetes
[43],
raw
extracts,
poor
solubility,
poor
stability,
short
biological
half-life,
and
rapid
elimination
hinder
skin inflammation [44,45]. However, despite promising biological activities of plant raw extracts,
their clinical application. Moreover, their large molecular size negatively affects passive absorption,
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poor solubility, poor stability, short biological half-life, and rapid elimination hinder their clinical
application. Moreover, their large molecular size negatively affects passive absorption, and their
pharmacokinetics is further modified by the highly acidic gastric pH and pre-systemic metabolism [46].
These aspects, together with the individual variation of extracts constituents, led research interest
towards the synthesis of systems able to effectively deliver these substances.
2. Nanosized Drug Delivery Systems
Nanotechnology is already employed in traditional drug delivery and tissue engineering [47],
as it offers the possibility to develop devices particularly adapted to improve the therapeutic efficacy
of natural bioactive molecules [48]. Indeed, nanocarriers are alternatives for traditional formulation
approaches, enabling to increase drug bioavailability, permit a site-specific targeted delivery, as well as
reducing toxic side effects [49–51].
Since the 1970s, when Nobel Prize winner Christian de Duve described the structure and
properties of lysosomes in biological tissues, drug administration protocols have significantly
evolved due to the introduction of nanosized drug delivery systems [52]. The latter can be
defined as ultra-dispersed solid organic or inorganic structures displaying a sub-micrometer size,
typically comprised between 10 and 100 nm. The upper limit is dictated by the vector’s ability to
pass cellular interstices, while the lower limit is fixed by the threshold for first-pass elimination by
kidneys. Moreover, such dimensions permit a good biodistribution of long-circulating nanocarriers [53].
If compared to traditional formulations, the use of nanovectors for drug delivery offers many
advantages: more efficient delivery of water insoluble drugs at high dose, protection for the drug from
hostile environments (e.g., acidic pH in the digestive tract), and targeted and controlled delivery to
achieve precise administration to a specific tissue over a determined period of time [54].
Various materials and structures have been employed as nanocarriers for either passive or
active targeting. Metal particles, such as iron oxide or gold nanosized assemblies, can be surface
modified to act as drug carriers [55,56]. However, organic materials are more versatile, and their
properties and performances can be finely tuned by tailoring their chemical composition, size, shape,
structures morphology, and surface properties [57], as depicted in Figure 2. Lipid-based particles,
such as liposomes, or cubosomes, are supramolecular assemblies of amphiphilic molecules, in which
hydrophobic drugs can be encapsulated [58,59]. Another class of natural carriers employed in drug
delivery is cyclodextrins (CD), cyclic oligosaccharides characterized by a hydrophilic outer surface,
and able to load guest molecules in their lipophilic inner cavity via non-covalent inclusion interactions.
As well as other nanocarriers, the use of CD can increase drug solubility, bioavailability, safety,
and stability of drug formulations [60]. Polymers provide even more versatility in nanocarriers
engineering, being nanoparticles (NP), nanocapsules (NC), dendrimers and copolymer micelles among
the numerous examples of polymer-based assemblies that serve as a reservoir for the loaded drug [61].
In nanoparticles and nanocapsules, drugs can be encapsulated in or conjugated to polymer chains.
Dendrimers are made up of several branched polymer chains stemming from a central core, in which
the active principle can be conjugated or complexed. Polymer micelles result from the self-assembly
in water of amphiphilic copolymers into a core–shell structure. The hydrophobic core can be act as a
reservoir of hydrophobic drugs while the hydrophilic corona provides water solubility and colloidal
stability [62].
Tailored engineering and design of polymeric carriers allow precise and controlled administration
of the cargo drug. A passive delivery occurs when the loaded drug is released by diffusion or erosion
of the nanovector, an active delivery can instead be achieved employing stimuli-responsive materials
as drug carriers. In stimuli-responsive (or smart) materials, a variation in structure or morphology is
triggered by an external stimulus, such as pH variations, contact with concentrated ionic solution or
enzymes, exposition to light, ultrasound, electric field, magnetic field or heating [63].
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Figure
Figure 2.
2. Examples
Examples of
of organic
organic material-based
material-based nanosized
nanosized drug
drug delivery
delivery systems.
systems.
In this frame, the surface properties of the nanocarrier determine the interaction with body
In this frame, the surface properties of the nanocarrier determine the interaction with body
environment to a great extent [64]. For example, nanovectors with negative or positive surface
environment to a great extent [64]. For example, nanovectors with negative or positive surface
charges have increased reticuloendothelial clearance. Steric stabilization with biological or synthetic
charges have increased reticuloendothelial clearance. Steric stabilization with biological or synthetic
macromolecules, such as opsonin or polyethylene glycol (PEG), prolongs circulation times and
macromolecules, such as opsonin or polyethylene glycol (PEG), prolongs circulation times and prevents
prevents nanoparticle loss [65]. Targeting strategies are aimed to overcome side effects and
nanoparticle loss [65]. Targeting strategies are aimed to overcome side effects and minimize systemic
minimize systemic drug administration. These are classified into passive and active targeting [66].
drug administration. These are classified into passive and active targeting [66]. Passive targeting is
Passive targeting is achieved by changing the physiochemical characteristics, pH or hydrophobicity
achieved by changing the physiochemical characteristics, pH or hydrophobicity of NP and utilizes the
of NP and utilizes the “enhanced permeability and retention effect” of inflamed blood vessels.
“enhanced permeability and retention effect” of inflamed blood vessels. Active targeting, differently,
Active targeting, differently, uses biomarkers (e.g., mutant genes, RNAs, proteins, lipids,
uses biomarkers (e.g., mutant genes, RNAs, proteins, lipids, carbohydrates, and small metabolite
carbohydrates, and small metabolite molecules) to reach the target sites [67]. The addition of a
molecules) to reach the target sites [67]. The addition of a targeting moiety onto the surface of NP
targeting moiety onto the surface of NP increases selective cellular binding and internalization
increases selective cellular binding and internalization through receptor-mediated endocytosis [53].
through receptor-mediated endocytosis [53]. In this regard, key properties of nanoparticles (NP)
In this regard, key properties of nanoparticles (NP) utilized as plant-derived anti-inflammatory delivery
utilized as plant-derived anti-inflammatory delivery systems greatly depend on size, surface
systems greatly depend on size, surface characteristics, and targeting strategies.
characteristics, and targeting strategies.
Even though the use of nanocarriers as drug-delivery systems offers many advantages,
Even though the use of nanocarriers as drug-delivery systems offers many advantages, some
some drawbacks need to be addressed, e.g., instability during blood circulation, low renal clearance,
drawbacks need to be addressed, e.g., instability during blood circulation, low renal clearance,
limited accumulation in specific tissues, and low uptake by target cells. Moreover, case by case
limited accumulation in specific tissues, and low uptake by target cells. Moreover, case by case
evaluation of the interactions between nanocarriers and biological systems is of key importance to
evaluation of the interactions between nanocarriers and biological systems is of key importance to
assess the reliability of the delivery systems. The successful translation of nano-formulations to the
assess the reliability of the delivery systems. The successful translation of nano-formulations to the
clinic involves careful assessment of their safety profiles, which, among other end-points, includes the
clinic involves careful assessment of their safety profiles, which, among other end-points, includes
evaluation of immunotoxicity [68]. Moreover, since physico-chemical properties of nanoparticles,
the evaluation of immunotoxicity [68]. Moreover, since physico-chemical properties of
such as surface charge and size, modulate uptake and interactions with cells, control over surface
nanoparticles, such as surface charge and size, modulate uptake and interactions with cells, control
modification and biodegradation of nanovectors contributes to minimize potential health risks that are
over surface modification and biodegradation of nanovectors contributes to minimize potential
associated with occupational exposure to such materials [69]. The main challenges associated with
health risks that are associated with occupational exposure to such materials [69]. The main
nano-toxicity evaluations are related to the development of more accurate and fully-characterized
challenges associated with nano-toxicity evaluations are related to the development of more
reference materials and methods. In addition, there is the need to develop a paradigm for predictive
accurate and fully-characterized reference materials and methods. In addition, there is the need to
toxicological testing of nanomaterials, taking into consideration the physico-chemical properties of the
develop a paradigm for predictive toxicological testing of nanomaterials, taking into consideration
material that lead to molecular or cellular injury, with the aim to triage novel nanomaterials for further
the physico-chemical properties of the material that lead to molecular or cellular injury, with the
in vivo testing [70].
aim to triage novel nanomaterials for further in vivo testing [70].
This review provides a focus on recent advances in the preparation and characterization
This review provides a focus on recent advances in the preparation and characterization of
of nanosized vectors able to release phytochemicals endowed with anti-inflammatory activity.
nanosized vectors able to release phytochemicals endowed with anti-inflammatory activity.
Different delivery technologies will be discussed, according to chemical structure and natural source
Different delivery technologies will be discussed, according to chemical structure and natural
source of the bioactive molecules to be released. In particular, organic nanovectors loaded with
Int. J. Mol. Sci. 2017, 18, 709
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of the
bioactive molecules to be released. In particular, organic nanovectors loaded with polyphenols,
phytocannabinoids, phytosterols, carbohydrates, essential oils, and terpenoids will be reviewed
polyphenols, phytocannabinoids, phytosterols, carbohydrates, essential oils, and terpenoids will be
(Figure
3). For
each 3).
phytochemical
class, a focus
will
be given
togiven
the relationship
between
structure
reviewed
(Figure
For each phytochemical
class,
a focus
will be
to the relationship
between
andstructure
properties
of
nanocarriers
and
phytodrugs
release
behavior.
and properties of nanocarriers and phytodrugs release behavior.
Figure 3. Nanoparticle-mediated delivery of different classes of anti-inflammatory natural compounds.
Figure 3. Nanoparticle-mediated delivery of different classes of anti-inflammatory natural compounds.
3. Anti-Inflammatory Phytoconstituents and Their Nanoparticle-Mediated Delivery
3. Anti-Inflammatory Phytoconstituents and Their Nanoparticle-Mediated Delivery
3.1. Polyphenols
3.1. Polyphenols
Polyphenols (PPH) are a large family of ubiquitous and varied molecules present as secondary
Polyphenols
(PPH) arevascular
a large plants.
familyThese
of ubiquitous
and varied
molecules
present
as secondary
metabolites
in numerous
natural compounds
range
from simple
molecules
to
complex
structures
that
have
in
common
the
presence
of
benzene
rings
bearing
one
or
several
metabolites in numerous vascular plants. These natural compounds range from simple molecules
hydroxylstructures
functions. that
In the
plant,
these active
principlesofplay
an important
role in
to complex
have
in common
the presence
benzene
rings bearing
onegrowth,
or several
reproduction,
resistance
to pathogens,
predators
and play
diseases
[71]. Nonetheless,
PPH are
potent
hydroxyl
functions.
In the plant,
these active
principles
an important
role in growth,
reproduction,
effectors
biologic processes
associated
with [71].
the pathogenesis
human
thanks tooftheir
resistance
to of
pathogens,
predators
and diseases
Nonetheless,ofPPH
are diseases
potent effectors
biologic
ability to interact with proteins, enzymes and membrane receptors, modulating the resulting
processes associated with the pathogenesis of human diseases thanks to their ability to interact with
activity [72]. Among their properties, the strong free radical scavenging action is probably the most
proteins, enzymes and membrane receptors, modulating the resulting activity [72]. Among their
studied, and is involved in the anti-inflammatory action of these molecules. In particular, quercetin
properties,
the strong free radical scavenging action is probably the most studied, and is involved
(QC), resveratrol (RE) and tannins are recognized as pain killers [73]. PPH are able to improve
in the
anti-inflammatory
of these
particular,
quercetin
(QC), resveratrol
health by strengtheningaction
the response
of molecules.
the immuneIn
system
towards
chronic diseases.
However, (RE)
andtheir
tannins
are recognized
painmetabolism
killers [73].
PPH
are able to improve
by strengthening
efficacy
depends on as
their
and
bioavailability,
defined ashealth
the amount
of the
the administrated
response of the
system
towards
chronic
diseases.InHowever,
their
efficacy
depends
drugimmune
that is able
to reach
the systemic
circulation.
general, PPH
have
a relatively
on their
metabolism and
as the amount
of the
administrated
druglow
that is
low bioavailability
due bioavailability,
to both intrinsicdefined
factors (chemical
structure,
molecular
weight and
and extrinsic
factors In
(low
stabilityPPH
in the
gastrointestinal
environment,
extensive
ablehydrosolubility)
to reach the systemic
circulation.
general,
have
a relatively low
bioavailability
due to
II metabolism
and rapid
elimination)
[74]. Consequently,
clinical
applications of and
PPHextrinsic
are
bothphase
intrinsic
factors (chemical
structure,
molecular
weight and low
hydrosolubility)
limited.
avoid these
drawbacks,
nanodelivery
systems able
to maintain
theIIstructural
integrity
factors
(lowTostability
in the
gastrointestinal
environment,
extensive
phase
metabolism
andof
rapid
these
bioactive
molecules
have
been
developed
[75].
For
example,
nanosized
vectors
encapsulating
elimination) [74]. Consequently, clinical applications of PPH are limited. To avoid these drawbacks,
QC, a semi-lipophilic flavonol ubiquitous in plants, have been developed by Li et al. through the
nanodelivery
systems able to maintain the structural integrity of these bioactive molecules have
synthesis of solid lipid nanoparticles (SLN) of 155 nm of size composed of soya lecithin, Tween-80
been developed [75]. For example, nanosized vectors encapsulating QC, a semi-lipophilic flavonol
and polyethylene glycol (PEG), with a QC encapsulation efficiency of 91% [76]. These NP were able
ubiquitous in plants, have been developed by Li et al. through the synthesis of solid lipid nanoparticles
to increase the relative oral bioavailability of quercetin by 5.7-fold as compared to the free form.
(SLN)
of 155 nm nanocapsules
of size composed
soyabeen
lecithin,
Tween-80
and polyethylene
(PEG),
Lipid-coated
(NC)ofhave
reported
by Barras
et al., with a glycol
solubility
100 with
timesa QC
encapsulation
91%
[76]. These
NPfor
were
able
to increase
theand
relative
bioavailability
higher withefficiency
respect toof
free
quercetin,
stable
more
than
ten weeks,
with oral
no degradation
of quercetin
by
5.7-fold
as
compared
to
the
free
form.
Lipid-coated
nanocapsules
(NC)
have been
product being detected [77]. Pool et al. produced quercetin-loaded polylactic-co-glycolide (PLGA)
reported
by
Barras
et
al.,
with
a
solubility
100
times
higher
with
respect
to
free
quercetin,
stable for
NC with a more potent antioxidant action against peroxyl radical-induced lipid peroxidation,
resulting
in weeks,
a moreand
effective
anti-inflammatory
therapybeing
[78]. detected
Similarly, [77].
Wu et
al. et
synthesized
more
than ten
with no
degradation product
Pool
al. produced
quercetin-loaded polylactic-co-glycolide (PLGA) NC with a more potent antioxidant action against
peroxyl radical-induced lipid peroxidation, resulting in a more effective anti-inflammatory therapy [78].
Int. J. Mol. Sci. 2017, 18, 709
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Similarly, Wu et al. synthesized quercetin-loaded Eudragit-polyvinyl alcohol NP with particle size
of 85 nm, good polydispersity, drug loading of around 99% and enhanced antioxidant activity [79].
Finally, Chakraborty et al. examined the potency of orally administered quercetin-PLGA NP in a rat
model [80]. Nanoparticles were administered prior to alcohol induced gastric ulcer in the protection
against oxidative damages, demonstrating that QC-PLGA NP prevented 90% of this inflammation as
compared to the 20% of the free quercetin. Resveratrol, chemically known as 3,5,4-trihydroxystilbene,
is a naturally occurring polyphenol produced by a wide variety of plants in response to injury,
UV irradiation, ozone exposure and fungal attack [81]. Nanovectors delivering RE have been reported
by Singh and Pai, that described a sustained release of trans-resveratrol from orally administered
PLGA NP (drug encapsulation efficiency more than 78%, with a particle size of about 170 nm) [82].
The same authors encapsulated RE in Eudragit RL 100 NP with a drug incorporation efficiency
of 84% and average size of 180 nm. In vivo studies in a rat model showed prolonged plasma
levels up to 16 h, in comparison with free drug being cleared within 6 h [83]. Zu et al. developed
carboxymethyl chitosan NP as carrier for resveratrol [84]. These nanoparticles (155 nm-sized, with
an encapsulation efficiency of 44%) improved the solubility of resveratrol, thereby greatly affecting
the antioxidant activity of the drug. Additionally, resveratrol loaded SLN were synthesized with a
controlled release profile, due to an initial burst release of 40% caused by the active principle associated
with the particle shell, and a subsequent prolonged release of the drug located in the lipid matrix.
In this system, the efficiency of the cellular uptake depended on the molecular interactions with
the biological membrane organization, lipid rafts and the actin cytoskeleton invaginations for the
receptor mediated entrance [85]. Resveratrol loaded SLN have been also prepared by Pandita et al.
with a drug incorporation efficiency of 89% and average diameter of 134 nm [86]. This drug delivery
system showed prolonged release in vitro up to 120 h in a Wistar rat model, enhancing plasma
bioavailability compared to free drug suspension. Finally, cyclodextrins-resveratrol complexes
have been used to increase concentration of polyphenol in aqueous solution, while maintaining
its biological activity. For example, spherical cyclodextrin-based nanosponges showed increasing
solubility and stability, together with good drug encapsulation efficiency, compared to free RE [87].
Ellagitannin (ET) and ellagic acid (EAC) are active substances belonging to the phenolic class of tannins
most present in pomegranate (Punica granatum), a fruit-bearing shrub that originated in the region
from Iran to northern India [71]. Nanosized drug delivery systems protect these molecules inside
the nanoparticulate core, thus preventing degradation and increasing bioavailability. For example,
Bala et al. synthesized ellagic acid-loaded PLGA NP which showed a rapid initial release of EAC
in pH 7.4 phosphate buffer, followed by a slower sustained release [88]. Further, the authors tested
the influence of the stabilizers p-dimethylaminobenzaldehyde (DMAB) and polyvinyl alcohol (PVA)
on size, loading efficacy, release kinetics in PBS, stability, cytotoxic activity and in situ intestinal
permeability of these nanoparticles [88]. A similar study was conducted also on ellagic acid-loaded
PLGA-polycaprolactone (PCL)NP [89]. Both investigations resulted in improved tannin bioavailability
with potential therapeutic applications. In the last few decades, there has been considerable interest
in the active compounds in turmeric called curcuminoids, among which the most abundant is
curcumin (90%), studied for its antioxidant, anti-inflammatory, anticancer, antiviral, and antifungal
properties [90]. However, a very small percentage of the orally administered curcumin is detected in
blood plasma, while the vast majority is eliminated in the feces and the urine [67]. Several recent in vitro
studies have suggested that the anti-inflammatory action of curcumin may be linked to its ability to
limit the production of inflammatory mediators [91–93], inhibit extracellular matrix degradation and
chondrocyte apoptosis [94], and act as an anti-oxidant by decreasing the over-production of reactive
oxygen species [95]. Zhang et al. demonstrated in vivo that topical application of curcumin NP was
efficacious not only in slowing osteoarthritis disease progression, but also on pain relief [96]. Using a
post-traumatic osteoarthritis mouse model, they showed that the topical application of curcumin
encapsulated in hydrogel/glass based NP preserves the chondroprotective activity of curcumin,
and may increase its bioavailability (Figure 4).
Int. J. Mol. Sci. 2017, 18, 709
7 of 23
Int. J. Mol. Sci. 2017, 18, 709
7 of 23
Int. J. Mol. Sci. 2017, 18, 709
7 of 23
Int. J. Mol. Sci. 2017, 18, 709
7 of 23
Figure 4. Topical application of nanoencapsulated curcumin slowed the progression of
Figure 4. Topical application of nanoencapsulated curcumin slowed the progression of osteoarthritis
osteoarthritis induced by destabilization of the medial meniscus (DMM) in mice. Mice with DMM
induced
destabilization
of topical
the medial
meniscus
mice. Mice with
DMM were
werebytreated
daily with
application
of (DMM)
curcuminin nanoparticles
or vehicle.
Mice treated
treated daily
with topically
topical application
of
curcumin
nanoparticles
or
vehicle.
Mice
treated
topically
with
curcumin
with curcumin nanoparticles (Nano-C) exhibited improved Safranin O staining (A); lower
nanoparticles
(Nano-C)
exhibited
improved Safranin
staining
Osteoarthritis
Osteoarthritis
Research
Society International
(OARSI)Oscores
(B); (A);
and lower
reduced
synovitis (C); Research
and
Figure
4. International
Topical application
nanoencapsulated
curcumin
slowed
the(C);
progression
subchondral
bone (OARSI)
plate ofthickness
eight
weeks after
surgery
compared
toof that in vehicle
Society
scores(D)
(B);atand
reduced
synovitis
and subchondral
bone plate
osteoarthritis induced by destabilization of the medial meniscus (DMM) in mice. Mice with DMM
control
(Veh)
(* p <weeks
0.05, t-test,
= 5/group).
Reproduced
from
[96] (https://www.ncbi.nlm.nih.gov/
thickness
(D)
at eight
afternsurgery
compared
to that
in vehicle
control (Veh) (* p < 0.05, t-test,
were treated daily with topical application of curcumin nanoparticles or vehicle. Mice treated
pmc/articles/PMC4891896).
Figure
4.
Topical
application
of
nanoencapsulated
curcumin
slowed
the progression of
n
=
5/group).
Reproduced
from
[96]
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891896).
topically with curcumin nanoparticles (Nano-C) exhibited improved Safranin O staining (A); lower
osteoarthritis induced by destabilization of the medial meniscus (DMM) in mice. Mice with DMM
Osteoarthritis Research Society International (OARSI) scores (B); and reduced synovitis (C); and
were treated
topical an
application
of curcumin
nanoparticles
or vehicle. Mice
treated
Wangdaily
et al.with
reported
increment
in curcumin
anti-inflammatory
activity
when formulated in
subchondral bone plate thickness (D) at eight weeks after surgery compared to that in vehicle
Wang
et al.
reported
an increment
in
curcumin
anti-inflammatory
activity
when
formulated
topically
with
curcumin
nanoparticles
(Nano-C)
exhibited
improved
Safranin
O staining
(A);
lowervastly
oil
in
water
(o/w)
nanoemulsions
[97].
Emulsion-based
formulations
have
been
employed
in in
control (Veh) (* p < 0.05, t-test, n = 5/group). Reproduced from [96] (https://www.ncbi.nlm.nih.gov/
Osteoarthritis
Research
Society
International
(OARSI)
scores
(B);
and
reduced
synovitis
(C);
and
oil pmc/articles/PMC4891896).
inpharmaceutical,
water (o/w) nanoemulsions
Emulsion-based
formulations
have been
vastly
employed
cosmetic and food[97].
industry
to protect active
ingredients against
external
factors,
to
subchondral bone plate
thicknessand
at eight
weeks after
compared
to that in vehicle
in pharmaceutical,
cosmetic
food
industry
to surgery
protect
active
ingredients
against
external factors,
enhance their stability,
and (D)
to mask
bad
odors or
taste
[98].
Liposomes
have also
been employed
as
control (Veh) (* p < 0.05, t-test, n = 5/group). Reproduced from [96] (https://www.ncbi.nlm.nih.gov/
Wang
et al.
reported
an increment
in curcumin
anti-inflammatory
activity
when formulated
nanovectors
for curcumin
and
release
[99].[98].
Encapsulation
ofhave
curcumin
in liposomes,
to enhance
their
stability,
and encapsulation
to mask
bad odors
or taste
Liposomes
alsoinbeen
employed as
pmc/articles/PMC4891896).
oil in water
(o/w)using
[97]. Emulsion-based
formulations
have been
employed
obtained
commercially
available and
lecithin,
was[99].
reported
by vastly
Takahashi
et al.in [100].inResults
nanovectors
fornanoemulsions
curcumin
encapsulation
release
Encapsulation
of curcumin
liposomes,
pharmaceutical,
cosmetic
and food industry
to protect
active
ingredients against
external factors,
to
showed
that
encapsulated
curcumin
was
characterized
by
increased
bioavailability,
faster
Wang et
al. reported
an increment
in curcumin
anti-inflammatory
activity
when formulated
in Results
obtained
using
commercially
available
lecithin,
was
reported
by
Takahashi
et
al.
[100].
showed
enhance
their stability, and and
to mask
bad absorption
odors or taste
have also
been employed
as
pharmacokinetics
better
of[98].
theLiposomes
drug inhave
rats.
Overall,
Table 1 summarizes
the
oil
in
water
(o/w)
nanoemulsions
[97].
Emulsion-based
formulations
been
vastly
employed
in
that
encapsulated
curcumin
was
characterized
by
increased
bioavailability,
faster
pharmacokinetics
nanovectors for curcumin encapsulation and release [99]. Encapsulation of curcumin in liposomes,
nanosized
delivery
systems
used for
anti-inflammatory
properties.
pharmaceutical,
cosmetic
and
food industry
to polyphenols
protect active with
ingredients
against external
factors, to
and better
absorption
of the
drug in
rats. Overall,
Table
summarizes
nanosized
obtained
using
commercially
available
lecithin,
was reported
by1 Takahashi
et al.the
[100].
Results delivery systems
enhance their stability, and to mask bad odors or taste [98]. Liposomes have also been employed as
showed
that
encapsulated
curcumin
was characterized
by increased bioavailability, faster
used
for
polyphenols
with
anti-inflammatory
properties.
nanovectors for curcuminTable
encapsulation
anddelivery
release [99].
Encapsulation
of curcumin
in liposomes,
1. Nanosized
systems
for anti-inflammatory
polyphenols.
pharmacokinetics and better absorption of the drug in rats. Overall, Table 1 summarizes the
obtained using commercially available lecithin, was reported by Takahashi et al. [100]. Results
Bioactive
Principle
Nanovector
Type of Delivery System
Experimental Model
Reference
nanosized delivery
systems
used for polyphenols
with anti-inflammatory
properties.
Table 1.curcumin
Nanosized
delivery
systems
anti-inflammatory
polyphenols.
showed that encapsulated
was
characterized
by
increased
bioavailability,
faster
NP offor
soya
lecithin,
In vivo (rats)
[76]
and PEG Table 1 summarizes the
pharmacokinetics and better absorption of the drug in Tween-80
rats. Overall,
Quercetin
Table
1. Nanosized delivery systems for anti-inflammatory
polyphenols.
PLGA
NP
Bioactive
Principle
Type
of Delivery System
Experimental
Model
nanosized
delivery
systems used forNanovector
polyphenols with
anti-inflammatory
properties.
In vitro
[78] Reference
quercetin
Nanovector Nanoparticles
Type of Delivery containing
Experimental Model
Reference
NPSystem
of soya lecithin,
alcohol
In
vivo (rats)
NP of soya Eudragit-polyvinyl
lecithin,
In vitro
[79]
In vivo (rats)
[76]
Tween-80
and
PEG
Table 1. Nanosized delivery systems
for
anti-inflammatory
polyphenols.
NP
Tween-80 and quercetin-loaded
PEG
Quercetin
Quercetin
PLGA
NP
Quercetin-PLGA
NP
In
vivo
(rats)
[80]
PLGA
NP
Bioactive Principle
Nanovector
Type of Delivery System
Experimental
Reference
In vitroModel
[78]
In
vitro
Nanoparticlescontaining quercetin
Nanoparticles
quercetin
Lipid-coated
NC
NP of soyacontaining
lecithin,
Nanocapsules
In vitro
[77,78]
In
vivo
(rats)
[76]
Eudragit-polyvinylQuercetin-PLGA
alcohol
NC In vitro
Tween-80
and PEG
[79]
Eudragit-polyvinyl
alcohol
Quercetin
quercetin-loaded NP PLGA NP
In
vitro
In vivo
PLGAquercetin-loaded
NP
NP
[82]
In vitro
[78]
Quercetin-PLGA NP
In vivo
(rats)
[80]
containing quercetin
containing resveratrol
(Wistar male rats)
Nanoparticles
Resveratrol
Lipid-coated
NC
Quercetin-PLGA
NP
In
vivovivo
(rats)
Eudragit-polyvinylEudragit
alcohol RL 100 NP In vitro
In
vitro/In
[83]
NanocapsulesNanoparticles
[77,78]
In vitro
[79]
Quercetin-PLGA NC
quercetin-loaded
NP
Lipid-coated
NC
Carboxymethyl
PLGA NP NP
In vivo
vitro
vivo
(rats)
[84]
NanocapsulesQuercetin-PLGA
In vivo
(rats) In vitro/InIn
[80]
[82]
chitosan
NP
Quercetin-PLGA (Wistar
NC male rats)
containing resveratrol
Lipid-coated NC
Resveratrol
SLN
with a controlled
Nanocapsules
In vitrovivo
[77,78]
Nanoparticles Solid lipid
Eudragit RL
100
NPNP
In vitro/In
[83]
In vitro
[85]
PLGA
containing
Quercetin-PLGA
NC
In vivo (Wistar male rats)
Carboxymethyl release profile
nanoparticles
PLGA NP resveratrol In vitro/In
In vivo
vivo (rats)
[84]
Resveratrol loaded SLN
In vivo (Wistar[82]
male rats)
[86]
chitosan NP
containing resveratrol
(Wistar male rats)
Nanoparticles
Eudragit
100 NP
InInvitro/In
vivo
Resveratrol
Resveratrol
Cyclodextrins
CD-basedRL
nanosponges
vitro
[87]
SLN with a controlled
Nanoparticles
Eudragit RL 100 NP
In vitro/In
[83]
In vitrovivo
[85]
Solid lipid
release profileEllagic acid-loaded
Carboxymethyl
Carboxymethyl
nanoparticles
Ellagic acid
Nanoparticles
In vitro
[88]
vitro/In
vivo
(rats)
[84]
In vitro/In
vivo (rats)
Resveratrol loaded SLNPLGA NP
In In
vivo
(Wistar
male
rats)
[86]
chitosan NP chitosan NP
Cyclodextrins
CD-based nanosponges
In vitro
[87]
SLN with a controlled
[85]
Solid lipid
SLN
with a controlledIn vitro
Ellagic
acid-loaded
release
profile
In vitro
Ellagic acid
Nanoparticles
In vitro
[88]
Solid lipid
nanoparticles
PLGA NP release profile
Resveratrol
loaded
SLN
In
vivo
(Wistar
male
rats)
[86]
nanoparticles
Cyclodextrins
CD-based nanosponges
In vitro In vivo (Wistar
[87] male rats)
Resveratrol loaded SLN
Ellagic acid-loaded
Ellagic acid
Nanoparticles
In [88]
vitro
Cyclodextrins
CD-based nanospongesIn vitro
PLGA NP
Bioactive Principle
[76]
[78]
[79]
[80]
[77,78]
[82]
[83]
[84]
[85]
[86]
[87]
Int. J. Mol. Sci. 2017, 18, 709
8 of 23
Table 1. Cont.
Bioactive
Int. J. Mol. Sci.
2017, 18,Principle
709
Nanovector
acid
Ellagic18,
acid
Int. J. Mol. Sci.Ellagic
2017,
709
Type of Delivery System
Ellagic acid-loaded
Ellagic
PLGA NP
acid-loaded
PLGA NP
Experimental
8 of Model
23
In vitro
[88]
Reference
8 of 23
In vitro
[88]
Nanoparticles
Nanoparticles
In vivo (rats with
In vivo
(rats with
induced
nephrotoxicity)
induced
nephrotoxicity)In
ellagic acid NP
PLGA-PCL ellagic acid NP
PLGA-PCL ellagic acid NP
PLGA-PCL
Curcumin
Curcumin
Curcumin
[89]
vivo [89]
(rats with
induced nephrotoxicity)
In vivo (rats with
Hydrogel/glass
[96]
post-traumatic
osteoarthritis)
In vivo (rats
with In vivo (rats with
Hydrogel/glass
Hydrogel/glass
[96]
post-traumatic
osteoarthritis)
o/w nanoemulsion
post-traumatic osteoarthritis)
Nanoemulsions
containing
curcumin
In vitro
[98]
o/w nanoemulsion
o/w nanoemulsion
in the oilcurcumin
phase
Nanoemulsions
containing
In vitro
[98]
Nanoemulsions
curcumin
In vitro
Lipid
in the oilcontaining
phase
Lecithin liposomes
In vivo (rats)
[100]
in
the
oil
phase
nanoparticles
Lipid
Lecithin liposomes
In vivo (rats)
[100]
nanoparticles
polyethylene
glycol; PLGA, polylactic-co-glycolic acid; NC, nanocapsules;
Nanoparticles
Nanoparticles
Nanoparticles
[89]
[96]
[98]
NP, nanoparticles; PEG,
Lipid nanoparticles
Lecithin liposomes
In vivo (rats)
[100]
NP,solid
nanoparticles;
PEG, polyethylene
glycol; PLGA,
polylactic-co-glycolic
acid;
NC,
nanocapsules;
SLN,
lipid
nanoparticles;
CD,
cyclodextrins;
PCL,
polycaprolactone;
o/w,
oil
in
water.
NP, nanoparticles; PEG, polyethylene glycol; PLGA, polylactic-co-glycolic acid; NC, nanocapsules; SLN, solid lipid
SLN, solid lipid nanoparticles; CD, cyclodextrins; PCL, polycaprolactone; o/w, oil in water.
nanoparticles; CD, cyclodextrins; PCL, polycaprolactone; o/w, oil in water.
3.2. Phytocannabinoids
3.2. Phytocannabinoids
Phytocannabinoids
are defined as the lipophilic substances deriving from the hemp plant,
3.2.
Phytocannabinoids
Phytocannabinoids
are defined
as the lipophilic
substances
from the hemp
plant,
Cannabis
sativa L., (Cannabaceae).
The cannabis
extract contains
more deriving
than 460 compounds
of which
Cannabis
sativa
L.,
(Cannabaceae).
The
cannabis
extract
contains
more
than
460
compounds
of
which
Phytocannabinoids
areAmong
defined
as the
theprimary
lipophilic
substances
deriving from
the hemp plant,
around 70
are phytocannabinoids.
these,
psychoactive
phytocannabinoid
is
around 70 are phytocannabinoids.
these,
the primary
psychoactive
phytocannabinoid
is
Δ-9-tetrahydrocannabinol,
commonly Among
known as
Δ9-THC
[101], extract
while
other
analogs
available
are460
Cannabis sativa L., (Cannabaceae).
The
cannabis
contains
more
than
compounds of
Δ-9-tetrahydrocannabinol,
commonly
known as Δ9-THC [101],
while other analogs
availableIn
are
cannabidiol
(CBD), cannabigerol,
Δ-9-tetrahydrocannabivarin,
cannabidavirin
and cannabinol.
which
around
70
are
phytocannabinoids.
Among
these,
the
primary
psychoactive
phytocannabinoid
cannabidiol
(CBD),and
cannabigerol,
cannabidavirin
cannabinol.
®, a marketed and
particular,
Δ9-THC
CBD are theΔ-9-tetrahydrocannabivarin,
main components of Sativex
medicine
for theIn
®, a marketed
is
∆-9-tetrahydrocannabinol,
commonly
known
as
∆9-THC
[101],
while
other
particular,
Δ9-THC
and
CBD
are
the
main
components
of
Sativex
medicine
for theanalogs available
treatment of cancer pain [102]. Phytocannabinoids act by modulating cannabinoid receptors, which
treatment
of
cancer
pain
[102].
Phytocannabinoids
act
by
modulating
cannabinoid
receptors,
which and cannabinol.
are
cannabidiol
(CBD),
cannabigerol,
∆-9-tetrahydrocannabivarin,
cannabidavirin
are involved in fundamental physiological processes of central and autonomic nervous systems,
® , asystems,
are
in fundamental
physiological
of central
autonomic
nervous
In involved
particular,
∆9-THC
and
CBD
areprocesses
the main
components
of Sativex
marketed medicine for
immune,
endocrine,
reproductive
and
cardiovascular
activity
[103].and
Moreover,
phytocannabinoids
immune,
endocrine,
reproductive
and cardiovascular
activitythe
[103].
Moreover,Gphytocannabinoids
link
other
receptors
like
the potential
receptor,
deorphanized
protein-coupled
the
treatment
of cancer
painvanilloid
[102]. type-1
Phytocannabinoids
act by modulating
cannabinoid receptors,
link other
like the
potential vanilloid type-1
receptor,
theT-type
deorphanized
G protein-coupled
receptor,
thereceptors
peroxisome
proliferator-activated
receptors
and the
Ca2+ channel.
All these
which
are
involved
in
fundamental
physiological
processes
of
central
and
autonomic
receptor,
the peroxisome
proliferator-activated
receptors andresponse
the T-type
Ca2+ channel.
All also
these nervous systems,
targets
regulate
the anti-nociceptive
and anti-inflammatory
(Figure
3) but are
immune,
endocrine,
reproductive
cardiovascular
activity
[103].
phytocannabinoids
targets
regulate
the of
anti-nociceptive
andand
anti-inflammatory
response
(Figure
3)Moreover,
but are
also
involved
in
the control
sleep [104], obesity
[105],
epilepsy [106], breast
cancer
cell migration
[107],
involved
in
the
control
of
sleep
[104],
obesity
[105],
epilepsy
[106],
breast
cancer
cell
migration
[107],
link
other
receptors
like
the
potential
vanilloid
type-1
receptor,
the
deorphanized
and lipid and glucose metabolism [108]. Further, innumerable therapeutic indications have been G protein-coupled
and
lipidfor
and
glucose
metabolism
[108].asFurther,
innumerable
therapeutic
indications
have
been
reported
phytocannabinoids
such
analgesic,
anticonvulsant,
hypnotic,
tranquilizer,
receptor,
the
peroxisome
proliferator-activated
receptors
and
the T-type
Ca2+
channel. All these
reported
for
phytocannabinoids
such
as
analgesic,
anticonvulsant,
hypnotic,
tranquilizer,
anesthetic,
anti-inflammatory,
antibiotic,
antiparasite,
antispasmodic,
nausea
relieving,
appetite
targets regulate the anti-nociceptive and anti-inflammatory response (Figure 3) but are also involved
anesthetic,diuretic,
anti-inflammatory,
antiparasite,
nausea extract
relieving,
stimulant,
antitussive antibiotic,
and expectorant
[109].antispasmodic,
However, cannabis
is appetite
today
in the control
ofantitussive
sleep [104],
obesity
[105],
epilepsy
[106],
breast
cancer
cell migration [107],
stimulant,
diuretic,
and
expectorant
[109].
However,
cannabis
extract
is today
considered as a potential drug of abuse, and medicine uses nanotechnology to specifically target
the
andprinciple
lipidasand
glucose
metabolism
[108].
Further,
innumerable
therapeutic
have been
considered
a potential
drug
of abuse, and
medicine
usesside
nanotechnology
to specifically
target
the
active
avoiding
the
psychotropic
action
and other
effects.
For example,
Esposito
etindications
al.
active
principle
avoiding the
psychotropic
action
and
other to
side
effects. Forphytocannabinoids
example,
Espositotranquilizer,
etinal.
reported
phytocannabinoids
such
asaanalgesic,
anticonvulsant,
hypnotic,
anesthetic,
described
thefor
development
and
optimization
of
method
encapsulate
described
the lipid
development
and optimization
a method
to encapsulate
phytocannabinoids
in
nanostructured
carriers
[110].
Such
vectorsofwere
produced
by a melt
and ultrasonication
anti-inflammatory,
antibiotic,
antiparasite,
antispasmodic,
nausea
relieving, appetite
stimulant,
nanostructured
lipid
carriersto [110].
Such
vectors were
produced
by a encapsulation
melt and ultrasonication
protocol
specifically
designed
optimize
nanoparticle
recovery
and
drug
efficiency
diuretic, antitussive and expectorant [109]. However, cannabis extract is today considered as a
protocol
specifically
nanoparticle
recovery
and drugcarrier
encapsulation
efficiency
[110].
Similarly,
Durandesigned
Lobato to
et optimize
al. proposed
a valuable
oral delivery
for cannabinoid
potential
drug of abuse,
and
uses
nanotechnology
to carrier
specifically
target the active principle
[110]. Similarly,
et medicine
al. based
proposed
a valuable
oral delivery
cannabinoid
derivatives
againstDuran
chronicLobato
pain states
on lipid
NP formulations
[111].
Suchfor
vectors
were
avoiding
the
psychotropic
action
and
other
side
effects.
For
example,
Esposito
et al. described the
derivatives
againstsolvent-emulsion
chronic pain states
based on and
lipidoptimized
NP formulations
[111].
vectors were
developed
through
evaporation,
regarding
the Such
physicochemical
developed
through
solvent-emulsion
evaporation,
and
optimized
regarding
the
physicochemical
development
and
optimization
of aunder
method
to encapsulate
phytocannabinoids
properties,
long-term
stability,
and integrity
simulated
gastric conditions.
In particular, the in nanostructured
properties,
long-term
stability,
and inclusion
integrity
simulated
In for
particular,
selection
of the
lipid
core
and the
ofproduced
lecithin
proved
beconditions.
key factors
the finalthe
lipid carriers
[110].
Such
vectors
wereunder
by gastric
a to
melt
and
ultrasonication
protocol specifically
selection
of
the
lipid
core
and
the
inclusion
of
lecithin
proved
to
be
key
factors
for
the final
properties
of
encapsulation,
integrity,
and
performance
of
the
carriers
[111].
The
same
authors
designed to optimize nanoparticle recovery and drug encapsulation efficiency [110]. Similarly,
properties
of encapsulation,
integrity,Inand
performance
the surface-modified
carriers [111]. The
same authors
prepared
surface
modified PLGANP.
particular,
plainofand
particles
were
Duran Lobato
al. proposed
oral delivery
carrier for cannabinoid
derivatives against
prepared
surface et
modified
PLGANP.a valuable
In particular,
surface-modified
were
successfully
developed
using a nanoprecipitation
method, plain
using and
chitosan
(CS), Eudragitparticles
RS, lecithin
chronic
pain
states
based
on
lipid
NP
formulations
[111].
Such
vectors
were
developed
through
successfully
developed
using
a
nanoprecipitation
method,
using
chitosan
(CS),
Eudragit
RS,
lecithin
and vitamin E as surface modifying agents. The nanoparticles exhibited mean particle size
and
vitamin
E
as
surface
modifying
agents.
The
nanoparticles
exhibited
mean
particle
size
solvent-emulsion
optimized
regarding
properties, long-term
distributions
in the rangeevaporation,
of 253–344 nm,and
spherical
shape and
controlledthe
zetaphysicochemical
potential values. High
distributions
in the range
of 253–344
nm, spherical
shape
and controlled
zeta lecithin
values.
values
of entrapment
efficiency
were obtained
for all
the formulations,
while
and
vitamin
stability,
and
integrity
under
simulated
gastric
conditions.
In potential
particular,
theHigh
selection of the lipid
values of entrapment
efficiency
were
obtained
all the
formulations,
while formulations
lecithin and vitamin
E-modified
particles
showed
higher
release
rates for
when
compared
to the for
other
[112]. of encapsulation,
core
and
the
inclusion
of
lecithin
proved
to
be
key
factors
the
final
properties
E-modified
showed
release
rates when
compared
to the other
[112].
Hernán
Pérezparticles
de la Ossa
et al. higher
developed
cannabidiol
loaded
PCL particles
as aformulations
suitable dosage
integrity,
of the cannabidiol
carriers [111].
same
prepared
Hernán
Pérezand
de the
laperformance
Ossa
et al. developed
loaded The
PCL
particlesauthors
as a These
suitable
dosage surface modified
form,
prepared
by
oil-in-water
emulsion–solvent
evaporation
technique
[113].
vectors
PLGANP.
In by
particular,
plainemulsion–solvent
and surface-modified
particles
form,
prepared
the oil-in-water
evaporation
techniquewere
[113].successfully
These vectors developed using
had
high
entrapment
efficiency
(around
100%).
CBD
dissolved
in
the
polymeric
matrix
the
a nanoprecipitation method, using chitosan (CS), Eudragit RS, lecithin
andofvitamin
E as surface
modifying agents. The nanoparticles exhibited mean particle size distributions in the range of 253–344
nm, spherical shape and controlled zeta potential values. High values of entrapment efficiency
Int. J. Mol. Sci. 2017, 18, 709
9 of 23
were obtained for all the formulations, while lecithin and vitamin E-modified particles showed
higher release rates when compared to the other formulations [112]. Hernán Pérez de la Ossa et al.
developed cannabidiol loaded PCL particles as a suitable dosage form, prepared by the oil-in-water
emulsion–solvent evaporation technique [113]. These vectors had high entrapment efficiency (around
100%). CBD dissolved in the polymeric matrix of the microspheres was slowly released in vitro
within ten days. The results suggested that PCL particles were an alternative delivery system for
long-term cannabinoid administration [94]. Martín-Banderas et al. produced ∆9-THC-loaded PLGA
Int. J. Mol. Sci. 2017, 18, 709
9 of 23
nanoparticles [114]. The nanoformulation was further improved by surface functionalization with CS
andmicrospheres
PEG, to optimize
the pharmacokinetics.
Encapsulation
efficiency
(around
95%)particles
was not affected by
was slowly
released in vitro within
ten days. The results
suggested
that PCL
delivery
system
for long-term
cannabinoid
administration
[94]. Martín-Banderas
thewere
typeanofalternative
polymeric
coating.
However,
CS and
PEG coatings
decreased
and increased, respectively,
al. produced
Δ9-THC-loaded
PLGA
nanoparticles
[114]. The formulations
nanoformulation
was
further
theet∆9-THC
release
kinetics. The
safety
of all PLGA-based
was
confirmed
by in vivo
improved by surface functionalization with CS and PEG, to optimize the pharmacokinetics.
compatibility studies; moreover, protein adsorption tests suggested that PEGylation protected the
Encapsulation efficiency (around 95%) was not affected by the type of polymeric coating. However,
phytodrug
against
immune
[114].
Table 2 the
actsΔ9-THC
as a summary
of synthesized
CS and PEG
coatings
decreasedprocesses
and increased,
respectively,
release kinetics.
The safety nanosized
delivery
systems forformulations
phytocannabinoids.
of all PLGA-based
was confirmed by in vivo compatibility studies; moreover, protein
adsorption tests suggested that PEGylation protected the phytodrug against immune processes
[114]. Table 2 Table
acts as2.
a summary
of delivery
synthesized
nanosized
delivery systems for
phytocannabinoids.
Nanosized
systems
for anti-inflammatory
phytocannabinoids.
Table 2. NanosizedNanovector
delivery systems for
anti-inflammatory
phytocannabinoids.
Bioactive Principle
Type
of Delivery System
Experimental Model
Bioactive Principle
∆-9-Tetrahydrocannabinol
Δ-9-Tetrahydrocannabinol
Nanovector
Type of Delivery
System
Experimental Model
Reference
Nanostructured
Lipid nanoparticles
In vitro
Nanostructured
lipid carriers
Lipid nanoparticles
In vitro
[110]
lipid carriers
Lipid NP
In vitro
Lipid NP
containing lecithin
In vitro
[111]
containing lecithin
PLGA
NP
In
vitro/In
vivo
PLGA NP
In vitro/In vivo
[112]
Nanoparticles
loaded loaded
Nanoparticles Cannabidiol
Cannabidiol
In vitro
In vitro [113]
PCL NPPCL NP
Δ9-THC-loaded
In vivo (immunocompetent
[114]
In vivo (immunocompetent
PLGA NP
∆9-THC-loaded
PLGA NPC57BL/6 mice)
C57BL/6 mice)
Reference
[110]
[111]
[112]
[113]
[114]
3.3. Phytosterols
3.3. Phytosterols
Phytosterols (plant sterols and stanols) are naturally occurring compounds ubiquitously found
in vegetable oils, cereal grains, nuts, legumes, fruits, and vegetables. In particular, the term
Phytosterols (plant sterols and stanols) are naturally occurring compounds ubiquitously found
phytosterol refers to more than 200 different compounds among which sitosterol, campesterol,
in sitostanol
vegetableand
oils,
cereal grains, nuts, legumes, fruits, and vegetables. In particular, the term
campestanol are the most diffused. Phytosterols have various bioactive properties
phytosterol
refers
to more than effect
200 different
compounds
amongcholesterol
which sitosterol,
such as blood cholesterol-lowering
via partial inhibition
of intestinal
absorption, campesterol,
anti-atherogenic
effects and,are
particularly
for β-sitosterol,
immune have
stimulating
anti- properties
sitostanol
and campestanol
the most diffused.
Phytosterols
variousand
bioactive
inflammatory
activities. Furthermore, several
have suggested
theofbeneficial
effects
of plant absorption,
such
as blood cholesterol-lowering
effect studies
via partial
inhibition
intestinal
cholesterol
sterols against the development of different types of cancer, such as colorectal, breast and prostate
anti-atherogenic
effects and, particularly for β-sitosterol, immune stimulating and anti-inflammatory
cancer [115]. Despite their structural similarity to cholesterol, their bioavailability is limited. In
activities.
Furthermore, several studies have suggested the beneficial effects of plant sterols against
particular, absorption is less than 2% for phytosterols, while it is 30–60% for cholesterol. On this
thebasis,
development
different typescan
of cancer,
suchcontribute
as colorectal,
breastthe
and
prostate cancer [115].
the use ofof nanotechnology
dramatically
improving
phytosterols
Despite
their structural
similarity
to cholesterol,
their
is limited. phytosterols
In particular, absorption
pharmacokinetics.
To this
aim, Leong
et al. prepared
andbioavailability
characterized water-soluble
nanodispersions.
In particular,
he studied
of fourfor
different
types of On
organic
is less
than 2% for
phytosterols,
whilethe
it effects
is 30–60%
cholesterol.
thisphases
basis, the use of
(hexane,
isopropyl
alcohol,
ethanol,
and
acetone),
their
ratio
with
the
aqueous
phase
and
the use of
nanotechnology can dramatically contribute improving the phytosterols pharmacokinetics.
To this
conventional homogenization vs. high-pressure homogenization on the vectors obtained.
aim, Leong et al. prepared and characterized water-soluble phytosterols nanodispersions. In particular,
Phytosterol nanodispersions were finally produced by emulsification-evaporation using hexane
he [116].
studied
theeteffects
of four different
types
of organic
(hexane, isopropyl
ethanol,
Rossi
al. synthesized
phytosterols
colloidal
particlesphases
using antisolvent
precipitationalcohol,
in
andpresence
acetone),
their
ratio
with
the
aqueous
phase
and
the
use
of
conventional
homogenization
vs.
of a non-ionic surfactant. The resulting colloidal particles had rod-like shape with some
degree
of
crystallinity.
Moreover,
the
colloidal
dispersions
had
good
stability
ensured
by
surface
high-pressure homogenization on the vectors obtained. Phytosterol nanodispersions were finally
charge, due
to the presence of water and hydroxyl
groups on
the particle
and by steric phytosterols
produced
by emulsification-evaporation
using hexane
[116].
Rossi surface,
et al. synthesized
stabilization, due to the use of a non-ionic stabilizer [117]. Turk et al. produced stable suspensions
colloidal particles using antisolvent precipitation in presence of a non-ionic surfactant. The resulting
of submicron particles of phytosterol by rapid expansion of a supercritical solution into aqueous
colloidal
rod-like
shapetowith
some
degree
crystallinity.
Moreover,
solutionparticles
using fourhad
different
surfactants
impede
growth
and of
agglomeration
of the
submicron the colloidal
dispersions
had
good
stability
ensured
by
surface
charge,
due
to
the
presence
of
water
particles. The obtained sizes were about 500 nm and, in most cases, a bimodal particle
sizeand hydroxyl
distribution
was
obtained.
Long-term
stability
studies
indicated
modest
particle
growth
over
groups on the particle surface, and by steric stabilization, due to the use of a non-ionic 12
stabilizer [117].
months
Table 3stable
showssuspensions
examples of of
nanosized
delivery
systems
for anti-inflammatory
Turk
et al. [118].
produced
submicron
particles
of phytosterol
by rapid expansion
phytosterols.
of a supercritical solution into aqueous solution using four different surfactants to impede growth
and agglomeration of the submicron particles. The obtained sizes were about 500 nm and, in most
Int. J. Mol. Sci. 2017, 18, 709
10 of 23
cases, a bimodal particle size distribution was obtained. Long-term stability studies indicated modest
12 months [118]. Table 3 shows examples of nanosized delivery
10 of 23 systems for
anti-inflammatory phytosterols.
particle
growth
over
Int.
J. Mol. Sci.
2017, 18, 709
Table 3. Nanosized delivery systems for anti-inflammatory phytosterols.
Bioactive Principle
Table
Bioactive Principle
Nanovector delivery
Type of
Deliveryfor
System
Experimental Model
Reference
3. Nanosized
systems
anti-inflammatory
phytosterols.
Nanovector
Nanodispersion produced by
emulsification-evaporation
Type of Delivery System
In vitro
Nanodispersion produced by
Colloidal
particles using
emulsification-evaporation
In vitro
Phytosterol
Phytosterol
antisolvent precipitation
Nanodispersion
Nanodispersion
Colloidal particles using
antisolvent precipitation
Suspensions of submicron
Suspensions
of submicron
particles
of phytosterol
particles of phytosterol
[116]
Experimental Model
In vitro
Reference
In vitro
[116]
In vitro
[117]
In vitro
[118]
[117]
[118]
3.4. Carbohydrates
3.4. Carbohydrates
Carbohydrates are one of the major components of plants and are essential to the proper growth
andCarbohydrates
developmentare
of one
vegetables.
In fact,
carbohydrate
components
maketoup
of the primary
of the major
components
of plants
and are essential
the90%
proper
cell wall
are critical
to wall function.
Three typescomponents
of polysaccharides,
i.e.,
growth
andand
development
of vegetables.
In fact, carbohydrate
make up 90%
of high
the molecular
primary
cell wall and aremainly
critical contribute
to wall function.
Three
types of pectin,
polysaccharides,
i.e., high
weight carbohydrates,
to plant
structure:
hemicelluloses
and cellulose.
molecular
weight
carbohydrates,
mainly
contribute
to
plant
structure:
pectin,
hemicelluloses
and
Pectins are most abundant in the plant primary cell walls and in the middle lamellae,
and are
cellulose.
most abundant
in the plant acid.
primaryHemicelluloses
cell walls and in the
lamellae,
and
defined Pectins
by theare
presence
of galacturonic
andmiddle
cellulose
represent
the pure
are defined by the presence of galacturonic acid. Hemicelluloses and cellulose represent the pure
structural portion of the plants and are differentiated by the fact that hemicelluloses are small,
structural portion of the plants and are differentiated by the fact that hemicelluloses are small,
branched carbohydrate compounds made of different monosaccharides, while cellulose is made
branched carbohydrate compounds made of different monosaccharides, while cellulose is made of
of long
unbranched
composed
exclusively
of held
glucose,
heldbytogether
bybonds.
hydrogen bonds.
long
unbranched
fibrils fibrils
composed
exclusively
of glucose,
together
hydrogen
Moreover,hemicellulose
hemicellulose
synthesized
theGolgi,
Golgi,while
whilecellulose
celluloseisissynthesized
synthesizedininthe
the cytoplasm,
Moreover,
is issynthesized
in inthe
near the plasma
membrane
[119]. Many
plant
polysaccharides
have a strong
action.
cytoplasm,
near the
plasma membrane
[119].
Many
plant polysaccharides
have aanti-inflammatory
strong antiinflammatory
action.
For
example,
such
as
Echinacea
purpurea
and
Echinacea
angustifolia
(Asteraceae)
For example, such as Echinacea purpurea and Echinacea angustifolia (Asteraceae) that are known for their
that
are known for their and
immunostimulating
skin repairing
Aqueous
fractions
immunostimulating
skin repairingand
properties
[120].properties
Aqueous[120].
fractions
obtained
from the roots
obtained from the roots of these asteraceae contain echinacin, a polysaccharide with promising antiof these asteraceae contain echinacin, a polysaccharide with promising anti-inflammatory activity
inflammatory activity in the skin of mice subjected to croton oil induced inflammation. A pectin
in the skin of mice subjected to croton oil induced inflammation. A pectin isolated from the aerial
isolated from the aerial parts of Comarum palustre (Rosaceae), the comaruman, was found to possess
parts
of Comarum palustre
(Rosaceae), theactivity.
comaruman,
was found
possess immunomodulating
and
immunomodulating
and anti-inflammatory
In particular,
the to
galacturonan
fragments
anti-inflammatory
activity.
In
particular,
the
galacturonan
fragments
obtained
by
partial
hydrolysis
of
obtained by partial hydrolysis of pectin (with molecular weight up to 10 kDa) were able to decrease
pectin
molecular
up toto10fibronectin
kDa) weretoable
to decrease
vitrothetheparent
adhesion
of neutrophils
in
vitro(with
the adhesion
of weight
neutrophils
a greater
extentinthan
pectin
[121,122].
Popov et
a preventive
of comaruman
on aceticPopov
acid-induced
to fibronectin
toal.
a demonstrated
greater extent
than the effect
parent
pectin [121,122].
et al. colitis
demonstrated a
in
mice [123].effect
The oral
of this
pectin
for two dayscolitis
prior to
of colitis
reduces
preventive
of administration
comaruman on
acetic
acid-induced
ininduction
mice [123].
The oral
administration
neutrophil infiltration and enhances colon-bound mucus compared with the vehicle-treated colitis
of this pectin for two days prior to induction of colitis reduces neutrophil infiltration and enhances
group.
colon-bound mucus compared with the vehicle-treated colitis group.
The sulfated polysaccharides like xylose, glucose, arabinose, galactose and galactosamine
The
sulfated tripartita
polysaccharides
likeshowed
xylose,anti-inflammatory
glucose, arabinose,
galactose
galactosamine
present
present
in Artemisia
(Asteraceae)
properties
dueand
to their
ability
in
Artemisia
tripartita
(Asteraceae)
showed
anti-inflammatory
properties
due
to
their
ability
to alter
to alter macrophage function, neutrophil count, and complement fixation function [124]. However,
macrophage
function,
neutrophil
count,
and
complement
fixation
function
[124].
However,
the
most
the most recent studies on nano-delivery of anti-inflammatory carbohydrates deal with the fresh
extract
Aloe vera,
succulent plant of
native
to northern Africacarbohydrates
that has rapidlydeal
spread
across
the extract of
recentofstudies
on anano-delivery
anti-inflammatory
with
the fresh
world
[125].aIn
particular,plant
the fresh
gel to
mainly
consists
of water
and mesophyll
cells (0.9%
Aloe vera,
succulent
native
northern
Africa
that(99.1%)
has rapidly
spread across
the world [125].
dry
matter) with
the predominant
sugar represented
by mannose
as mannose-6-phosphate,
In particular,
the fresh
gel mainly consists
of water (99.1%)
and mesophyll
cells (0.9% dry matter) with
followed by other sugars in varying concentrations. Overall, arabinose, xylose, mannose, galactose,
the predominant sugar represented by mannose as mannose-6-phosphate, followed by other sugars
and glucose account for 69.2% of the total [125]. Liposomes containing Aloe vera gel having intrinsic
in varying concentrations. Overall, arabinose, xylose, mannose, galactose, and glucose account for
anti-inflammatory action, and with particle size of 200 nm have been prepared by Takahashi et al.
69.2%
of theskin
totalcollagen
[125]. Liposomes
containing
veracell
gel having
intrinsic
anti-inflammatory
action,
to
enhance
synthesis and
growth Aloe
of skin
lines [126].
Encapsulation
and
and with particle
sizeextract
of 200onnm
have
beenforprepared
by Takahashi
et al.
enhance
stabilization
of Aloe vera
cotton
fabric
wound dressing
application
hasto
been
recentlyskin collagen
accounted
[127].
Moreover,
co-encapsulation
of Aloe
vera with curcumin
enhanced the delivery
synthesisfor
and
growth
of skin
cell lines [126].
Encapsulation
and stabilization
of Aloe vera extract
of
the
phytocompounds
and
their
antioxidant
activity
[128].
Esmaeili
et
al.
prepared
polyamide
NC Moreover,
on cotton fabric for wound dressing application has been recently accounted
for [127].
co-encapsulation of Aloe vera with curcumin enhanced the delivery of the phytocompounds and
their antioxidant activity [128]. Esmaeili et al. prepared polyamide NC containing Aloe vera by
Int. J. Mol. Sci. 2017, 18, 709
11 of 23
Int. J. Mol. Sci. 2017, 18, 709
11 of 23
the emulsion diffusion technique. In particular, sebacoyl chloride, Aloe vera extract and olive oil
containing
Aloe vera
the emulsion
diffusion
technique.
particular,
sebacoyl
chloride,
Aloe verasulfoxide,
were dissolved
inby
a complex
organic
phase
made ofInacetone,
ethyl
acetate
and dimethyl
extract
and
olive
oil
were
dissolved
in
a
complex
organic
phase
made
of
acetone,
ethyl
acetate
while diethylenetriamine was solubilized in water to form the aqueous phase. Tweenand
and gelatin
dimethyl
sulfoxide,
while diethylenetriamine
was solubilized
in water
to form
the aqueous
phase.
were used
as stabilizers.
Nanocapsule dimensions
depended
on the
polymer
to oil ratio,
the relative
Tween
andofgelatin
were and
usedplant
as stabilizers.
Nanocapsule
depended
on the
polymer to
amount
polymers
extract and
the use ofdimensions
surfactants.
Optimized
conditions
resulted in
oilnanocapsules
ratio, the relative
amount
of
polymers
and
plant
extract
and
the
use
of
surfactants.
Optimized
of 115 nm [129]. Table 4 summarizes the available nanosized vectors for carbohydrates
conditions resulted in nanocapsules of 115 nm [129]. Table 4 summarizes the available nanosized
with anti-inflammatory activity derived from plants.
vectors for carbohydrates with anti-inflammatory activity derived from plants.
Table 4. Nano sized delivery systems for anti-inflammatory carbohydrates.
Table 4. Nano sized delivery systems for anti-inflammatory carbohydrates.
Bioactive
Principle
Bioactive Principle
Nanovector
Nanovector
Mannose-6-phosphate
Mannose-6-phosphate
Liposomes
Liposomes
Nanocapsules
Nanocapsules
TypeType
of Delivery
System
of Delivery
System
Experimental
Experimental
Model
Reference
Reference
Model
Liposomes
containing
Liposomes
containing
AloeAloe
veravera
gel gel
Invitro
vitro
In
[123]
[123]
Liposomes
containing
Liposomes
containing
Aloe gel
veraco-encapsulated
gel co-encapsulated
Aloe vera
curcumin
withwith
curcumin
In
Invitro
vitro
[125]
[125]
In vitro
[126]
Polyamide NC
Polyamide NC
In vitro
[126]
3.5. Essential Oils
3.5. Essential Oils
Essential oils (EOs) are hydrophobic, volatile, natural, complex compounds characterized by a
oils (EOs)
are hydrophobic,
volatile, natural,
complex
compounds
characterized by
strong Essential
odor, formed
by aromatic
plants as secondary
metabolites.
Traditional
EOs extraction
techniques,
usuallyformed
based on
or hydro-distillation,
date back
to the middle
ages, when
theyextraction
a strong odor,
bysteam
aromatic
plants as secondary
metabolites.
Traditional
EOs
were
developed
in
Arabic
Spain.
Known
for
their
antibacterial
[130]
and
fungicidal
[131]
activity,
techniques, usually based on steam or hydro-distillation, date back to the middle ages, when they
and
fordeveloped
their fragrance
and flavor,
are also
employed
in food [130]
preservation
[132] and[131]
in activity,
were
in Arabic
Spain. they
Known
for their
antibacterial
and fungicidal
medicine
analgesic,
sedative,
anti-inflammatory,
and
localpreservation
anesthetic remedies
[133].
and for as
their
fragrance
and flavor,
they are alsospasmolytic
employed in
food
[132] and
in medicine
EOs
have
been
extensively
studied,
and
there
is
much
literature
regarding
their
desirable
as analgesic, sedative, anti-inflammatory, spasmolytic and local anesthetic remedies [133]. EOs have
properties, however they are also very sensitive to the effects of light, oxygen, humidity and high
been extensively studied, and there is much literature regarding their desirable properties, however
temperature, so that their applications are limited [134]. Novel technologies for the administration
they are also very sensitive to the effects of light, oxygen, humidity and high temperature, so that
of plant extracts may have remarkable advantages over conventional formulations in terms of
their applications are limited [134]. Novel technologies for the administration of plant extracts may
enhancement of solubility, bioavailability, protection from toxicity, enhancement of pharmacological
have remarkable
advantages
conventional
formulationsdistribution,
in terms ofsustained
enhancement
of solubility,
activity,
enhancement
of stability,over
improved
tissue macrophages
delivery,
bioavailability,
protection
toxicity, enhancement
of pharmacological
and
protection from
physical from
and chemical
degradation [135].
Parris et al. haveactivity,
reportedenhancement
the
of stability, of
improved
macrophages
sustained
delivery,
and method,
protection from
encapsulation
oregano tissue
and cassia
pure EOs distribution,
in corn zein NC
via phase
separation
physicalinand
chemical
degradation
[135].[136].
Parris
et al. have
reported
the encapsulation
of oregano
resulting
a fast
and high
yield procedure
Reportedly,
EOs
loaded particles
have limited
digestibility
the stomach,
slow release
in the
and more
rapidresulting
release ininthe
and cassiainpure
EOs in corn
zein NC
via small
phaseintestine,
separation
method,
a large
fast and high
intestine.
It is worth[136].
noticing
how, in their
encapsulated
form, little
if no
interaction
of the EO
yield procedure
Reportedly,
EOs
loaded particles
have
limited
digestibility
inwith
the stomach,
other
components
in
the
feed
was
found.
Zein,
a
prolamine
protein
found
in
maize,
known
for
its noticing
slow release in the small intestine, and more rapid release in the large intestine. It is worth
superior
biodegradability
and
biocompatibility,
has
also
been
used
to
nanoencapsulate
thymol
and
how, in their encapsulated form, little if no interaction of the EO with other components in the feed
carvacrol EOs via liquid–liquid dispersion method [137]. One of the most promising methods for
was found. Zein, a prolamine protein found in maize, known for its superior biodegradability and
the solubilization and stabilization of natural active agents involves the use of cyclodextrins (CD) as
biocompatibility, has also been used to nanoencapsulate thymol and carvacrol EOs via liquid–liquid
carriers [138]. In aqueous solution, the slightly polar CD cavity is occupied by water molecules and
dispersion method [137]. One of the most promising methods for the solubilization and stabilization
therefore they can be readily substituted by appropriate “guest molecules”, which are less polar
of natural
active
agentsetinvolves
use of cyclodextrins
(CD) as carriers
Inofaqueous
than
water [139].
Cevallos
al. have the
performed
studies on the encapsulation
and[138].
release
thymol solution,
thecinnamaldehyde
slightly polar from
CD cavity
is The
occupied
by water
and
they canthebe readily
and
CD [140].
importance
of thismolecules
work lays in
the therefore
studies concerning
substituted
by
appropriate
“guest
molecules”,
which
are
less
polar
than
water
[139].
Cevallos et al.
influence of water adsorption by CDs on the release of encapsulated compounds. Results
showed
have
performed
studiesappropriated
on the encapsulation
and release
thymol and flavors
cinnamaldehyde
from
the
relevance
of selecting
storage conditions
forofhydrophobic
encapsulated
in CD [140].
CD
for predicting
the
shelflays
lifeinof
products formulated
with
nanoencapsulated
Theorimportance
of this
work
thefunctional
studies concerning
the influence
of water
adsorption by CDs on
compounds.
Olivera
et al. reported
the preparation
of alginate/cashew
gum
NP via spray-drying,
the release of
encapsulated
compounds.
Results showed
the relevance
of selecting
appropriated storage
aiming
at
the
development
of
a
biopolymer
blend
for
encapsulation
of
Lippiasidoides
essential
oil,functional
conditions for hydrophobic flavors encapsulated in CD or for predicting the shelf life of
primarily
composed
of
thymol
(50–70%)
[141].
In
the
last
decades,
encapsulation
techniques
have
products formulated with nanoencapsulated compounds. Olivera et al. reported the preparation of
frequently been supported by innovative controlled and triggered release. Stimuli-responsive
alginate/cashew gum NP via spray-drying, aiming at the development of a biopolymer blend for
materials have therefore been employed as shell material for capsules and vector for drugs and
encapsulation of Lippiasidoides essential oil, primarily composed of thymol (50–70%) [141]. In the
last decades, encapsulation techniques have frequently been supported by innovative controlled and
triggered release. Stimuli-responsive materials have therefore been employed as shell material for
Int. J. Mol. Sci. 2017, 18, 709
12 of 23
capsules
and
vector
for drugs and other active agents [142]. Bizzarro et al. recently
reported
on the
Int.Int.
J. Mol.
Sci.
2017,
18,18,
709
1212
of of
2323
J. Mol.
Sci.
2017,
709
preparation of cumin and basil oil-loaded polyamide capsules able to release their cargo oil under
other
active
agents
[142].
Bizzarro
etet
al.al.
recently
onon
the
preparation
ofof
cumin
and
basil
oilother
active
agents
[142].
Bizzarro
recentlyreported
reported
the
preparation
cumin
and
basil
oil- capsules
UV-light
irradiation
[143].
Photo-responsive
as well
as
other
stimuli-responsive
polymeric
loaded
polyamide
capsules
able
to
release
their
cargo
oil
under
UV-light
irradiation
[143].
Photoloaded
polyamide
capsules
able
to
release
their
cargo
oil
under
UV-light
irradiation
[143].
Photohave been vastly reviewed in the literature [144]. Table 5 summarizes the nanosized delivery systems
responsive
asas
well
stimuli-responsive
polymeric
capsules
have
reviewed
inin
the
responsive
wellasasother
other
stimuli-responsive
polymeric
capsules
havebeen
beenvastly
vastly
reviewed
the
proposed
for
anti-inflammatory
essential oils.
literature
literature[144].
[144].Table
Table5 5summarizes
summarizesthe
thenanosized
nanosizeddelivery
deliverysystems
systemsproposed
proposedforforantiantiinflammatory
essential
oils.
inflammatory
essential
oils.
Table 5. Nanosized delivery systems for anti-inflammatory essential oils.
Table
5. 5.
Nanosized
delivery
systems
forfor
anti-inflammatory
essential
oils.
Table
Nanosized
delivery
systems
anti-inflammatory
essential
oils.
Bioactive Principle
Nanovector
Type of Delivery System
Experimental Model
Bioactive
Principle
Bioactive
Principle
Oregano
and
Cassia
EOEO
Oregano
and
Cassia
Thymol
and
carvacrol
Thymol
and
carvacrol
Thymol
and
carvacrol
Oregano and Cassia EO
Reference
Nanovector
of of
Delivery
System
Model
Nanovector Type
Type
Delivery
System Experimental
Experimental
Model Reference
Reference
Nanoparticles
Corn zein NP
In vitro
Nanoparticles
Corn
zein
NPNP
In In
vitro
[136]
Nanoparticles
Corn
zein
vitro
[136]
[136]
Nanoparticles
Nanoparticles
Nanoparticles
In In
vitro
vitro
[137]
[137]
In vitro
[137]
Cinnamon
and
thyme
EOEO
Cyclodextrins
Inclusion
in in
CD
In In
vitro
Cinnamon
and
thyme
Cyclodextrins
Inclusion
CD
vitro
Cinnamon and thyme EO
Cyclodextrins
Inclusion in CD
LippiasidoidesEO
(50–70%
Thymol)
gum
NPNP
In In
vitro
LippiasidoidesEO
(50–70%
Thymol) Nanoparticles
Nanoparticles Alginate/cashew
Alginate/cashew
gum
vitro
LippiasidoidesEO
(50–70%
Thymol)Nanocapsules
Nanoparticles Polyamide
Alginate/cashew
gum NP
Cumin
and
basil
EOEO
NC
In In
vitro
Cumin
and
basil
Nanocapsules
Polyamide
NC
vitro
[140]
[140]
[141]
[141]
In vitro
[143]
[143]
[141]
In vitro
[143]
Cumin and basil EO
Nanocapsules
Corn
zein
NPNPzein NP
Corn
zein
Corn
Polyamide NC
In vitro
[140]
3.6.
Terpenoids
3.6.
Terpenoids
Among
Amonga awide
widespectrum
spectrumofofnatural
naturalproducts,
products,terpenoids
terpenoidsplay
playa asignificant
significantrole
roleininprevention
prevention
3.6. Terpenoids
and
andtreatment
treatmentofofanti-inflammatory
anti-inflammatoryconditions.
conditions.These
Thesecompounds
compoundsare
areproduced
producedasassecondary
secondary
Amongofof
a different
wide
spectrum
of natural
terpenoids
play
a significant
role
in prevention and
metabolites
organisms,
such
lichens,
asaswell
metabolites
different
organisms,
suchasproducts,
asplants,
plants,mosses,
mosses,algae,
algae,
lichens,
wellas
asinsects,
insects,
microbes
InInrecent
ofofthe
microbesand
and
marineorganisms
organisms[145].
[145].
recentyears,
years,the
themolecular
molecularbasis
basis
theanti-inflammatory
anti-inflammatory
treatment
of marine
anti-inflammatory
conditions.
These
compounds
are
produced
as secondary metabolites
effect
ofofplant-derived
terpenoids
has
atatthe
center
ofofextensive
research.
Several
studies
effect
plant-derived
terpenoids
hasbeen
been
thealgae,
centerlichens,
extensive
research.
Several
studiesand marine
of
different
organisms,
such as plants,
mosses,
as well
as insects,
microbes
demonstrated
that
terpenoid
ingredients
can
suppress
nuclear
factor-κB
(NF-κB)
signaling,
the
demonstrated
that
terpenoid
ingredients
can
suppress
nuclear
factor-κB
(NF-κB)
signaling,
the
organisms [145]. In recent years, the molecular basis of the anti-inflammatory effect of
plant-derived
major
majorregulator
regulatorininthe
thepathogenesis
pathogenesisofofinflammatory
inflammatorydiseases
diseasesand
andcancer
cancer[146].
[146].Terpenoids
Terpenoidsare
area a
terpenoids has been at the center of extensive research. Several studies demonstrated that terpenoid
very
verydiverse
diversegroup
groupofofmolecules,
molecules,with
withextraordinary
extraordinaryvarying
varyingchemistry,
chemistry,structure
structureand
andfunction.
function.
ingredients
can suppress
nuclear
factor-κBthe
(NF-κB)
signaling,
the
major
regulator
in the
pathogenesis
These
number
Thesecompounds
compoundsare
areclassified
classifiedaccording
accordingtotothe
numberofofisoprene
isopreneunits
unitsand
andcarbon
carbonatoms
atoms[147].
[147].
of
inflammatory
diseases
cancer
[146]. Terpenoids
are a very
diverse
groupp-of
Notably,
the
terpenes
includes
D-limonene,
squalene,
linalool,
artemisinin,
Notably,
thelist
listofof
terpenesand
includes
D-limonene,
squalene,geraniol,
geraniol,
linalool,
artemisinin,
p- molecules,
with
extraordinary
varying
chemistry,
structure
and function.
These
compounds
are classified
cymene,
thymol
Targeted
ofoftypically
hydrophobic
terpenoids
has
cymene,
thymoland
andβ-carotene.
β-carotene.
Targeteddelivery
delivery
typically
hydrophobic
terpenoids
hasalso
also
been
the
subject
ofof
massive
research,
finding
applications
inin
a wide
variety
ofof
fields.
Among
natural
been
the
subject
massive
research,
finding
applications
a wide
variety
fields.
Among
natural
according
to the
number
of isoprene
units
and carbon
atoms
[147].
Notably,
the
list of terpenes
terpenoids,
squalene
is
one
of
the
most
widespread,
present
in
olives,
shark
liver
oil,
wheat
terpenoids,
squalene
is
one
of
the
most
widespread,
present
in
olives,
shark
liver
oil,
wheat
germ
includes D-limonene, squalene, geraniol, linalool, artemisinin, p-cymene, thymolgerm
and β-carotene.
and
applications
[148].
the
andeven
evenhuman
humanskin
skin
cells,and
andpossesses
possessesversatile
versatile
applications
[148].
Lacatusu
etal.al.reported
reported
the research,
Targeted
delivery
ofcells,
typically
hydrophobic
terpenoids
has
alsoLacatusu
been
theetsubject
of massive
design
designand
andcharacterization
characterizationofofsoft
softlipid
lipidnanocarriers
nanocarriersbased
basedononbioactive
bioactivepumpkin
pumpkinand
andamaranth
amaranth
finding applications in a wide variety of fields. Among natural terpenoids, squalene is one of the most
oils,
oils,rich
richininsqualene,
squalene,forforco-encapsulation
co-encapsulationand
andco-delivery
co-deliveryofofUV-A
UV-Aand
andUV-B
UV-Bfilters
filters(avobenzone
(avobenzone
widespread,
present
inThe
olives,
shark
liver
oil, reported
wheat
germ
even human
skin cells, and possesses
andoctocrylene)
[149].
group
later
the
preparation
ofofsqualene-based
andoctocrylene)
[149].
Thesame
same
group
later
reported
theand
preparation
squalene-based
versatile
applications
[148]. Lacatusu
et
al.delivery
reported
design and
nanocarriers
forforthe
and
ofofthe
hydrophilic
and
lipophilic
nanocarriers
theencapsulation
encapsulation
anddrug
drug
delivery
hydrophilic
andcharacterization
lipophilicactives,
actives,of soft lipid
nanocarriers
based
on bioactive
pumpkin
and
amaranth
rich in for
squalene,
co-encapsulation
confirming
protective
and
effect
ofof
squalene
sensitive
confirmingthe
the
protective
andstabilizing
stabilizing
effect
squaleneasoils,
asprotective
protective
forhighly
highlyfor
sensitive
molecules
[150].
On
other
hand,
squalene
can
also
bebe
employed
asas
active
agent.
Adamczak
al.al. group later
molecules
[150].
On
the
other
hand,
squalene
can
also
employed
active
agent.
Adamczak
et
and
co-delivery
ofthe
UV-A
and
UV-B
filters
(avobenzone
andoctocrylene)
[149].
The et
same
developed
a
method
of
preparation
of
polyelectrolyte
multilayer
capsules,
containing
squalene
developed
a
method
of
preparation
of
polyelectrolyte
multilayer
capsules,
containing
squalene
as
reported the preparation of squalene-based nanocarriers for the encapsulation andasdrug
delivery
hydrophobic
phase,
byby
membrane
emulsification
technique
[151,152].
InIn
that
work,
squalene
served
hydrophobic
phase,
membrane
emulsification
technique
[151,152].
that
work,
squalene
served
of hydrophilic and lipophilic actives, confirming the protective and stabilizing effect of squalene as
asasboth
bothactive
activeagent
agentand
andsolvent
solventcargo
cargoforforhydrophobic
hydrophobicdrug.
drug.Alongside
Alongsideitsitsanti-inflammatory
anti-inflammatory
protective
for highlybeen
sensitive molecules
[150]. On
the other hand, squalene
canhas
also be employed as
activity,
activity,squalene
squalenehas
has beenreported
reportedhaving
havingininvitro
vitrocytoprotective
cytoprotectiveactivity
activity[153],
[153],and
and hasbeen
been
active
Adamczak
et al.
developed
a method
of
preparation
ofcarotenoid
polyelectrolyte
multilayer
found
effective
forforalopecia
areata
treatment
[154].
is isa acarotenoid
showing
good
foundagent.
effective
alopecia
areata
treatment
[154].Lycopene
Lycopene
showing
good capsules,
containing
squalene
as hydrophobic
phase,
by and
membrane
emulsification
technique
[151,152].
In that
pharmacological
properties
including
commonly
found
inin
pharmacological
properties
includingantioxidant
antioxidant
andanti-inflammatory,
anti-inflammatory,
commonly
found
tomatoes,
red
carrots,
watermelons,
and
other
red
fruits
and
vegetables
AsAs
such,
lycopene
tomatoes,
red
carrots,
watermelons,
and
other
red
fruits
and
vegetables
[155,156].
such,
lycopene
work,
squalene
served
as both active
agent
and
solvent
cargo [155,156].
for
hydrophobic
drug.
Alongside its
has
a limited
systemic
absorption
due
toto
a very
low
aqueous
solubility.
overcome
this
drawback,
has
a limited
systemic
absorption
due
ahas
very
low
aqueous
solubility.
To
overcome
this
drawback,
anti-inflammatory
activity,
squalene
been
reported
havingToin
vitro
cytoprotective
activity [153],
lycopene
nanosized
delivery
systems
have
been
recently
engineered.
Butnariu
and
Giuchici
lycopene
nanosized
delivery
systems
have
been
recently
engineered.
Butnariu
and
Giuchici showing
and has been found effective for alopecia areata treatment [154]. Lycopene is a carotenoid
developed
developednanoemulsions
nanoemulsionsbased
basedononaqueous
aqueouspropolis
propolisand
andlycopene,
lycopene,which
whichwere
weretested
testedasas
good pharmacological properties including antioxidant and anti-inflammatory, commonly found
protective
protectiveagents
agentsagainst
againstacute
acuteUV-A-induced
UV-A-inducedinflammation
inflammationononratratpaw.
paw.AAbetter
bettertherapeutic
therapeuticeffect
effect
in
tomatoes,
red carrots,
watermelons,
andcoupled
other
red
fruits
andtime
vegetables
[155,156].
was
noticed
totoa astandard
with
extended
was
noticedcompared
compared
standardsuspension,
suspension,
coupled
with
extended
timeinterval
intervalof
oftested
tested As such,
lycopene has a limited systemic absorption due to a very low aqueous solubility. To overcome
this drawback, lycopene nanosized delivery systems have been recently engineered. Butnariu and
Giuchici developed nanoemulsions based on aqueous propolis and lycopene, which were tested
as protective agents against acute UV-A-induced inflammation on rat paw. A better therapeutic
Int. J. Mol. Sci. 2017, 18, 709
13 of 23
effect was noticed compared to a standard suspension, coupled with extended time interval of tested
parameters [157]. More recently, stable lycopene-loaded SLN based on myristic acid or orange wax
have been described, highlighting that chemical stability of lycopene entrapped in the SLN was
Int. J. Mol. Sci. 2017,
18, 709
13 (CD)
of 23 constitute
significantly
enhanced
[158,159]. As reported in the previous sections, cyclodextrins
Int. J. Mol. Sci. 2017, 18, 709
13 of 23
one
of
the
most
reliable
nanocarriers
for
hydrophobic
molecules,
such
as
essential
oils
and
Int. J. Mol. Sci. 2017, 18, 709
13 of
23 terpenoids.
Int. J. Mol. Sci. 2017,
709 recently, stable lycopene-loaded SLN based on myristic acid or orange
13 wax
of 23
parameters
[157].18,More
Forparameters
example,[157].
a method
to
load lycopene
into maltodextrin
and cyclodextrin
hasorbeen
recently
Morehighlighting
recently,
stable
lycopene-loaded
SLN
based
on myristic
acid
orange
wax proposed
have
been described,
thatlycopene-loaded
chemical stability
of based
lycopene
entrapped
inorthe
SLN wax
was
parameters
[157].
More
recently,
stable
SLN
oneffect
myristic
acid
orange
bysignificantly
Seo
et
al.
[160].
The
comparison
of
the
anti-inflammatory
of
nanoencapsulated
and free
parameters
[157].
Morehighlighting
recently, As
stable
lycopene-loaded
SLN
on myristic
acidinorthe
orange
have been described,
that
chemical
stability
of based
lycopene
entrapped
SLN wax
was
enhanced
[158,159].
reported
in thestability
previous
have been described,
highlighting
that
chemical
ofsections,
lycopenecyclodextrins
entrapped in(CD)
the constitute
SLN was
have
been
highlighting
chemical
stability
of sections,
lycopene
entrapped
in(CD)
thelycopene
SLN
lycopene
ondescribed,
macrophage
cell lines
demonstrated
that
nanoencapsulation
of
significantly
enhanced
[158,159].
Asthat
reported
in the
previous
cyclodextrins
constitute
one
of
the
most
reliable
nanocarriers
for hydrophobic
such
as essential
oils was
and can further
significantly
enhanced
[158,159].
As reported
in the previousmolecules,
sections, cyclodextrins
(CD) constitute
significantly
enhanced
[158,159].
As
reported
in
the
previous
sections,
cyclodextrins
(CD)
constitute
one of its
theanti-inflammatory
most
reliable
nanocarriers
forlycopene
hydrophobic
molecules,
such
as essential
oils been
and
terpenoids.
For
example,
a
method
to
load
into
maltodextrin
and
cyclodextrin
has
improve
effect
during
tissue-damaging
inflammatory
conditions.
one of the most reliable nanocarriers for hydrophobic molecules, such as essential oils and
one
of interaction
the
most
reliable
forp-cymene,
hydrophobic
molecules,
such
as
essential effect
oils been
and
terpenoids.
For
example,
a nanocarriers
method
to
load
lycopene
into
maltodextrin
and
cyclodextrin
has
recently
proposed
by
Seo
et
al.
[160].
The
comparison
of
the
anti-inflammatory
of
The
between
β-CD
and
one
of
the
main
anti-inflammatory
constituents
of
terpenoids. For example, a method to load lycopene into maltodextrin and cyclodextrin has been
terpenoids.
For example,
alycopene
method
to
load
lycopene
into
maltodextrin
andthat
cyclodextrin
has
been
recently proposed
byfree
Seo
et al. on
[160].
The
comparison
of the anti-inflammatory
effect
of
nanoencapsulated
and
macrophage
cell
lines
demonstrated
nanoencapsulation
thyme
andproposed
cumin EOs,
been
extensively
studied of
[161,162].
Encapsulationeffect
of p-cymene
in CD
recently
by has
Seo also
et al.
[160].
The comparison
the anti-inflammatory
of
recently
proposed
byfree
Seolycopene
et its
al. anti-inflammatory
[160].
The comparison
of thetissue-damaging
anti-inflammatory
effect of
nanoencapsulated
and
on
macrophage
celleffect
linesduring
demonstrated
that nanoencapsulation
of
lycopene
can further
improve
inflammatory
nanoencapsulated
and reported
free
lycopene
on macrophage
cell
linesThis
demonstrated
that nanoencapsulation
has
been
successfully
by
Quintans
et
al.
[163].
study
involved
the
oral
administration
of
nanoencapsulated
and free
lycopene
on macrophage celleffect
lines during
demonstrated
that nanoencapsulation
of lycopene can further
improve
its anti-inflammatory
tissue-damaging
inflammatory
conditions.
of lycopene caninclusion
further improve
its anti-inflammatory
effect
during
tissue-damaging
inflammatory inclusion
p-cymene/CD
complexes
to
inhibit
mice
edema.
Interestingly,
p-cymene/β-CD
of
lycopene
can further
improve
its and
anti-inflammatory
tissue-damaging inflammatory
conditions.
The interaction
between
β-CD
p-cymene, oneeffect
of theduring
main anti-inflammatory
constituents
conditions.
conditions.
provided
and EOs,
morehas
powerful
same
of freeofp-cymene
at early stage,
The faster
interaction
between
β-CDbeen
andinhibition
p-cymene, than
one
ofthe
the
main amount
anti-inflammatory
constituents
of
thyme
and
cumin
also
extensively
studied
[161,162].
Encapsulation
p-cymene
in
The interaction between β-CD and p-cymene, one of the main anti-inflammatory constituents
The interaction
between
β-CD
and
p-cymene,
one
ofal.the
main This
anti-inflammatory
of thyme
and cumin
EOs, hasreported
alsocan
been
extensively
studied
[161,162].
Encapsulation
of constituents
p-cymene
in
CD
has
been
successfully
by
Quintans
et
[163].
study
involved
the
oral
indicating
that
CD
nanocarriers
improve
p-cymene
anti-nociceptive
and
anti-inflammatory
effects.
of thyme and cumin EOs, has also been extensively studied [161,162]. Encapsulation of p-cymene in
of
thyme
and
cumin
EOs,
has
also
been
extensively
studied
[161,162].
Encapsulation
of
p-cymene
in
CD
has
been
successfully
reported
by
Quintans
et
al.
[163].
This
study
involved
the
oral
administration
of
p-cymene/CD
inclusion
complexes
to
inhibit
mice
edema.
Interestingly,
pOther
authors
thereported
encapsulation
of other
terpenoids
CD. Menezes
discussed the
CD has
been reported
successfully
by Quintans
et al.
[163]. Thisinstudy
involved et
theal.oral
CD
has beeninclusion
successfully
reported
by
et to
al. inhibition
[163]. This
involved
theof oral
administration
of p-cymene/CD
inclusion
complexes
inhibit
mice
edema.
Interestingly,
pcymene/β-CD
provided
andQuintans
more
powerful
thanstudy
the
same
amount
free
inclusion
complex
of β-CD
andfaster
(−)-linalool
[164], to
a monoterpene
alcohol
compound
administration
of p-cymene/CD
inclusion
complexes
inhibit mice
edema.
Interestingly,
p-prevalent in
administration
of stage,
p-cymene/CD
inclusion
complexes
to can
inhibit
mice
edema.
Interestingly,
pcymene/β-CD
inclusion
provided
faster
and
more
powerful
inhibition
than
the same
amount of free
p-cymene
at
early
indicating
that
CD
nanocarriers
improve
p-cymene
anti-nociceptive
cymene/β-CD
provided
faster
andspecies
more powerful
inhibition
than the
same amount
free
essential
oils
ofinclusion
various
aromatic
plant
[165]. can
Other
studies,
carried
out byof
cymene/β-CD
inclusion
provided
faster
and
powerful
inhibition
than
the
same
amount
ofQuintans-Júnior,
free
p-cymene
at early
stage,
indicating
that
CDmore
nanocarriers
improve
p-cymene
anti-nociceptive
and
anti-inflammatory
effects.
Other
authors
reported
the encapsulation
of
other
terpenoids
in
CD.
p-cymene
at
early
stage,
indicating
that
CD
nanocarriers
can
improve
p-cymene
anti-nociceptive
confirmed
that
(
−
)-linalool-CD
complexes
produced
superior
anti-nociceptive
effect,
p-cymene
at
early
stage,
indicating
that
CD
nanocarriers
can
improve
p-cymene
anti-nociceptive
and
anti-inflammatory
effects.
Other
authors
reported
the
encapsulation
of
other
terpenoids
in
CD.with respect
Menezes
et al discussed
the inclusion
complex
of β-CD
and (−)-linalool
[164],terpenoids
a monoterpene
and anti-inflammatory
effects.
Other authors
reported
the encapsulation
of other
in CD.
toalcohol
thatanti-inflammatory
ofcompound
(−al
)-linalool
alone,
in
experimental
pain
protocols
[166].
In
analogy
with
and
effects.
Other
authors
reported
the
encapsulation
of
other
terpenoids
in
CD.
Menezes
et
discussed
the
inclusion
complex
of
β-CD
and
(−)-linalool
[164],
a
monoterpene
prevalent
essential complex
oils of various
aromatic
plant species
[165].a Other
studies, this result,
Menezes et al discussed
theininclusion
of β-CD
and (−)-linalool
[164],
monoterpene
Menezes
et
al
discussed
the
inclusion
complex
of
β-CD
and
(−)-linalool
[164],
a
monoterpene
alcohol
compound
prevalent
in
essential
oils
of
various
aromatic
plant
species
[165].
Other
studies,
Guimarães
etbyal.Quintans-Júnior,
reported
the encapsulation
of carvacrol,
a terpenoid
phenol
present in the
carried
confirmed
that
(−)-linalool-CD
complexes
produced
superior
antialcohol out
compound
prevalentthat
in essential
oils
of various
aromatic
plant species
[165]. Other
studies,
alcohol
compound
prevalent
in
essential
oils
of
various
aromatic
plant
species
[165].
Other
studies,
carried
out
by
Quintans-Júnior,
confirmed
that
(−)-linalool-CD
complexes
produced
superior
antinociceptive
effect,
with
respect
to
that
of
(−)-linalool
alone,
in
experimental
pain
protocols
[166].
Incancer pain
essential
oilbyofQuintans-Júnior,
oregano, with
β-CD, that
improves
the pharmacological
response
carried out
confirmed
(−)-linalool-CD
complexes produced
superior on
anticarried
out
by
Quintans-Júnior,
confirmed
that (−)-linalool-CD
complexes of
produced
superior
antinociceptive
effect,
with respect
to
that
of
(−)-linalool
alone,
in
experimental
pain
protocols
[166].
In
analogy
with
this
result,
Guimarães
et
al.
reported
that
the
encapsulation
carvacrol,
a
terpenoid
experimental
protocols
[167]. to
It that
is worth
mentioning
the terpene-cyclodextrin
inclusion
systems
nociceptive effect,
with respect
of (−)-linalool
alone,that
in experimental
pain protocols [166].
In
nociceptive
effect,
withessential
respect
to that
of
alone,
in
experimental
protocols
[166]. In
analogypresent
with
this
result,
Guimarães
etoregano,
al.(−)-linalool
reported
that
theimproves
encapsulation
ofpain
carvacrol,
a terpenoid
phenol
in
the
oil
of
with
β-CD,
the
pharmacological
response
analogy
with
this
result,
Guimarães
et
al.
reported
that
the
encapsulation
of
carvacrol,
a
terpenoid
have
been
vastly
reviewed
inoil
literature
[168].
Overall,
Table 6the
recaps
the main
nanosized
delivery
analogy
with
Guimarães
al.
reported
that
theimproves
encapsulation
of
a terpenoid
phenol
present
in result,
the essential
ofetoregano,
with
β-CD,
pharmacological
response
on
cancer
painthis
experimental
protocols
[167].
Itwith
is worth
thatpharmacological
thecarvacrol,
terpene-cyclodextrin
phenol
present
in the essential
oil
of oregano,
β-CD,mentioning
improves the
response
systems
for
anti-inflammatory
terpenoids.
phenol
present
the
oil ofreviewed
oregano,
with
β-CD,mentioning
improves
the
response
on cancer
pain in
experimental
protocols
[167]. Itin
isliterature
worth
thatpharmacological
the terpene-cyclodextrin
inclusion
systems
haveessential
been vastly
[168]. Overall,
Table
6 recaps the
main
on cancer pain experimental protocols [167]. It is worth mentioning that the terpene-cyclodextrin
on
cancer systems
pain
experimental
[167]. Itinisliterature
worth mentioning
that the
terpene-cyclodextrin
inclusion
have
been protocols
vastly
reviewed
[168]. Overall,
Table
6 recaps the main
nanosized
delivery
systems
anti-inflammatory
terpenoids.
inclusion systems
have
beenforvastly
reviewed in literature
[168]. Overall, Table 6 recaps the main
Table
6.
Nanosized
delivery
systems
for
anti-inflammatory
terpenoids.
inclusion
systems
have
been
vastly
reviewed
in
literature
[168].
Overall,
Table
6 recaps the main
nanosized delivery systems for anti-inflammatory terpenoids.
nanosized delivery systems for anti-inflammatory terpenoids.
nanosized delivery
systems
for anti-inflammatory
Table
6. Nanosized
delivery systemsterpenoids.
for anti-inflammatory terpenoids.
Table 6. Nanosized Nanovector
delivery systemsType
for anti-inflammatory
terpenoids.
Bioactive Principle
of Delivery Systems
Experimental Model
Bioactive Principle
Nanovector
Typefor
of Delivery
Systems Experimental
Table 6. Nanosized
delivery systems
anti-inflammatory
terpenoids. Model Reference
Table 6. Nanosized delivery systems for anti-inflammatory terpenoids.
Squalene
Squalene
Bioactive
Principle
Nanovector
Type of Delivery Systems Experimental Model Reference
Bioactive Principle
Nanovector
Type Polyelectrolyte
of Delivery
Systems Experimental Model Reference
Polyelectrolyte
Squalene
Nanocapsules
In vitro Model
[151]
Bioactive
Principle
Nanovector
Type of Delivery Systems Experimental
Nanocapsules
In vitroReference
Squalene
multilayer
NC NC
multilayer
Polyelectrolyte
Squalene
Lycopene
Lycopene
Lycopene
Lycopene
Lycopene
p-Cymene
p-Cymene
p-Cymene
p-Cymene
Int. J. Mol. Sci. 2017, 18, 709
p-Cymene
Nanocapsules
Nanocapsules
Nanocapsules
Nanoemulsions
Nanoemulsions
Nanoemulsions
Nanoparticles
Nanoemulsions
Nanoemulsions
Nanoparticles
Nanoparticles
Cyclodextrins
Nanoparticles
Nanoparticles
Cyclodextrins
Cyclodextrins
Cyclodextrins
Cyclodextrins
Polyelectrolyte
multilayer NC
Polyelectrolyte
multilayer
NC
Aqueous
propolis
multilayer
NCpropolis
Aqueous
and lycopene
Aqueous
propolis
and
lycopene
Aqueous
propolis
and SLN
lycopene
Aqueous
propolis
and lycopene
SLN SLN
and lycopene
Inclusion
SLNin CD
SLNin CD
Inclusion
Inclusion
Inclusion
in CD in CD
Inclusion in CD
In vitro
[151]
In vitro
[151]
vivo
In vitro
[151]
In vivo [157]
(albinoIn
guinea
vivo pigs)
[157]
(albino
guinea[158,159]
pigs)
In
vivo
vitro
(albinoIn
[157]
Inguinea
vivo pigs)
(albino guinea pigs)
[157]
In vitro [158,159]
Inguinea
vitro
(albinoIn
pigs)
[160]
In vitro
vitro
[158,159]
In
In vitro
vitro In vitro[158,159]
[160]
In vitro
[160]
In vitro
[160]
Cyclodextrins
Inclusion in CD
In vitro
12 of 23
[162,163]
Cyclodextrins
Inclusion in CD
In vitro
[162,163]
Cyclodextrins
Cyclodextrins
Cyclodextrins
Cyclodextrins
Inclusion in CD
Inclusion in CD
Inclusion
in CD in CD
Inclusion
Cyclodextrins
in CD in CD
In and
vitro basil
Cyclodextrins
In vitro
other active agents [142]. Bizzarro et al. recently
reported onInclusion
theInclusion
preparation
of cumin
oil-[162,163]
Cyclodextrins
Inclusion in CD
In vitro
[162,163]
loaded polyamide (−)-Linalool
capsules able to release their cargo oil under UV-light irradiation [143]. Photoresponsive as well as
other stimuli-responsive polymeric capsules have been vastly reviewed in the
(−)-Linalool
(−)-Linalool
literature [144]. Table
5 summarizes the nanosized delivery systems proposed for anti(−)-Linalool
(−
)-Linalool
Cyclodextrins
Inclusion in CD
In vivo (rodents)
[164,166]
inflammatory essential oils.
In vivo (rodents)
[164,166]
In vivo (rodents)
[164,166]
In vivo (rodents)
[164,166]
In vivo (rodents)
Table 5. Nanosized delivery systems for anti-inflammatory essential oils.
Carvacrol
Bioactive Principle
Carvacrol
Carvacrol
Oregano and Cassia
EO
Carvacrol
Thymol and carvacrol
Carvacrol
Nanovector
Type of Delivery System Experimental Model Reference
Nanoparticles
Corn zein NP
In vitro
[136]
In vivo (rodents with
Cyclodextrins
Inclusion in CD
[167]
induced
tumors)
In vivo (rodents with
Cyclodextrins
Inclusion in CD
[167]
In vivo (rodents with
tumors)
Cyclodextrins
Inclusion in CD
[167]
In induced
vivo (rodents
with
induced
tumors)
Cyclodextrins
Inclusion in CD
[167]
In
vivo
(rodents
with
NanoparticlesCyclodextrins
Corn zein NP Inclusion inIn
vitro induced tumors)
[137]
CD
induced tumors)
Cinnamon and thyme EO
LippiasidoidesEO (50–70% Thymol)
Cumin and basil EO
Cyclodextrins
Nanoparticles
Nanocapsules
Inclusion in CD
Alginate/cashew gum NP
Polyamide NC
In vitro
In vitro
In vitro
[140]
[141]
[143]
3.6. Terpenoids
Among a wide spectrum of natural products, terpenoids play a significant role in prevention
and treatment of anti-inflammatory conditions. These compounds are produced as secondary
Reference
[151]
[157]
[158,159]
[160]
[162,163]
[164,166]
[167]
Int. J. Mol. Sci. 2017, 18, 709
Int. J. Mol. Sci. 2017, 18, 709
14 of 23
14 of 23
4. Conclusions
4. Conclusions
Nowadays,phytochemicals
phytochemicals have
have promising
promising potential
potential to
Nowadays,
to prevent
prevent and/or
and/ortreat
treatinflammatory
inflammatory
diseases.
However,poor
poorwater
watersolubility,
solubility,stability
stability and
and bioavailability,
side
effects
diseases.
However,
bioavailability,together
togetherwith
withthe
the
side
effects
reported
when
used
in
therapy,
have
limited
their
clinical
application
so
far.
Nanosized
drug
reported when used in therapy, have limited their clinical application so far. Nanosized drug
delivery
systems
increase
the solubility
and stability
of phytochemicals,
enhance
their
delivery
systems
can can
increase
the solubility
and stability
of phytochemicals,
enhance their
absorption,
absorption,
protect
them
from
premature
enzymatic
degradation
or
metabolism
in
the
body,
protect them from premature enzymatic degradation or metabolism in the body, and prolongand
their
prolong their circulation time, limiting their side effects. A schematic diagram of the effects of
circulation time, limiting their side effects. A schematic diagram of the effects of nanoparticle-delivered
nanoparticle-delivered phytocompounds on the main cellular pathways involved in inflammation
phytocompounds on the main cellular pathways involved in inflammation is reported in Figure 5.
is reported in Figure 5.
Nanotechnology represents a promising approach, which has already provided significant steps
Nanotechnology represents a promising approach, which has already provided significant
forward to bringing anti-inflammatory phytochemicals much closer to clinical applications. In this
steps forward to bringing anti-inflammatory phytochemicals much closer to clinical applications. In
frame, the increase in the number of nanotoxicological studies in the literature is related to a growing
this frame, the increase in the number of nanotoxicological studies in the literature is related to a
awareness
sensibility
ethics the
of nanotechnology.
Additional
research research
is needed
growing and
awareness
and towards
sensibilitythe
towards
ethics of nanotechnology.
Additional
is to
improve
the
cost-effectiveness
and
long-term
safety
of
nanosized
drug
delivery
systems,
through
needed to improve the cost-effectiveness and long-term safety of nanosized drug delivery systems,
thethrough
use of biocompatible
materials materials
and un-harmful
release processes,
aimed to
establish
a stronger
the use of biocompatible
and un-harmful
release processes,
aimed
to establish
a
correlation
smart
nanoparticle
design anddesign
rigorous
assessment
for future applications
stronger between
correlation
between
smart nanoparticle
andsafety
rigorous
safety assessment
for future
in biomedicine.
applications in biomedicine.
Figure
Schematicdiagram
diagramofofthe
thephytocompounds
phytocompounds effects
involved
Figure
5. 5.
Schematic
effects on
onthe
themain
maincellular
cellularpathways
pathways
involved
inflammation. After
After cell
cell internalization
internalization of
nanovector, encapsulated
areare
in in
inflammation.
of aa nanovector,
encapsulatedphytocompounds
phytocompounds
released
intocytoplasm.
cytoplasm. Their
action
is elicited
via inhibition
of nitric
released
into
Theiranti-inflammatory
anti-inflammatory
action
is elicited
via inhibition
ofoxide
nitric(NO)
oxide
production
by by
nitric
oxide
synthase
(iNOS);
reduction
of of
arachidonic
acid
and
(NO)
production
nitric
oxide
synthase
(iNOS);
reduction
arachidonic
acidmetabolites
metabolites
and
prostaglandins
through
inhibition
of
the
cyclooxygenase
(COX)
and
Phospholipase
A2
(PLA2)
prostaglandins through inhibition of the cyclooxygenase (COX) and Phospholipase A2 (PLA2)
pathways;
and
regulationofofnuclear
nuclearfactor
factor NF-κB
NF-κB and
and mitogen-activated
(MAPKs)
pathways;
and
regulation
mitogen-activatedprotein
proteinkinases
kinases
(MAPKs)
pathways,
which
modulate
the
expression
of
proand
anti-inflammatory
mediators
including
pathways, which modulate the expression of pro- and anti-inflammatory mediators including cytokines,
cytokines, chemokines, and adhesion molecules.
chemokines, and adhesion molecules.
Int. J. Mol. Sci. 2017, 18, 709
15 of 23
Acknowledgments: This work was supported by Progetto PON01_01802: “Sviluppo di molecole capaci di
modulare vie metaboliche intracellulari redox-sensibili per la prevenzione e la cura di patologie infettive, tumorali,
neurodegenerative e loro delivery mediante piattaforme nano tecnologiche”; PON01_02512: “Ricerca e sviluppo
di bioregolatori attivi sui meccanismi epigenetici dei processi infiammatori nelle malattie croniche e degenerative”;
PON03_00106: “Materiali Avanzati per la Ricerca ed il comparto Agroalimentare, Laboratorio Pubblico-Privato,
MAReA”; and PRIN 2012-201288JKYY: “Nanotecnologie per variare i programmi di sviluppo osseo nella parete
vasale per la prevenzione e trattamento delle patologie associate alla calcificazione ectopica arteriosa”.
Author Contributions: Raffaele Conte, Anna Calarco and Pierfrancesco Cerruti conceived and designed the
paper; Raffaele Conte and Valentina Marturano wrote the paper; and Gianfranco Peluso helped to evaluate and
edit the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
DDS
PPH
NP
NC
SLN
QC
RE
PLGA
ET
EAC
PEG
PVA
DMAB
PBS
PCL
THC
CBD
CS
EO
CD
Drug delivery systems
Polyphenols
Nanoparticles
Nanocapsules
Solid lipid nanoparticles
Quercetin
Resveratrol
Polylactic-co-glycolic acid
Ellagitannin
Ellagic acid
Polyethylene glycol
Polyvinyl alcohol
p-dimethylaminobenzaldehyde
Phosphate-buffered saline
Polycaprolactone
Tetrahydrocannabinol
Cannabidiol
Chitosan
Essential oils
Cyclodextrins
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