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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5976_Библиотеки_им_академика_М_И_Перельмана
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FIGURE 15.4B Chemical structure of polyphenols with biological relevance (resveratrol).
FIGURE 15.4C Chemical structure of polyphenols with biological relevance (quercetin).
FIGURE 15.4D Chemical structure of polyphenols with biological relevance (curcumin).
FIGURE 15.4A Chemical structure of polyphenols with biological relevance (epigallocatechin).
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therapeutic strategy. Tumorigenesis, a process by which a cancer mass grows triggered by
chronic inflammation [62], can be arrested by a series of molecular inhibitions that limit
the growth of neoplastic tissues [63]. Nevertheless, free radicals can have a paradoxical effect
on cancer, because, on one side, they can induce carcinogenesis but, on the other side, if at
higher concentrations, toxicological phenomena occur, leading to cell death [64]. The modu-
lation of a redox state in patients, by assessing free radicals and administering antioxidant
compounds (i.e., polyphenols) can synergistically work in favor of the patient, when in treat-
ments. Antican cer mechanisms of polyphenols have bee n described, being the cell signaling
pathways affected, as follows: (a) the mitogen-activated protein kinase (MAPK) pathway;
(b) the pathway of nuclear factor-kb (NF-kb) activation and (c) the signal transducer and acti-
vator of transcription (STAT) pathway [65,66]. These pathways are inhibited by polyphenols,
as well as extracellular matrix remodeling and angiogenesis. Proinflammatory cytokines pro-
duction, tumor proliferation, activation of metalloproteinases, and production of angiogenic
mediators are inhibited by polyphenols, presenting as preventive of the progression, and of
the metastatic ability of cutaneous melanoma.
Fig. 15.4AeD shows four compounds that are well studied among the scientific commu-
nity. However, many other compounds are present within the mentioned four families of
polyphenols, which may find a potential application in cancer treatment and/or its prevention
[67]. Flavonoids are one of the most common families, being flavones, isoflavones, and antho-
cyanins examples of compounds. Other examples, such as xanthohumol and isoxanthohumol,
which are chalconesda subcategory of flavonoids, were found to have an application in can-
cer, as seen elsewhere [68], inhibiting NF-kb transcription factor [69]. Other studies showed
that epigallocatechin-3-gallate (EGCG), present in green tea, inhibits cancer cell growth by pre-
venting the activation of vascular endothelial growth factor (VEGF) receptor [70]. This effect is
similar to the VEGF antibodies, such as bevacizumab, which inhibits angiogenesis, tumor
growth, and metastasis [71]. This major polyphenolic compound also decreases NF-kb pro-
duction, inflammation, interleukin 1b (IL-1b) secretion, and cell growth of melanoma cells.
All these represent the possible biological effects of EGCG on melanoma cells [72](Fig. 15.5).
FIGURE 15.5 Molecular mechanisms of the biological action of epigallocatechin-3-gallate (EGCG) on melanoma
cells.
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Other polyphenols such as oleuropein, hydroxytyrosol, resveratrol, and quercetin have
been showing important anticancer activity. The first two can be obtained from olive oil,
and the latter two from red wine , products that are widely consumed daily. These four poly-
phenols inhibit NF-Kb activity which will influence inflammation promoted by cyclooxyge-
nase 2 (COX-2) and matrix metalloproteinase 9 (MMP-9). Also, by acting on inflammation,
they will indirectly inhibit tumor angiogenesis [73].
Extensive research has been conducted with different phenolic compounds. Pop and Diac-
oneasa [59] compiled most of these studies in a review, detailing both in vitro and in vivo
studies [59]. The authors refer to various melanoma cell lines, such as A375 and its respective
variants, SK-MEL-24, RPMI-7951, and HT-144 to mention a few [74]. The studies in which the
latter cell lines were used demonstrated an overall decrease in cell viability and, thus, their
proliferation, and an increase in apoptotic events. The cancer growth inhibition promoted
by these polyphenolic compounds may be the needed breakthrough for less aggressive ther-
apies. One of the limitations of the conventional guidelines for cancer treatment is the severity
of adverse reactions in patients, which can lead to noncompliance or even early interruption of
treatments. The search and need for better therapeutic approaches are the main aims of cur-
rent research strategies, with polyphenols getting even more attention. Even if information
on in vivo assays and clinical trials is scarce [75,76], there is an overall focus on deepening
the knowledge about these compounds for future uses [77,78]. However, despite the advan-
tages of polyphenols, they present some limitations [79]. Their low bioavailability, the lack
of stability, and an ineffective encapsulation system limit their delivery and further application
in current therapies. Thus, in the next sections, strategies to overcome these limitations will be
discussed, focusing on nanoencapsulation of polyphenols for their delivery to the skin.
3.2 Nanoencapsulation of polyphenols for transdermal delivery
Drug delivery systems have been widely propo sed as valid alternatives to overcome
certain limitations presented by drug molecules [80]. The case of polyphenols is no different
since their low bioavailability and the lack of stability pose serious problems on formulation
design, rendering the use of conventional drug delivery systems ineffective [81]. To optimize
anticancer activity of polyphenols, well-characterized polyphenol-loaded nanoparticles can
be a promising alternative, through induction of cell cycle arrest at different phases of cancer
cell cycle, activation of caspase enzymes, reduction of tumor vascularization, reduction of tu-
mor cell invasion and metastasis, and induction of mitochondrial damage [82].
Nanoparticles possess unique properties, such as high surface-area-to-volume ratio, and
controllable physicochemical and biological properties via surfa ce functionalization.
Figs. 15.6 and 15.7 show a graphic representation of a nanoparticle and its properties.
The use of nanotechnology to deliver polyphenols might be advantageous to:
• Enhance the solubility of highly hydrophobic polyphenol s;
• Provide sustained and controlled release of encapsulated polyphenols;
• Increase the stability of therapeutic polyphenols by chemical or physical means;
• Deliver higher concentrations of polyphenols to target areas due to an EPR effect;
• Provide targeted treatments when modified with cell-specific ligands;
• Reduce systemic side effects [82].
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FIGURE 15.6 Polyphenol nanocarrier formulations and their mechanisms as anticancer agents.
FIGURE 15.7 Schematic representation of a nanoparticle and its fundamental features.
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Several parameters should be considered when developing a nanoparticulate system. Size
and surface charge are the first two worth of a mention. In fact, nanoparticle sizes between 10
and 100 nm are the most adequate to increase biodistribution. As for the surface charge, it can
greatly influence their interactions with cells, thus being a key factor in biological responses
[83]. The surface charge can be modulated as nanoparticles are extremely versatile as to the
possibility of linking polymers (e.g., polyethylene glycol (PEG)) or other sterically stabilized
ligands, rendering an increased half-life for these nanosystems in the bloodstream. The mod-
ulation of the surface charge should be one of the optimization steps. An optimized set of
characteristics involving these parameters may potentiate cell uptake [84,85]. Besides the up-
take, the type of surface is determinant to the solubility of nanoparticles, their stability, and
clearance. Moreover, the use of nanoparticles may provide two types of targeting: active and
passive. Passive targeting can be achieved by changing the physicochemical features of the
nanosystem, such as size, shape, ligand density, and linker length [86]. Active targeting is
endowed by functionalization of nanoparticles’ surface, which improves biokinetics and bio-
distribution. There is also a new generation of nanosystems that does not fit the generic cate-
gorization of active/passive targeting. These respond to environmental stimuli, that is, the
presence of a certain molecule or structur e or physicochemical parameter triggers the release
of the encapsulated drug. The modulation of pH can be helpful in tumorigenic environments,
as it is known that these locations are more acidic than healthy tissues. The accumulation of
acidic metabolites in tumor sites, caused by hypoxic conditions, can work favorably for the
release of drugs, if the nanosystem is formulated to respond to lower values of pH [87]. Other
stimuli, as for example, high concentration of glutathione, the presence of free radicals, the
application of an external magnetic or ultrasounds and a temperature trigger, among others,
can also be used to potentiate a targeted therapy [88,89]. These so called “smart” carriers
should not be overlooked, as they can use certain environmental conditions to exert the ther-
apeutic effect and can be the next phase on nanoformulation development [90].
Considering that polyphenols are intended to be encapsulated in nanocarriers, the type of
nanoparticulate system, the diffusion rate of polyphenols and the desired time to obtain a
therapeutic effect will certainly support the selection of the system. Upon formulation, all ma-
terials should be selected considering a specific clinical application, prioritizing biocompati-
bility while improving the release of polyphenols [91,92]. Moreover, minimizing adverse side
effects that can be promoted by the materials or the system itself is one of the priorities in
formulation development. To this day, the Food and Drug Administration (FDA) has
approved several biomaterials to be used in accordance with the intended route of adminis-
tration [93,94]. However, extensive research must still be performed to evaluate their interac-
tions with tissues and toxicity hazards, so that they can find a use, especially with
polyphenols. More and more nanomaterials, alongside the ones that are already known,
must be subject of clinical studies to conclude on the more efficient formulation combinations,
between matrix and polyphenols, which would enhance their therapeutic effect while
ensuring safety.
Nanotechnology has its advantages on formulation development, as it was discussed in
the section herein. Nevertheless, although being a promising solution to overcome the short-
comings of conventional polyphenol delivery, the use of nanosystems also finds limitations
[87,95e97]. Table 15.2 shows a summary of the advantages and disadvantages of nanocar-
riers in comparison with conventional products [96,98,99].
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Despite the disadvantages presented in Table 15.2, there is a case of success regarding a
nanoparticle-based formulation developed for anticancer therapy. Abraxane is one of the
most important therapeutic strategies for the treatment of metastatic breast cancer, with a
formulation relying on albumin-based nanoparticles for the targeted delivery of paclitaxel
[100]. Approved since 2006, it gave the scientific community and those working on pharma-
ceutical technology a wide range of possibilities and hope on the successful development and
approval of nanosystem-based therapies [101,102]. Over the next few sections, this chapter
will focus on the pathways of penetration of polyphenols and the strategies currently
researched for the transdermal delivery of polyphenols.
3.3 Pathways of penetration of polyphenols-loaded nanoparticles through the
skin
Transdermal drug delivery has been used for the application of several substances on the
skin for many years. Upon comparison with more conventional routes of administration
(e.g., oral and intravenous), transdermal drugdeliverypresentsitselfasanoninvasive
route, with higher patient compliance, while avoiding first pass metabolism [103,104].
Potential advantages and limitations o f transdermal route are summarized in Table 15.3.
TABLE 15.2 Advantages and disadvantages of nanocarriers versus conventional drug delivery systems.
Nanocarrier drug delivery systems Conventional formulations
Advantages Increased bioavailability controlled and sustained drug
release active targeting surface multifunctionalities high
surface-to-volume ratio
Well-defined toxicity, stability, and
pharmacokinetics, less expensive
Disadvantages Unpredictable toxicity, stability, and pharmacokinetics
reduced shelf life
Uncontrollable release untargeted drug
delivery undesirable pharmacokinetics
TABLE 15.3 Advantages and limitations of transdermal delivery.
Advantages Disadvantages
Increased bioavailability Local irritation at the site of application
Controlled pharmacokinetics: Steady drug plasma levels Low drug concentration
Improved pharmacodynamics: Prolonged duration of action of drugs Low permeability
Avoidance of first pass metabolism
Reduced dosage frequency
Reduced adverse effects
Patient compliance
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Despite being general, they also apply t o the transdermal delivery of polyphenols-loaded
nanoparticles.
Considering all aspects of the skin, the SC appears as the rate limiting step for the delivery
of drugs, whether the administration is topical (local effect) or transdermal (systemic effect).
Moreover, furrows present on the skin, subject to interindividual variation, can work both
ways: by limiting the action of drug-loaded nanosystems by premature uptake and, at the
same time, by increasing their residence time, thus enabling a more sustained release of
drug [105e107]. Despite this insight, studies cons idering furrows are scarce and related infor-
mation is limited. Thus, the focus of the present section will be on the main routes of perme-
ation of skin, which include the transcellular, intercellular or paracellular, and the
transappendageal routes (hair follicles and sweat glands), as depicted in Fig. 15.8.
The transappendageal route seems to be the most appropriate choice, since it facilitates,
through the hair follicles, polyphenol or entire nanoparticulate complex entry to systemic cir-
culation, if the transdermal action is preferred [108]. For topically applied nanoparticulate
systems, hair follicles can act as reservoirs to achieve a time-dependent controlled and pro-
longed release of nanosystems [109e111].
Regardless of the pathwaydtranscellular, intercellular, and transappendagealdpassive
diffusion is the main transport mechanism by which nanoparticles penetrate the skin across
the SC [112]. Chemically, the diffusion of a drug through skin follows this simplified Fick’s
diffusion law, which is expressed as follows:
J ¼ D
m
DC P
L
(15.1)
FIGURE 15.8 Schematic diagram of the three skin penetration pathways: intercellular, intracellular and trans-
appendageal. Reproduced with permission from Qindeel M, Ullah MH, Fakhar-Ud-Din, Ahmed N, & Rehman AU. Recent
trends, challenges and future outlook of transdermal drug delivery systems for rheumatoid arthritis therapy. Journal of
Controlled Release 2020;327:595-615.
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The J is the diffusion flux across the skin, D
m
is the coefficient of diffusion in the skin, DC is
the concentration difference between each side of the skin, P is the partition coefficient of
drug, and L is the diffusion path, meaning the thickness of the skin [113]. Zillich et al.
[114] investigated a mathematical model fo r the release of polyphenols from a lipidic formu-
lation. A major influence of both the lipophilicity and molecular size of polyphenols on diffu-
sion was described. In this case, small hydrophilic polyphenols released faster and displayed
better skin penetration. Moreover, all components of the tested emulsion concentrated on the
epidermis and dermis [114].
The previous work aligns itself with the four characteristics of passive skin permeation
stated in the work of Richard et al. [113]. The authors refer a smaller molecular size as a
potentiator of their diffusion through the skin, an adequate partition coefficient for a better
affinity toward a highly hydrophobic structure, the solubility of the active principle, and
lastly, its degree of ionization [113]. In the case of polyphenols and considering the previous
data, a successful diffusion process is favored by low molecular weight, high lipophilicity,
and a significant lipid/water partition coefficient. It is important to say that these are the
physicochemical features required for the transport through transcellular route. Importantly,
when the skin barrier is compromised, which occurs in some conditions, permeation is facil-
itated [115,116].
The transcellular route is, however, less applicable for the transdermal transport system
[117], being that the transappendageal pathway the preferred for nanoparticle systems, as
mentioned elsewhere [118e120]. In fact, one of the main features of nanoparticles, in derma-
tological application, is their tendency to penetrate and accumulate into hair follicles, thereby
increasing the accumulation of encapsulated polyphenol. It was calculated that the residence
time of the nanoparticle-based delivery systems in the hair follicles was 10 days, compared to
short-term residence time in the SC [121]. This may happen due to the rigid hair shaft which
acts as a geared pump, because of the zig-zag structure of cuticular layers along the hair shaft
that moves particles deeper into hair follicles. The nanoparticles penetrate down to different
depths depending on their size [122,123]. In a study with nanoemulsions, thos e with size
above 500 nm were found to aggregate superficially in the follicular openings [124]. The envi-
ronment of the follicular infundibulum produces a continuous stream of sebum from the outlet
of the sebaceous gland that moves toward the follicular orifice. Therefore, nanoparticles that
can penetrate beyond follicular infundibulum or below the excretory duct of the sebaceous
gland, cannot be removed by sebum [123].
These penetration mechanisms and their physiological implications on skin aid nanopar-
ticles to either remain on the SC or penetrate to deeper layers, to exert their therapeutic effect
[103]. In the next section the focus shifts to the type of drug delivery systems that can be used
to deliver polyphenols through the skin.
3.4 Transdermal delivery of polyphenols using drug delivery systems
The skin is a protective barrier, defending the host from external pathogens [12]. There are
strategies in the market for the delivery of drugs through the skin, but overall, the permeation
of molecules is dependent on their diffusion [125], as stated by the simplified Fick’s diffusion
law. As this chemical parameter varies between drug molecules, certain mechanisms were
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developed to enhance permeation through skin [126]. Structures like micr oneedles [127], and
processes of iontophoresis [128] and electroporation [129] are three of the many examples that
can be used with this aim. However, data regarding their use on therapeutic approaches and,
specifically, clinical scenarios of melanoma, are scarce. Drug diffusion to the neoplasia in a
melanoma model has been investigated using these methods [130e132], but these are still
new technologies that require more studies and an understanding on how they can be
included in the current therapeutic guidelines for melanoma. Therefore, the remainder of
this chapter will focus on the proposed strategies for the transdermal delivery of polyphenols.
The design of a therapeutic and/or preventive strategy of transdermal delivery of poly-
phenols in the context of cutaneous melanoma requires the polyphenol to penetrate the
skin and reach the tumor, which depending on the stage, will be located at different depths.
The evolution of pharmaceutical technology allowed the production of nanoscale vehicles
which, due to their very small size, present several advantages over conventional cutaneous
distribution strategies, such as.
• Ability to reach the deeper layers of the skin;
• Active or passive targeting of the tumor;
• Ability to reduce the skin adverse effects induced by polyphenols, such as local irrita-
tion after administration;
• Ability to increase the stability of the polyphenol;
• Possibility of more controlled and prolonged release of the polyphenol.
A promising approach on passive targeting of tumors is that mediated by superparamag-
netic iron oxide nanoparticles (SPIONs). These enclose the use of ions with magnetic proper-
ties, so when a magnetic field is applied on the outside, it enables a redirection of the
nanoparticles to a target site. Their application has been described not only in drug delivery
or therapy [133], but also in areas of imaging and diagnosis [134]. Despite polyphenols-
associated SPION formulations not being developed so far, this is still a very promising
approach to be applied in melanoma treatment. As for the active targeting, the m ost common
strategies comprise the addition of moieties to the nanoparticle structure, adding specificity
for biomarker molecular recognition and selectivity for specific site binding and fast receptor-
mediated endocytosis into skin cancer cells [ 135,136]. Additionally, physicochemical param-
eters [87] regarding the size of the nanoparticles [137,138], their surface charge [100,139], the
inherent properties of the used matrix materials [140], the amount of encapsulated drug [141],
and the transdermal mechanism by which the nanosystems enter the skin [125] must be taken
into consideration for the optimization of the formulation.
The use of nanosystems to deliver drugs through the transdermal route has been analyzed
by Desai et al., investigating various types of carriers [142]. Although there is a fair concern
on the inability of nanosystems to cross the SC, the transappendageal route is referred as the
preferred way for nanoparticle internalization. If nanoparticles encapsulating polyphenols
are considered, the active principle can use several of the skin transdermal mechanisms to
enter, resulting in a therapeutic effect. In this case, the drug can enter by itself, if released
earlier, or reach deeper areas while inside the nanosystem, being then released further inside
[142,143]. The next subsections will detail several types of nanosystems and describe the stra-
tegies used to enhance polyphenol transdermal delivery.
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3.4.1 Liposomes
Liposomes were the first developed nanocarriers for skin drug delivery [144]. They are
biodegradable lipid vesicles, mainly composed of one or multiple lipid bilayers of mixtures
of phosphatidylcholines with long or short hydrocarbon chains. They have high morpholog-
ical diversity, as a function of hydration, temperature used for assembly, and composition
[145]. Liposomes can enter the skin by several mechanisms, which include intact vesicular
skin penetration, penetration enhancing effect by transepidermal osmotic gradient and hy-
dration force, lateral diffusion of vesicles in the SC, and via the transappendageal pathway
[146,147]. The skin permeation of liposomes is dependent on lipid composition, size, and sur-
face charge. The positive charge of liposomes is helpful for binding with the negatively
charged skin cells and hair follicles, through an ion-exchange mechanism [148,149]. As for
the composition, liposomes made from more rigid-structured lipids have a less efficient pene-
tration profile, while liposomes made from less rigid-structured lipids can penetrate up to the
epidermal-dermal junction [150]. Additionally, besides their promising penetrating and diffu-
sion properties, in cancer-related approaches liposomes have an increased retention time in
the interstitial fluid due to the EPR effect [151], derived from tumor angiogenesis, promoting
an increased concentration at the desired site and a more sustained drug release.
One of the examples regarding the use of polyphenol-loaded liposomes in a melanoma
was described by Caddeo et al. [152]. The authors propose a new path on the treatment of
inflammation and oxidative stress associated with skin cancer. The work was performed us-
ing a mouse model of skin lesion and showed that topical administration of liposomes co-
delivering quercetin and resveratrol led to a remarkable amelioration of tissue damage,
with a significant reduction of edema and leukocyte infiltration, proposing a novel approach
to treat skin cancer. The cellular uptake of the polyphenols was higher when incorporated
into liposomes more specifically coloaded with quercetin rather than as single agents [152].
Another work further demonstrated enhanced proliferative and photoprotective effects of
resveratrol-loaded liposomes in an in vitro model (HEK 293 cell line) [153].
The literature makes available a substantial amount of recent works using liposomes and
its derivatives as polyphenols carriers, both for general anticancer approaches [154,155] and
for melanoma adjuvant therapy [156,157].
3.4.2 Lipid-based nanoparticles
Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have been
applied to increase the physicochemical stability of both incorporated polyphenols and par-
ticulate systems for transcutaneous delivery. Comparing to liposomes, these lipid nanocar-
riers provide better protection of encapsulated polyphenols from enzymatic degradation,
while preventing transepidermal water loss and controlling the release profile of polyphe-
nols. These nanocarriers present low toxicity, as the materials used in their preparation are
biocompatible and biodegradable [142].
SLNs are prepared using lipids that are solid at room temperature, their surface being
covered by a surfactant shell that stabilizes the dispersion [142,158]. Nevertheless, they pre-
sent some limitations that include the limited drug loading capacity and the ability to easily
release the encapsulated drugs, including polyphenol s, before reaching the target site. A sec-
ond generation of lipid nanoparticles, NLCs, was developed to overcome the mentioned
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