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limitations [159]. These carriers are composed of a mixture of solid and liquid lipids, in which
the liquid phase is either embedded into a solid lipid matrix or localized at the surface of the
solid shell with the surfactant layer [158,160]. Due to their composition, some studies sug-
gested that SLNs and NLCs can penetrate through junctions of corneocytes and accumulate
for several hours. This mechanism can allow the release of polyphenols in a controlled and
prolonged manner [161,162]. SLNs and NLCs show adhesiveness by forming a monolayer
on the skin when the particle size is below 200 nm. This can be used favorably on the skin
since this monolayer film is hydrophobic, conferring an occlusive component to the formula-
tion. Thus, the loss of water is delayed, resulting in the reduction of corneocyte packing and
the subsequent opening of intercorneocyte gaps, facilitating transdermal polyphenol perme-
ation [163]. Moreover, the interaction rate of these lipid nanocarriers with the skin lipids and
sebum is dependent on the W/O partition coefficient of the encapsulated polyphenol, the
formulation type, the location of polyphenol in the formulation, and the type of interacting
skin lipids.
Several studies have reported the use of nanocarriers as resveratrol vehicles, to improve
skin conditions that include melanoma. SLN loaded wi th resveratrol contributed to its effec-
tiveness in decreasing cell proliferation and demonstrated potential benefits to prevent mel-
anoma [164]. On another approach, Chen et al. [165] suggested that lipid nanoparticles are
promising viable carriers for the transdermal delivery of resveratrol and vitamin E to provide
long-lasting antioxidant benefits to the skin, thus helping to prevent melanoma. In their
work, resveratrol, vitamin E, and EGCG were formulated into lipid nanoparticles (SLNs
and NLCs), with several highly uniform and stable formulations. Only resveratrol and
vitamin E lipid nanoparticles provided effective protection against UV-induced degradation
[165].
Overall, these lipidic nanocarrier systems can be useful for transdermal skin delivery of
several actives that can be found elsewhere [154,166e 170].
3.4.3 Polymer nanoparticles
Polymer nanoparticles are usually more stable in vivo compared to liposomes and surfac-
tant micelles. Due to the ir considerably large size, polymeric micelles can be used to codeliver
two or more polyphenols in combination therapies. For skin delivery of anticancer polyphe-
nols, polymer nanoparticles can be prepared from natural and synthetic polymers [171].
One of the most well-studied natural polymers is chitosan. Its cationic character and the
inherent biocompatibility and adhesive properties make this polysaccharide an attractive ma-
trix in anticancer strategies [172]. Chitosan nanoparticles present two major advantages, be-
ing those that prolonged the sustained release of drugs and their mucoadhesive ability. It is
suggested that the drug delivery mechanism is based on the hydration and degradation of
chitosan, which depends on its molecular weight and degree of deacetylation. Thus, the spe-
cific composition of chitosan is essential to define drug kinetics [173]. In a review work of
[174], ellagic acid-loaded chitosan nanoparticles and films are mentioned as potential adju-
vants for the prevention of melanoma [174]. Alginate and albumin are alternatives of natural
origin. The former is a biocompatible and biodegradable [175] anionic polysaccharide deri ved
from brown algae [176], but alginate-based nanoparticles are not as extensively studied for
transdermal drug delivery as their chitosan counterparts. Albumin is a serum protein also
described as biocompatible and biodegradable, being already used as matrix material of a
15. New and revisited approaches on the transdermal delivery of polyphenols-loaded nanoparticles358
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commercial formulation of nanoparticles (Abraxane). In the work of Camargo et al. [177], al-
bumin nanoparticles of 150 nm and 45% of curcumin encapsulation efficiency were described
to provide prolonged release of the payload, as the release profile is dependent on curcumin
diffusion through the albumin matrix. The authors used a murine melanoma model, through
which they noticed an increased survival rate upon treatment with curcumin-loaded albumin
nanoparticles (50% at day 29), in comparison with the free drug (0% at day 29). Additionally,
the effect of the encapsulation of curcumin was also seen in the average volume of the tu-
mors. By the end of the treatment, the authors reported that the group treated with the nano-
system had tumors with an average volume of 0.5 mm
3
, whereas the volume of the tumors in
the group treated with the free group had an average of more than 1.5 mm
3
[177]. The liter-
ature is, in any case, scarce on studies featuring albumin nanoparticles for transdermal drug
delivery.
The most well-known synthetic polymers are poly-lactic acid (PLA), poly-ε-caprolac tone
(PCL), poly-glycolic acid (PGA), and poly-lactic-co-glycolic acid (PLGA) [178e180]. These
have proven biocompatibility and are metabolized through physiological pathways. PLGA
is one of the most used and studied copolymer, being approved by the regulatory authorities
for various medical and pharmaceutical applications. This hydrophobic polymer is able to
encapsulate a wide range of drugs, from hydrophilic to lipophilic, and benefits from the
easy surface modification with specific ligands [181]. EGCG-loaded PLA-PEG nanoparticles
exhibited about 10-fold dose advantage over nonencapsulated EGCG [182]. Nanoparticles
bearing a combination of synthetic and natural polymers were also described for transdermal
polyphenols delivery. Chitosan- or alginate-coated PLGA nanoparticles loaded with resver-
atrol evidenced more effective controlled release rates and light protection compared with
uncoated nanoparticles [183]. Other less known combinations of polymers can constitute,
in the near future, adequate platforms for the encapsulation of drugs, despite the lack of
works pertaining to their use [184,185]. Resveratrol-loaded PCL nanocapsules were devel-
oped by Carletto et al. [186] and tested both in in vitro (B16F10 murine cell line) and
in vivo melanoma models. The results showed concentration-dependent reduction of cell
viability, significant reduction of tumor volume with an increase in the inflammatory infil-
trates of melanoma and, lastly, an important inhibition on metastasis formation [186].
Concerning macromolecular structures, cyclodextrins (CDs) consist of cyclic oligosaccha-
ride molecular structures including six (a-), seven (b-), or eight (g-)
D-glucopyranose units
linked together by a-(1,4) glycosidic linkages. These structures are quite popular due to their
ability to form molecular complexes with drug molecules [187]. The b-CD is the most
commonly used, due to its easy synthesis, low price, and large loading capacity for hydro-
philic molecules [188]. Sun et al. [189] proposed a hydrogel encapsulating curcumin and their
inclusion complexes with hydroxypropyl-b-cyclodextrin. Besides the increase in the solubility
of the drug, the authors reported an important decrease in the relative growth of cells from
the B16eF10 line, upon treatment with the CD formulation [189]. Other uses in the encapsu-
lation of various polyphenols can be found elsewhere, although mentions to melanoma are
scarce to nonexistent regarding cyclodextrins and polyphenols [155].
The possibility to use encapsulated polyphenols as adjuvant therapy is also worth of a
mention. For example, the anticancer potential of polymer-based nanoparticles of tea cate-
chins can be combined with antimelanoma drugs such as cisplatin and mutated B-RAF inhib-
itors to enhance tumor cell apoptosis and/or minimize tumor cell proliferation, metastasis,
3. Melanoma: pathophysiolog y and therapeutic approaches 359
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and angiogenesis, while limiting unwanted toxicity of chemotherapeutic agents observed in
free form [ 190].
Overall, due to their rigid and nonlipidic surface, polymer nanoparticles are only able to
penetrate the superficial layers of the SC [124]. In addition to this, polymeric nanoparticles
permeate through the transappendageal pathway to create high local concentrations of
loaded polyphenols which can further diffuse to the viable layers of the skin [142]. These
polymer nanoparticles are gaining wide attention from scientists due to their EPR effect at
the site of action. This is important, especially due to the multidrug resistance phenomena
occurring in presence of p-glycoprotein on the surface of tumors, which eventually excludes
the polyphenol out [191].
3.4.4 Inorganic nanoparticles
An additional type of nanosystem paving its way into therapeutics refers to inorganic
nanoparticles, specifically those using inorganic metals and metallic oxides [192]. The most
common materials used in these systems are silver and gold for the first category, and tita-
nium dioxide (TiO
2
) and zinc oxide (ZnO) for the latter. Both TiO
2
and ZnO have the special
feature of reflecting UV light, depending on their size [193]. TiO
2
and ZnO nanoparticles pre-
sent in sunscreens with solar protection factors of 50þ are the most widely found nanosys-
tems in everyday life [194]. In the sunscreens, these nanosystems create a protective layer
over the skin, avoiding the penetration of UV rays. This protective action contrasts with
the therapeutic effect conferred by inorga nic metal-based nanoparticles, which surface is
frequently modified with multifunctional moieties that enhance their abilities for gene deliv-
ery and/or chemotherapy [195e197]. These more advanced strategies of formulation devel-
opment in the context of skin cancer, including melanoma, are detailed elsewhere [198].
The information pertaining to clinical trials was also searched, looking for polyphenol-
loaded nanosystems tested on melanoma. The results indicated that, independently of the
status of the trial, from the 2293 studies related to melanoma, only 10 matched to clinical trials
using nanoparticles, despite not having encapsulated polyphenols. A reasonable explanation
for this is the fact that nanotechnologies and phytochemicals applied to cancer prevention
and treatment are at an initial stage of research. Moreover, melanoma is a less prevalent can-
cer, thus contributing to the scarcity of data in clinical trials. Transdermal delivery of drugs
mediated by nanocarriers is a field requiring more studies, to design efficient antimelanoma
nanosystems. There is still much work to be done to understand and better evaluate the ef-
ficacy, safety, and quality provided by the delivery of polyphenols through the skin via
nanosystems.
Nevertheless, efforts on the modulation of the immune system [35], the discovery of mo-
lecular markers for melanoma and, possibly, new therapeutic targets [199] and the determi-
nation of their genomic profile [39] promise to be the lines of research for the coming years.
Despite melanoma being uncommon when compared to other skin cancers, its negative
implication on human society makes it even more important to understand, for better
addressing the future. Despite all the advantages on melanoma targeting, the nanoscale sys-
tems presented and discussed herein show, to this day, many limitations to their use. More-
over, there are concerns on the potential toxicological effect that these structures might trigger
in the human body. The next section will address the toxicity concerns and suggest possible
viable solutions.
15. New and revisited approaches on the transdermal delivery of polyphenols-loaded nanoparticles360
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3.5 Toxicity considerations regardi ng polyphenol-loaded nanocarriers
The scientific knowledge concerning nanotechnology and the different related drug delivery
strategies already proposed as alternative therapies keeps growing. As previously discussed,
nanocarrier -mediated drug delivery strategies can be a viable approach for polyphenols deliv-
ery in melanoma therapy, but there are concerns regarding their toxicity, which are transversal
to other applications. The lack of data on nanoparticle clearance is widely referred, often
signaling their potential to accumulate on site. Moreover, the absence of adequate in vivo
models, guidelines, and standardized safety tests that would enable better understanding of
toxicity mechanisms is also mentioned as a limitation for the application of nanoscale systems.
Although there are evidences of anticancer activity of dietary polyphenols [200], there are
concerns regarding their antioxidant properties. As such, the antioxidant properties of certain
molecules can be interpreted as paradoxal, because while the increased concentration protects
physiological melanocytes, it can also decrease the oxidative stress in cancerous cells leading
to their proliferation [64]. Notwithstanding, polyphenols can be used as adjuvants of conven-
tional therapies, protecting physiological melanocytes, while cancerous cells are eliminated.
This is an issue that deserves further research [201].
There are also significant concerns associated with the use of nanoparticles. The primary
concerns are related with the easiness of nanoparticles penetration in cell membranes,
creating a potentially toxic effect. When endocytosis occurs with such a material, an inflam-
matory reaction might be induced, either prooxidant or antioxidant [202]. There is evidence
that an oxidative stress response occurs, which, when paired with mitochondrial distribution,
may result in some problems that remain to be clarified [203]. Another limiting factor relies
on the duration of permanence of the nanosystems in the body [202,204]. One example is the
use of flexible hydrophilic polymers, specifically those incorporating PEG, which reduces
opsonization of the nanosystems, giving them opportunity to remain in circulation for longer
periods of time [205], potentially aiding to their accumulation in diverse organs. It is well
known that many components of nanoparticles, such as nucleic acids, antibody fragments,
peptides and proteins might be recognized by the immune system as antigens, resulting in
increased immunotoxicity [206]. Other components, such as emulsifiers, can also trigger toxic
adverse effects [207]. The endpoints evaluated to define the toxicity profile of nanoparticles
may include: oxidative stress, inflammatory response, genotoxicity, carcinogenicity, as well
as respiratory, cardiovascular, central and peripheral nervous system, hematopoietic and
lymphatic system, developmental and reproductive toxicity [208].
In an environmental perspective, the increasing presence of nanoparticles may also have
negative consequences, but the current knowledge is insufficient to reach a convincing
consensus on the subject [209]. A possible solution for this matter should be procured based
on the toxicological potential of nanomaterials. One possibility entails a categorization system
for these materials and structures, being made available for the scientific community. This
approach will enable a better understanding of the biological interactions of nanomaterials
and nanosystems with several molecules and structures. After this database is sufficiently
broad and comprehensive, the next goal should be the compilation of all this information
in validated and standard test protocols, as well as reference standards, which will be subject
of approval by regulatory authorities. A more comprehensive overlook on this matter can be
found elsewhere [210e213].
3. Melanoma: pathophysiolog y and therapeutic approaches 361
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4. Conclusion and future perspectives
Melanoma is one of the most challenging and researched cancers due to its high mortality
rate. Naturally occurring polyphenols are being studied as promising alternative active
agents to prevent and treat cutaneous melanoma. The main limitation of polyphenols is its
low bioavailability signifying the relevant role of new delivery vehicles. Nanotechnology
thus appears as a useful and advanced tool, since it improves active intracellular delivery
of polyphenols, their pharmacokinetics, and pharmacodynamics. Transdermal drug delivery
enables a more efficient and local delivery of polyphenols, which may be useful in the context
of melanoma. This increases not only the amount of drugs at the intended site, but also re-
duces systemic adverse events linked to other routes of administration. From the research
made so far, it is suggested that the most efficient nanocarriers for transdermal delivery of
polyphenols are liposomes, along with lipid-based and polymer-based nanoparticles. Trans-
dermal delivery of nanosystems still remains to be better understood and there are funda-
mental issues that require further evaluation. The toxicity and kinetics of nanomaterials,
the relation between the dose and distribution of nanosystems across skin layers and the ther-
apeutic efficacy of encapsulated polyphenols, the permeation efficiency in healthy and
diseased skin, and the mechanisms of nanoparticle transport through the main skin layers
are the four key issues to be taken into consideration in their design and development.
Thus, further studies are required, including more advanced clinical studies, to demonstrate
the real potential of transdermal delivery of polyphenol-loaded nanosystems to melanoma
skin conditions. It is essential to standardize good manufacturing practices of nanoparticles,
as well as all regulatory aspects regarding formulations and medical devices incorporating
and/or carrying phytochemical -loaded nanocarrier drug delivery systems for human use.
As it is a growing technological area, it may be useful to build an integrative global network
of the various nanotechnology research centers for the prevention and treatment of mela-
noma, to provide a comprehensive sharing of knowledge in this new medical area to detect
associated errors and risks, strengths, and opportunities.
Acknowledgments
This work was funded by FEDERdFundo Europeu de Desenvolvimento Regional funds through the COMPETE
2020-Operational Program for Competitiveness and Internationalization (POCI), and by Portuguese funds through
Fundação para a Ciência e a Tecnologia (FCT) in the framework of the project POCI-01-0145-FEDER-032610 -
PTDC/MEC-DER/32610/2017. It was also funded by FCT in the scope of the projects UIDB/50006/2020 of the Asso-
ciate Laboratory LAQV, REQUIMTE, UIDB/04326/2020 of the Research Unit Center for Marine SciencesdCCMAR,
and UIDB/04565/2020 and UIDP/04565/2020 of the Research Unit Institute for Bioengineering and Biosciencesd
iBB, and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomydi4HB. Jorge
Pontes Ph.D. scholarship PD/BD/137064/2018 is also acknowledged to FCT.
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