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15
New and revisited approaches on the
transdermal delivery of polyphenols-
loaded nanoparticles for melanoma
prevention and treatment
Jorge F. Pontes
1
, Magda Fonseca
2
, Ana S. Macedo
3, 4, 5
,
Ana Grenha
1, 6, 7
and Pedro Fonte
1, 4, 5, 6
1
Center for Marine Sciences (CCMAR), University of Algarve, Gambelas Campus Faro,
Portugal;
2
Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto,
Portugal;
3
LAQV, REQUIMTE, Department of Chemical Sciences-Applied Chemistry Lab,
Faculty of Pharmacy, Universidade do Porto, Porto, Portugal;
4
iBBdInstitute for
Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico,
Universidade de Lisboa, Lisboa, Portugal;
5
Associate Laboratory i4HBdInstitute for Health
and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal;
6
Department of Chemistry and Pharmacy, Faculty of Sciences and Technology, University of
Algarve, Gambelas Campus, Faro, Portugal;
7
Research Institute for Medicines (iMed.ULisboa),
Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
List of abbreviations and acronyms
BRAF V-Raf murine sarcoma viral oncogene homolog B
c-Kit V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
CDs cyclodextrins
COX-2 cyclooxygenase 2
EGCG epigallocatechin-3-gallate
EPR (effect) enhanced permeation and retention (effect)
FDA Food and Drug Administration
CHAPTER
341
Phytopharmaceuticals and Herbal Drugs
https://doi.org/10.1016/B978-0-323-99125-4.00001-9 © 2023 Elsevier Inc. All rights reserved.
https://t.me/med1917
IL-1b interleukin 1b
MAPK mitogen activated protein kinase
MMP-9 matrix metalloproteinase 9
NF-kb nuclear factor-kb
NLC nanostructured lipid carriers
NRAS neuroblastoma RAS viral (v-Ras) oncogene homolog
PCL poly-ε-caprolactone
PD-1 programmed death-ligand 1
PEG polyethylene glycol
PGA poly-glycolic acid
PLA poly-lactic acid
PLA-PEG poly(lactic acid)-poly(ethylene glycol)
PLGA poly-lactic-co-glycolic acid
PNIPAAm poly-N-isopropylacrylamide
RNS reactive nitrogen species
ROS reactive oxygen species
SC Stratum corneum
SCC Squamous Cell Carcinoma
SLN solid lipid nanoparticles
SPION’s super-paramagnetic iron oxide nanoparticles
STAT signal transducer and activator of transcription
UV ultraviolet
VEGF vascular endothelial growth factor
WHO World Health Organization
1. Introduction
Human health and related topics have always been subject of intense research, both
regarding the molecular characterization and the development of therapies. Although several
disease conditions have been successfully addressed, others remain beyond the scientific un-
derstanding, with some cases resulting in terrible outcomes. The World Health Organization
(WHO) reported almost 20 million new cases of cancer in 2020 in the entire world, with breast,
lung, and colorectal cancers leading the list (11.7%, 11.4%, and 10%, respectively) [1]. For
Europe, the new cases present a fairly similar behavior, with prostate cancer appearing as
the fourth most common type of cancer [2]. Despite the importance of early detection and sub-
sequent treatments of these forms of cancer, other varieties should not be overlooked. Skin
cancer is one of those instances, as it can often be unnoticed by the affected individuals. In
the reports mentioned earlier, melanoma is the 18th and 7th most common form of cancer
worldwide and in Europe, respectively [1,2], even though this is the less frequent form of
skin cancer occurring in humans [3]. As a matter of fact, to simplify its characterization,
skin cancer can be divided in two categories, corresponding to melanoma cancers and nonme-
lanoma cancers. The latter are subdivided into subcategories, of which basal cell carcinoma
and squamous cell carcinoma are its major types [4,5]. Although all these pathological occur-
rences deserve an extensive analysis and debate, this chapter will focus mainly on melanoma.
Although not very common among skin neoplasia, it is considered the most aggressive type,
with increasing lethality if not detected early [6,7]. The diagnosis of melanoma is restricted to
visual analysis of potentially affected skin regions using a dermatoscope [8]. The majority of
15. New and revisited approaches on the transdermal delivery of polyphenols-loaded nanoparticles342
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cases present pigmented cells (melanocytes) that are darker than usual, though a few cases can
have different colorations, enabling an easier differentiation from benign lesions [9]. There are
several risk factors to consider upon a diagnosis of melanoma [6], which makes early and
continued monitorization of skin alterations of the utmost importance [10].
This chapter will detail the pathophysiology of melanoma, as well as current therapeutic
strategies employed in its eradication. This approach will be preceded by a description of skin
structures and their contribution for the development of cancer conditions. The focus then
shifts to the encapsulation of polyphenols, promising antioxidants for cancer adjuvant ther-
apy, in nanosystems as mediators of targeted delivery, highlighting their permeation mech-
anisms and toxicity concerns. Finally, the chapter will discuss future perspectives on the
subject to unveil the insights on the research pipeline.
2. Skin: anatomy and physiology
The human skin is a complex organ, covering a surface area of 2 m
2
for an average adult [11].
Its two main functions are to allow the contact of the human organism with the environment
and, at the same time, to protect it from external threats [12]. To do so, but not exclusively,
the skin is divided into three different layers: epidermis, dermis, and hypodermis (Fig. 15.1).
FIGURE 15.1 The skin with its many structures and components. Reproduced with permission from Benítez JM,
Montáns FJ. The mechanical behavior of skin: structures and models for the finite element analysis. Computers & Structures.
2017;190:75e107. https://doi.org/10.1016/j.compstruc.2017.05.003.
2. Skin: anatomy and physiology 343
https://t.me/med1917
The epidermis is the outer layer and consists of five different structures, which are from the
outside, the stratum corneum (SC), stratum lucidum, stratum granulosum, stratum spinosum, and
stratum germinativum with a thickness of 70e150 mm. The SC is the most superficial layer of
the skin, with several layers of dead cells [11]. It acts as a semipermeable barrier to the
entrance of compounds and is the most effective barrier. The SC is made of corneocytes
that are terminally differentiated keratinocytes, embedded in a highly ordered hydrophobic
matrix composed of ceramides, cholesterol and cholesterol esters, and fatty acids [14,15]. The
remaining layers help on the movement of components within, melanin production and its
further integration for protection against ultraviolet (UV) rays [15]. The dermis is 1e4mm
thick and is composed of connective tissue, sweat glands, hair follicles, and a network of cap-
illaries, lymphatic vessels, and nerve endings. Dermi s is also rich in collagen and elastin, two
fibrous proteins immersed in a gel of glyco saminoglycans, salts, and water [16]. The deepest
layer is the hypodermis, which is composed of loose, white, fibrous connective tissue, repre-
senting the storage compartment of the skin for fat [17,18].
Skin also contains numerous appendages including sweat ducts, glands, hair follicles, and
nails, which account for only about 0.1% of the total surface of human skin. Sebaceous glands
are present in association with each hair follicle and secreted sebum, a mixture of free fatty
acids, triglycerides, and waxes that provide protection, lubrication, and maintain the pH of
the skin at around 5.5 [19].
The skin can be considered a very dynamic, yet sensitive, environment, due to its natural
microbiome [20], alongside immunocompetent cells and other important structures. Two of
those examples are the Langerhans and dendritic cells, highly specialized leukocyt es respon-
sible for presenting the antigens to T cells [21,22]. These cells are one of the first lines of de-
fense of the host toward maintaining their homeostasis [18 ]. Melanocytes are other skin cells
with a role in protection, being responsible for protection against UV radiation. To do so, they
produce melanin, a pigment that accumulates on the SC to act as a chemical barrier toward
the impacts of radiation and the reactive oxygen spe cies (ROS) [23]. Finally, and in addition
to these barrier functions, the skin is also involved in temperature control, through sweat
glands and hair follicles [24], and in tissue repair [25].
Overall, the skin can be interpreted as one of the interfaces to human health, being its com-
plex environment herein discussed. Like other organs, it gives signals as warnings to changes,
which should not be overlooked. The next section details the phenotypic expression of mel-
anoma and its effect s on all these elements.
3. Melanoma: pathophysiology and therapeutic approaches
The hum an organism is a complex environment where homeostasis is the fundamental
point for health. All organs have their role in maintaining the equilibrium, and the skin is
a relevant part of it. As mentioned ear lier, this barrier protects all systems from external
threats potentially compromising well-being, but is often disregarded [12].
Skin structures were detailed in the previous section. From all of them, melanocytes have
relevance in the context of melanoma. As previously referred, these cells produce melanin, an
important pigment that protects an individual against UV radiation [26]. Even if the benefits
of UV radiation are yet to be fully understood, the stimulation they provide not only induces
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the production of melanin, but also has a major impact in the synthesis of vitamin D. Never-
theless, occupational and recreative sun exposure, often uncontrolled, can induce avoidable
stress on the skin [27 ]. Moreover, melanocytes, which are located at the epidermal-dermal
junction, are continuously attacked by other mutagenic agents, such as pollutants, excessive
free radicals, and heavy metals, among others. All these, along with age [28], can induce ge-
netic and metabolic transformations on cells overcom ing, at some point, their natural repair
mechanisms. When this occurs, melanocytes begin to proliferate abnormally and become un-
responsive to the regulatory signals from fibroblasts and keratinocytes. Additionally, the
signaling pathways that regulate melanocyte proliferation become aberrantly activated lead-
ing to melanoma. Refs. [29e32] summa rize some of the risk factors and their biochemical
implication on triggering melanoma. A more detailed discussion on risk factors can be found
elsewhere [6](Fig. 15.2).
The diagnosis of melanoma relies on the evaluation of suspicious regions of the skin
through the magnifying lens of a dermatoscope [8,27]. In cases that a visual analysis is insuf-
ficient, a physician can suggest a biopsy for histological analysis of the region, and at a later
stage, its genetic profiling [33]. Genetically, melanomas can fit into three categories: somatic,
familial [34], and metastatic [35]. The first one is the most commonly found profile, being the
v-Raf murine sarcoma viral oncogene homolog B proto-oncogene (BRAF) associated with
intermittent sun exposure [36], the NRAS linked to malignant cell growth [37], and the
v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene (c-KIT) related
with melanocyte development and proliferation [38] the most frequent somatic mutations
[39]. A more detailed look into melanoma genetics can be found elsewhere [40].
From a visual and histological point of view, melanoma can be categorized into cutaneous
and extracutaneous, the former being the most common malignant form. Extracutaneous
melanoma is out of scope of the present chapter. Cutaneous melanomas divide themselves
into four histological types [41], as described in Table 15.1.
In parallel with the information contained in the previous table, the dermatologist can use
a classification system to better perceive where the lesion of the patient fits. This classification
FIGURE 15.2 Molecular background of UV radiation and oxidative stress effects on melanoma initiation, pro-
gression, and metastatic potential.
3. Melanoma: pathophysiolog y and therapeutic approaches 345
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requires three different parameters: (1) Tumor (T), corresponding to the classification of the
primary cancerous occ urrence by size; (2) Node (N), which assesses if there is a regional
node metastasis and to where it spread to; and (3) Metastasis (M) that defines the extension
of the spreading in accordance with the location of its metastasis [43]. The classification sys-
tem is thus called TNM, specific details are available in published data [44]. Considering all
this information, a final interpretation of the data results in assigning the tumor to one of
these stages.
Stages 0, I, and II: Localized and confined to the primary site of the tumor
Stage III: Tumor with regional lymph node infiltration
Stage IV: Tumor with distant metastasis [45]
Each of the abovementioned stages has its subcategorization [6]. However, it was benefi-
cial to simplify these classification systems, for a better understanding of the wide scenario
(Fig. 15.3).
Both dermatologists and patients should consider that more advanced the stage of the tu-
mor, the lower the percentage of survival [6,45], as the aggressiveness can lead to very
complicated clinical scenarios, including death. Nevertheless, whichever the stage in which
the patient fits, there are, nowadays, approved therapeutic approaches that can prolong
life span and the quality of life of the patient [47]. In 2020, the European Journal of Cancer pub-
lished an update on the melanoma treatment guidelines [48]. A primary approach relies on
the surgical excision of the melanoma tumor [49]. Radiotherapy can be considered as an
option, in some situations, for example, if surgery will lead to disfiguration of the patient,
if there are predictions of surgical complications, and if metastasis are already too dissemi-
nated and cannot be caught by surgery alone [50]. Another approach that might be an option
is adjuvant therapy [51,52], with interferons or inhibition-based immunotherapy. In very
advanced cases of melanoma, a targeted therapy, which comprises a regimen with a specific
cocktail of monoclonal antibodies, might be considered, even if, to this day, these approaches
TABLE 15.1 Histological types of cutaneous melanoma [41,42].
Histological
types Cause Clinical findings
Superficial
spreading
melanoma
Intermittently sun-exposed skin, in the trunk
and extremities common with BRAF
mutation
Raised surface and haphazard coloration. Atypical
and immature melanocytes. Most common type
Lentigo maligna
melanoma
Chronically sun-exposed areas in the head
and neck
Large, flat, pigmented lesion, 2nd most common type
Nodular
melanoma
Common with NRAS genetic mutation Dermal tumor with a smooth, uniform pigmented
nodule with lack of surrounding flat discoloration.
More aggressive
Acral
lentiginous
melanoma
Higher probability to be originated from
genetic mutations (NRAS and KIT)
Broad lentiginous growth with invasion of the dermis.
Found in the plantar surface, being the rarest of these
types
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are still experimental and clinical trials underway [53]. Lastly, and for cases in which no ther-
apeutic response was obtained, due to overall resistance to immunotherapies, chemotherapy
is a valid approach [54,55]. Whichever the therapeutic regimen, the overall quality of life
might be affected [56]. Thus, more efficient therapies are required, as well as a constant up-
date of therapeutic guidelines. In this scenario, newer molecules and formulations are being
studied, and those will be the focus of the next sections.
3.1 Polyphenols for melanoma prevention and treatment
The evolution of the scientific knowledge allows a better understanding of diseases and
the corresponding potential therapies. The aim of therapeutic regimens is to, in the least
possible amount of time, cure the disease or, if a chronic disease is being approached, ease
symptoms. That is achieved by constant discoveries of new molecules, new process es, and
new possible therapeutic agents. Polyphenols are one of those cases [57]. These molecules
are phytochemicals that occur in nature and have proven efficacy in increasing cellular anti-
oxidant capacity, providing a preventive antioxidant action, thus eliminating or decreasing
oxidative stress [58]. This broad family of chemical compounds can be divided into four ma-
jor groups: flavonoids, phenolic acids, lignans, and stilbenes [59,60], and examples of mole-
cules can be found in Fig. 15.4AeD.
In brief, polyphenols have been known for their antioxidant, anti-inflammatory, and anti-
cancer properties, among others. Their main mechanism of action relies on the phenolic
group that can capture electrons from reactive nitrogen species (RNS) and ROS, resulting
in a more stable chemical structure (phenoxyl radical). This ensures that the radical chain
is stopped, and no further damage in cells is done [59]. However, it is described that, in
some cases, polyphenols can interfere with molecular pathways, inducing apoptosis, as
reported for resveratrol [61]. If melanoma is considered, polyphenols might be one alternative
FIGURE 15.3 A representative scheme of melanoma staging. Reproduced from Jaworek-Korjakowska J, Kleczek P.
eSkin: study on the smartphone application for early detection of malignant melanoma. Wireless Communications and Mobile
Computing. 2018;2018:1e11. https://doi.org/10.1155/2018/5767360.
3. Melanoma: pathophysiolog y and therapeutic approaches 347
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