gels

Review
Gel Formulations for Topical Treatment of Skin Cancer:
A Review
Marta Slavkova * , Borislav Tzankov, Teodora Popova and Christina Voycheva

Department of Pharmaceutical Technology, Faculty of Pharmacy, Medical University of Sofia, 1000 Sofia, Bulgaria;
[email protected] (B.T.); [email protected] (T.P.)
* Correspondence: [email protected]; Tel.: +359-2-9236527

Abstract: Skin cancer, with all its variations, is the most common type of cancer worldwide. Chemother-
apy by topical application is an attractive strategy because of the ease of application and non-
invasiveness. At the same time, the delivery of antineoplastic agents through the skin is difficult
because of their challenging physicochemical properties (solubility, ionization, molecular weight,
melting point) and the barrier function of the stratum corneum. Various approaches have been
applied in order to improve drug penetration, retention, and efficacy. This systematic review aims
at identifying the most commonly used techniques for topical drug delivery by means of gel-based
topical formulations in skin cancer treatment. The excipients used, the preparation approaches, and
the methods characterizing gels are discussed in brief. The safety aspects are also highlighted. The
combinatorial formulation of nanocarrier-loaded gels is also reviewed from the perspective of improv-
ing drug delivery characteristics. Some limitations and drawbacks in the identified strategies are also
outlined and considered within the future scope of topical chemotherapy.

Keywords: skin cancer; physical hydrogel; chemical hydrogel; composite gel; systematic literature review

1. Introduction
Skin is the largest organ in the human body, performing various functions ranging
Citation: Slavkova, M.; Tzankov, B.; from protection to metabolism. The abnormal growth of the skin cells is referred to as skin
Popova, T.; Voycheva, C. Gel
cancer and this is the most common cancer type worldwide [1]. There are various types of
Formulations for Topical Treatment
skin cancer, including benign and malignant variants such as melanoma, squamous cell
of Skin Cancer: A Review. Gels 2023,
carcinoma and basal cell carcinoma [2]. Even though skin cancer is lethal in only 2% of
9, 352. https://doi.org/10.3390/
cases in general, the malignant forms result in death in more than 80% of cases if not caught
gels9050352
early [1]. The management of skin cancer includes surgical excision, radiotherapy, topical
Academic Editors: Haoan Wu and drug delivery, and oral therapy [2]. Although surgical treatment is considered the first line
Xingchun Gao approach, topical therapy also has its role [3]. The most commonly prescribed medications
Received: 10 March 2023
are 5-fluorouracil [4–6] and imiquimod [5,7,8]. Other active pharmaceutical ingredients
Revised: 18 April 2023
(APIs) are either repurposed or subjected to investigation and evaluation because of their
Accepted: 20 April 2023 topical chemotherapeutic potential in various forms of skin cancer. Some examples are
Published: 22 April 2023 doxorubicin [9], vismodegib [10], sonidegib [11], and metformin [12]. Substances of natural
origin (curcumin [13,14], brucine [15], silymarin [16], chrysin [17], daidzein [18], and others)
are also considered suitable in the topical treatment of skin cancer.
The topical dermal route provides ease of administration, non-invasiveness, and
Copyright: © 2023 by the authors. reduced systemic effects with the associated limited side effects and improved patients’
Licensee MDPI, Basel, Switzerland. compliance [19,20]. Semisolid dosage forms occupy a serious part of the pharmaceutical for-
This article is an open access article mulations as they can be applied topically to the skin, cornea, nasal cavity, vagina, rectum,
distributed under the terms and etc. Their specific rheological behavior governs their ability to adhere to the application
conditions of the Creative Commons site and prolong the API’s release. A significant advantage of these dosage forms is their
Attribution (CC BY) license (https://
ease of formulation and the possibility to incorporate various active moieties [21]. These
creativecommons.org/licenses/by/
advantages apply especially for gels which, in comparison to the other semisolid dosage
4.0/).

Gels 2023, 9, 352. https://doi.org/10.3390/gels9050352 https://www.mdpi.com/journal/gels

Gels 2023, 9, 352 2 of 36

forms, have higher retention time, provide excellent spreadability, and possess somewhat
less long-term stability issues [22].
Nevertheless, there are some limitations arising from the properties of the API and the
structure and function of the skin, and conventional gels cannot be a universal dosage form
for treatment of skin conditions. In particular, if the cancerous cells are in a deeper layer
of the skin, conventional semisolid formulations cannot provide adequate delivery of the
chemotherapeutic [23]. Therefore, the combinatorial approach has been implemented in
recent years to overcome these issues and improve dermal drug delivery. The nanoformula-
tions solve major problems regarding the API solubility and penetration through skin layers,
and they can guarantee controlled drug release and the possibility of delivering larger
molecules or very hydrophilic compounds. However, their direct application is associated
with probable compromised stability and limited retention time [24]. Thus, the increased
number of publications researching the combinatorial drug delivery of nanocarrier-loaded
gels is no surprise. A further possibility for improved therapeutic efficiency while simulta-
neously limiting the side effects in the adjacent skin tissues is targeted delivery of the API to
the cancer cells [25,26]. The process can be either passive or active based on the underlying
mechanisms involved. The passive targeting relies mainly on the enhanced permeation
and retention effect (EPR). The tumor cells are characterized by excessive angiogenesis,
which leads to the existence of considerably large gaps in the vascular walls. Together with
the poor lymphatic drainage, it can be expected that nanoparticles of sufficient particle
size (20–200 nm [25]) will permeate and be retained at the tumor site [27]. The active
targeting is mainly related to the ligand functionalization of the nanoparticles. These
surface-attached moieties can interact with the cancerous cells that overexpress receptors or
proteins and lead to clathrin-mediated endocytosis and cell internalization [25]. Therefore,
the active targeting not only enhances tumor accumulation but also increases intracellular
delivery [28]. Possible overexpressed receptors that may be candidates for active targeting
in skin cancers are folate receptor α isoform, transferrin receptor 1 (TfR1), CD44 surface
markers for hyaluronic acid, and other proteins [25,26,28,29].
The aim of the current article is to systematically review the gel-based strategies for
the therapy of skin cancer and to identify the main drawbacks and future aspects of gel
development. The most commonly used excipients and their role are shortly discussed,
and the most typical methods for characterization are given in brief. The current article
summarizes the published approaches for gel-based formulations for the topical delivery
of chemotherapeutics.

2. Systematic Search
2.1. Search Strategy
The systematic review was conducting according to PRISMA guidelines [30]. The
records were retrieved after searching in major scientific databases, namely, Google Scholar,
PubMed, Scopus, ScienceDirect, and Web of Science. The search was limited to the title,
abstract, and keywords without the full text. The year of publication was limited up to
2022 inclusively. The terms searched were identical in all databases (“skin cancer” AND
“gel” OR “hydrogel” OR “nanogel”). The duplicates were removed from the identified
papers with the help of Zotero software (v. 6.0.22), and the rest were browsed for relevance.
The search strategy, flow diagram, and retrieved articles are presented in Figure 1.

2.2. Inclusion and Exclusion Criteria

Only research articles were considered relevant while all therapeutic guidelines for
medicinal practice, clinical guidelines, conference proceedings, book chapters, therapeutic
strategies, and updates, as well as all review papers, were excluded. Papers that do not
address the potential gel application as a topical dosage form in skin cancer therapy were
also excluded. Articles published in 2023 were not included in the search. No language
limitations were used in the current search strategy.
Gels 2023,9,9,352
Gels2023, 352 33 of
of 36
37

Figure 1.
Figure 1. Flow
Flow chart
chart of
of the
the systematic
systematic search
search strategy
strategy according
accordingto
toPage
Pageet
etal.
al.[30].
[30].

2.2. Inclusion
All papersandconsidered
Exclusion Criteria
as relevant (n = 156) were original articles discussing the
development,
Only research articles were characterization
evaluation, and/or of gel
considered relevant formulations
while used inguidelines
all therapeutic the potential
for
topical
medicinaltreatment
practice,ofclinical
skin cancer.
guidelines, conference proceedings, book chapters, therapeutic
strategies, and updates, as well as all review papers, were excluded. Papers that do not
3. Drug Delivery
address Hurdles
the potential in Skin Cancer
gel application Treatment
as a topical dosage form in skin cancer therapy were
also excluded. Articles published in 2023 were not parenteral,
Chemotherapy of skin cancer can be either oral, included inorthetopical. In No
search. the language
first case,
only a limited amount of the drug reaches the
limitations were used in the current search strategy. target site, while the rest reaches other organs,
tissues, and cells, and can cause harmful side effects. The case is quite similar
All papers considered as relevant (n = 156) were original articles discussing the de- in parenteral
application
velopment,together withand/or
evaluation, its invasiveness. Therefore,
characterization theformulations
of gel local application
usedon
indifferent skin
the potential
cancer
topical forms can of
treatment gain
skinin cancer.
therapeutic efficacy and safety. However, there are numerous
obstacles for drug penetration, which makes the topical delivery a challenging task.
3. Drug Delivery Hurdles in Skin Cancer Treatment
3.1. Skin Structure
Chemotherapy of skin cancer can be either oral, parenteral, or topical. In the first case,
Skin is a complex organ with the main function to “maintain the insides in and
only a limited amount of the drug reaches the target site, while the rest reaches other or-
outside out”, acting as a barrier [31]. It consists of three layers—the epidermis, dermis,
gans, tissues, and cells, and can cause harmful side effects. The case is quite similar in
and hypo-dermis—each having a different composition and properties [32] (Figure 2). The
parenteral application together with its invasiveness. Therefore, the local application on
inner hypodermis consists of adipose tissue and rarely plays an important role for drug
different skin cancer forms can gain in therapeutic efficacy and safety. However, there are
delivery [31]. The dermis (around 2–4 mm) [33] is built up by a collagen and elastin network
numerous obstacles for drug penetration, which makes the topical delivery a challenging
in a mucopolysaccharide gel which resembles a hydrogel structure. The vascularity of the
task.
dermis enables the transport of the most transdermally delivered drug molecules into the
blood, maintaining a high concentration gradient. This layer also includes appendages—
3.1. Skin Structure
hair follicles, sebaceous and sweat glands—which have an impact only on the initial
Skinthrough
diffusion is a complex organ
the skin [31].with
Thethe main function
outermost to “maintain
skin layer—the the insides in and
epidermis—consists out-
mainly
side out”, acting as a barrier [31]. It consists of three layers—the epidermis,
of cells, called keratinocytes, which play a lead role in topical drug delivery [34]. The dermis, and
hypo-dermis—each having a different composition and properties
epidermis has two avascular and hydrophobic sections, the viable epidermis and the [32] (Figure 2). The in-
ner hypodermis
stratum corneumconsists
(SC). The of viable
adiposeepidermis
tissue and rarely of
consists plays
fouranlayers
important role for drug
of keratinocytes at
delivery [31].
different stagesThe
of dermis (around melanocytes,
differentiation, 2–4 mm) [33] Merkel
is built up byand
cells, a collagen and elastin
Langerhans net-
cells. The
work in a mucopolysaccharide
differentiation of the epidermis gel which
starts fromresembles
inside to aoutside,
hydrogel andstructure.
results inThe
thevascularity
formation
of corneocytes—dead,
of the dermis enables the transport
anuclear, of the most
flattened, and transdermally
keratin-rich cells delivered
[33]. Thedrug molecules
corneocytes
intosurround
are the blood, bymaintaining
lipid matrix acomposed
high concentration gradient.
of triglycerides, This layer
cholesterol, also
free includes
fatty acids andap-
pendages—hair
ceramides, follicles,
and these sebaceous
structures act and
as thesweat
primeglands—which
barrier to thehave
entryanofimpact
macroonly
and on the
micro
initial diffusion
anticancer through
molecules thethe
across skin [31].limiting
skin, The outermost skin layer—the
drug delivery epidermis—consists
[35–37]. Normal melanin cells
are characterized
mainly with physiological
of cells, called keratinocytes,pH whileplay
which tumor cellsrole
a lead haveinatopical
pH in the
drugrange 5–6.5 [34].
delivery [38].
In
The the case of melanoma,
epidermis the acidic
has two avascular andpH is responsible
hydrophobic for the
sections, theinvasion of surrounding
viable epidermis and the
tissues
stratumand the malignant
corneum (SC). The cells have
viable higher metastatic
epidermis consists ofcapacity [39] of keratinocytes at dif-
four layers
ferent stages of differentiation, melanocytes, Merkel cells, and Langerhans cells. The dif-
ferentiation of the epidermis starts from inside to outside, and results in the formation of
 corneocytes—dead, anuclear, flattened, and keratin-rich cells [33]. The corneocytes are
surround by lipid matrix composed of triglycerides, cholesterol, free fatty acids and
ceramides, and these structures act as the prime barrier to the entry of macro and micro
anticancer molecules across the skin, limiting drug delivery [35–37]. Normal melanin cells
are characterized with physiological pH while tumor cells have a pH in the range 5–6.5
Gels 2023, 9, 352 4 of 36
[38]. In the case of melanoma, the acidic pH is responsible for the invasion of surrounding
tissues and the malignant cells have higher metastatic capacity [39]

Figure 2. Skin structure and routes of drug transport through cancerous skin after topical anticancer
Figure 2. Skin structure and routes of drug transport through cancerous skin after topical anticancer
treatment.
treatment.
Moreover, skin cancer studies revealed there are higher levels of keratin and lipids in
Moreover, skin cancer studies revealed there are higher levels of keratin and lipids
cancer cells compared to healthy cells, resulting in a thicker SC layer and consequently a
in cancer cells compared to healthy cells, resulting in a thicker SC layer and consequently
stronger barrier to drug entry, which makes it even more difficult for anticancer molecules
toa reach
strongerthebarrier
tumor to drug
site entry,This
[34,40]. which makes
is why it even more
transdermal difficult
drug dosageforforms,
anticancer mole-
employed
against actinic keratosis (AK) and basal cell carcinoma (BCC), require proper designem-
cules to reach the tumor site [34,40]. This is why transdermal drug dosage forms, to
ployed
reach theagainst
deeperactinic keratosis
epidermal layers(AK) and basal
[32,41,42]. Thecell carcinoma
optimal (BCC),
particle require to
size needed proper de-
achieve
sign to reachdelivery
transdermal the deeper epidermal
lies in the rangelayers [32,41,42].
200–400 nm [43].The optimal particle
Nanoparticles size needed
with sizes of aboutto
achieve
300 nm cantransdermal
reach deeperdelivery lies inthrough
skin layers the rangethe200–400 nm [43]. Nanoparticles
transappendgeal route [44]. with sizes
of about 300 nm can reach deeper skin layers through the transappendgeal route [44].
3.2. Skin Penetration Routes and Factors Influencing Skin Penetration
3.2. The
Skin penetration
Penetration Routes
of drugsandthrough
Factors Influencing
the skin canSkin Penetration
happen by three possible routes de-
pendingTheonpenetration of drugs through
the physicochemical propertiestheof
skin
thecan happen
active by three
substance: possible routes
intracellular (through de-
pending
the stratumoncorneum),
the physicochemical
intercellularproperties
(throughofthe thelipid
active substance:
matrix), and intracellular
through the (through
skin ap-
the stratum
pendages corneum),
(sweat glands orintercellular (through
hair follicles) the lipid
[31] (Figure matrix),
2). The and via
transport through the skin ap-
skin appendages
pendages
(shunt (sweat
route) glands
is more or hairfor
suitable follicles) [31] (Figure
hydrophilic 2). The
molecules, transport
but since the viafractional
skin appendages
area of
appendages
(shunt route) is is
relatively small, this
more suitable shunt route molecules,
for hydrophilic is not as important
but sincefor drug
the delivery
fractional [45].
area of
On the other ishand,
appendages highly
relatively lipophilic
small, drugroute
this shunt molecules
is not ascan easily pass
important through
for drug the skin
delivery [45].
intercellularly via thehighly
On the other hand, lipid matrix.
lipophilicThedrug
intercellular
molecules (transcellular)
can easily passroute is the the
through most com-
skin in-
plicated one because
tercellularly the drug
via the lipid matrix.molecule should repeatedly
The intercellular pass through
(transcellular) different
route is the media
most compli-
ofcated
the “brick wall” the
one because [46].drug
First, the permeant
molecule shouldshould
repeatedly partition into keratin-filled
pass through corneo-
different media of
cytes (hydrophilic environment), and after that it should diffuse through
the “brick wall” [46]. First, the permeant should partition into keratin-filled corneocytes the corneocytes,
followed by partitioning into the intercellular lipid matrix (lipophilic environment) [47].
Since crossing the lipid bilayers is involved in both transcellular and intercellular routes,
diffusion through these lipid media is highly important. Therefore, lipophilic drugs are
preferred candidates for transdermal delivery [31]. However, when passing through the
stratum corneum, molecules reach the more hydrophilic lower epidermal layers (viable
epidermis), and in the capillaries of the epidermal–dermal junction, they can be cleared,
entering the systemic circulation [41]. Thus, high lipophilicity hinders the clearance. Ideally,
Gels 2023, 9, 352 5 of 36

the permeant should possess moderate hydrophilic–lipophilic properties, expressed as a

logarithm partition coefficient (log Pwater/octanol ) in the range 1–3 [32,45].
Unfortunately, not all anticancer medications possess this desired hydrophilic–lipophilic
balance. For example, 5-fluorouracil, approved for actinic keratosis (AK) and superficial
basal cell carcinoma (sBCC), is a highly hydrophilic molecule (log P: −0.89) [48]. This
hydrophilicity restricts penetration through the hydrophobic stratum corneum and is re-
flected in low treatment efficacy for deeper laying lesions [48]. Furthermore, the insufficient
skin penetration of 5-FU requires frequent and higher administration doses, which leads
to side effects such as skin inflammation [49–51]. The situation with imiquimod, used for
the treatment of BCC, is similar. Due to its low water solubility, permeability within the
hydrophilic dermis media is difficult. Moreover, there is an interaction between the amine
groups of the drug molecule with the anionic components of the skin, limiting additional
imiquimod permeation, and resulting in reduced therapeutic effect [52,53].
Another factor that influences skin penetration is the molecular weight of a permeant
as the transport of molecules via the skin happens by passive diffusion under a concen-
tration gradient, following Fick’s law. According to the Stokes–Einstein equation, the
diffusion coefficient of a molecule increases with the increase in its approximate radius.
Therefore, a higher molecular weight is related to a higher approximate radius, so that the
diffusion coefficient is generally smaller and thus the diffusion is hindered. For transdermal
delivery, the drug’s molecular weight (MW) should be less than 500 Da [31,32], making the
penetration of anticancer drugs with higher molecular weight difficult.
Another problem arising in cancer therapy is multidrug resistance (MDR). The interac-
tion between the drug and the tumor media is a complex phenomenon and cancers can
exhibit significant resistance to various molecules. Multidrug resistance can be defined as
the decrease in the efficacy and potency of a drug to produce a therapeutic effect and is a
major problem that reduces the chemotherapies’ effectiveness [34,54]. Drug resistance in
skin cancers can be primary (intrinsic) or acquired. Primary resistance appears without
prior exposure to anticancer agents, and thus the initial response to treatment is poor [55].
Acquired resistance is developed during the application of the cytostatic drug, and it is
associated with devastating results after initially good ones [54,56].
Different mechanisms are associated with intrinsic resistance, such as changes in drug
transport and efflux pump, alteration in enzyme activation and DNA repair, modulation
of the apoptotic pathway, etc. [56–59]. Acquired drug resistance is affected mainly by
genetic or environmental factors that enable the progress of drug-resistant cancer cell
lines or induce enzyme mutations [54,55,60]. Therefore, understanding the modifications
in molecular processes involved in drug resistance can trigger the development of new
therapeutic strategies against skin cancers.
One of the potential factors leading to the sensitivity of drugs is the limited amount of
drug reaching the tumor cells. This is why the determination of the “maximum tolerated
dose” (MTD)—the highest single dose of an agent that does not cause significant or intoler-
able toxicity effects—is of great importance [54,61]. Therefore, any methods for increasing
the penetration of the anticancer drug through the skin, and thus increasing the amount
reaching the tumor cells, can lead to improved therapeutic outcomes.

3.3. Opportunities for Increasing Skin Penetration

Considering all the issues discussed and the factors involved in managing the transport
of anticancer drugs through the skin, the most important challenge of therapy is the
improvement in the drug uptake, allowing the drug to pass through the deeper layers of
skin, inside cancerous cells [32].
One of the techniques to augment penetration is the utilization of “penetration en-
hancers” [32,62], such as ethanol, Azones, fatty alcohols, glycols, and DMSO. These sub-
stances mainly disrupt the lipid bilayer packing, interacting with intercellular proteins [31].
It is important to know that water possesses enhancer properties, as the drug diffusion is
higher through hydrated skin; thus, occlusion is necessary for improved therapy [62].
Gels 2023, 9, 352 6 of 36

Many dosage forms are used for topical delivery of skin anticancer medication, such
as powders, aerosols, emulsions, and creams. However, hydrogels have superior proper-
ties [32,63]. Their structure allows them to be controlled at a molecular scale, which can be
used to modify the properties such as degradation rate, long-time release, tunable pore size,
and chemical and biological response to stimuli such as pH, enzymes, and temperature, in
accordance to desired values [64]. Moreover, hydrogel-based drug dosage forms exhibit
improved chemotherapy outcomes by increasing drug half-life, enabling controlled drug
release, and reducing nontargeted exposure [65–67].
The combination of gel formation technology and nanotechnology leads to the creation
of advanced drug delivery systems such as nanogels, liposomes, ethosomes, niosomes,
and transferosomes, improving the skin penetration and bioavailability, and can be po-
tentially used for topical skin cancer therapy [40,49,68]. These strategies either alone or in
combination are discussed in the following sections of the current review.

4. Gel-Based Formulations
According to European Pharmacopoeia, gels are a class of semisolid preparation
for cutaneous application, which consist of liquids gelled by means of a suitable gelling
agent [69]. They possess a three-dimensional network due to the formation of covalent or
noncovalent bonds of the polymer used with the medium [70]. Based on the polarity of the
liquid, the Pharmacopoeia further classifies them into hydrophilic and lipophilic gels [69].
There are a large number of other criteria in the literature, based on which the gels can be
distinguished: nature of the solvent, colloidal phases, rheology, the origin of the gelling
agent, etc. Three main types can be classified based on the nature of crosslinking, namely,
physical gels, covalently cross-linked gels and entanglement network gels [70]. This review
uses these three classes of gels in order to discuss their properties and application in
chemotherapeutics delivery in skin cancer. Physical gels can be prepared with natural,
synthetic, and semi-synthetic polymers such as carbomers, gelatin, marine polysaccharides,
and plant polysaccharides. Typically, these gels use temporary cross-linking and therefore
they are transient in nature. The second group are the covalently cross-linked gels, which
are also referred to as chemically cross-linked gels. In their structure, chemical bonds exist
between the macromolecules and the cross-linker and these bonds are susceptible only to
thermal degradation. These gels are characterized with high elasticity due to the larger
volume of solvent and the flexibility of the polymer chain. Polymeric hydrogels are a
subgroup in this class prepared by cross-linking a three-dimensional hydrophilic polymeric
network swollen in water. In the last class (entanglement networks), gels are formed when
the concentration and molecular weight of the polymer used exceed the critical molecular
mass of entanglement. Otherwise, they form dilute polymer solutions [70].
The systematic search retrieved 156 relevant records, as can be seen in Figure 1. The
distribution of papers between the different types of gels can be seen in Figure 3. Articles that
discuss the preparation and characterization of physical hydrogels comprise 25% (n = 39). None
of the retrieved records discusses the preparation of organogels. This is probably due to the
advantages of hydrogels, such as their ease of preparation, non-greasy nature, and cooling
sensation upon application [71]. Chemically cross-linked hydrogels account for 5% (n = 8). Even
though chemical hydrogels are extensively studied in chemotherapy, their primary application
is parenteral. Therefore, the current search provided only limited articles. Nanogels, which
are characterized by small particle sizes in the range of 20 to 250 nm, are subjects in about
5% of articles (n = 7). Nanocarrier-loaded gels are either physical or chemical hydrogels in
which different nanocomposites are incorporated. As can be seen on Figure 3, they represent the
majority of the identified articles, 59% (n = 92), due to the combined and versatile properties they
provide. In the group of others belong gels that do not fall into any of the previous categories,
such as bigels and emulgels, or that are unclear due to unavailable full text. In the following
sections, each of those types of gels is discussed in brief within the scope of topical dermal
delivery in skin cancer therapy.
 either physical or chemical hydrogels in which different nanocomposites are incorpo-
rated. As can be seen on Figure 3, they represent the majority of the identified articles, 59%
(n = 92), due to the combined and versatile properties they provide. In the group of others
belong gels that do not fall into any of the previous categories, such as bigels and emulgels,
Gels 2023, 9, 352 or that are unclear due to unavailable full text. In the following sections, each of those7 of 36
types of gels is discussed in brief within the scope of topical dermal delivery in skin cancer
therapy.

Figure 3.
Figure Typesofofgels
3.Types gelsused
usedforfor topical
topical drug
drug delivery
delivery in skin
in skin cancer
cancer treatment
treatment according
according to thetosys-
the
tematic search.
systematic search.

4.1. Physical
4.1. Physical Hydrogels
Hydrogels
Physical hydrogels
Physical hydrogels are
are those
those types
types of
of dosage
dosage forms
forms in
in which
which water
water with
with or
or without
without
other polar liquids is used as the medium and the gelling agent is physically
other polar liquids is used as the medium and the gelling agent is physically cross-linked cross-linked
due to
due to electrostatic
electrostatic interaction,
interaction,ionic
ionicinterchain
interchainbridges, crystallization
bridges, junctions,
crystallization hydropho-
junctions, hydro-
bic association, hydrogen bonds, or others [72]. The most typical characteristic
phobic association, hydrogen bonds, or others [72]. The most typical characteristic for these
for
gels is their reversibility and the temperature-dependent sol–gel transition.
these gels is their reversibility and the temperature-dependent sol–gel transition. Addi- Additionally,
the polymers
tionally, used in their
the polymers usedpreparation possess apossess
in their preparation good safety
a goodprofile
safetyasprofile
they are
as nontoxic,
they are
biocompatible, and non-reactive, and no residual cross-linkers can be found in comparison
nontoxic, biocompatible, and non-reactive, and no residual cross-linkers can be found in
to chemical hydrogels [70,73]. This section of the review discusses the application of various
comparison to chemical hydrogels [70,73]. This section of the review discusses the appli-
natural, synthetic, and semi-synthetic polymers suitable for the preparation of physical
cation of various natural, synthetic, and semi-synthetic polymers suitable for the prepara-
gels with chemotherapeutic agents for skin cancer.
tion of physical gels with chemotherapeutic agents for skin cancer.
4.1.1. Carbomer as a Gelling Agent
4.1.1. Carbomer as a Gelling Agent
Carbomers are synthetic high-molecular-weight polyacrylic acid derivatives cross-
Carbomers
linked with allylare synthetic
sucrose high-molecular-weight
or allyl pentaerythritol. Theypolyacrylic
are anionicacid derivatives
in nature cross-
and contain
linked with allyl sucrose or allyl pentaerythritol. They are anionic in nature
between 56 and 68% w/w carboxylic acid groups [74,75]. They are capable of forming hy- and contain
between 56 and
drogel bonds 68%
with w/w carboxylic
mucin, acidpossess
and therefore groupsbioadhesive
[74,75]. They are capable
properties [75].ofCommercially,
forming hy-
drogel bonds with mucin, and therefore possess bioadhesive
® properties
carbomers are available under the trade name Carbopol . The main difference between [75]. Commer-the
cially,
various carbomers are available
types of carbomers underon
is based thethe
trade name Carbopol
differences
®. The main and,
in their production difference be-
therefore,
tween the various
the resulting types of
properties carbomers
such is based
as solution on the
viscosity. differences
For in their production
example, Carbopol ® 934, 940,and,
and
941 are prepared by polymerization in benzene as a solvent, while the newer NF (National
Formulary, United States Pharmacopoeia) grades are synthesized in a benzene-free pro-
cess. Other variations could be due to the type and amount of cross-linker used [76]. The
technological procedure of carbomer gel preparation is well-established and is based on
the hydration of the polymer in water, resulting in an acidic dispersion with pH = 2.5–3.5
depending on carbomer type and concentration [77]. Then, neutralization with sodium
hydroxide, triethanol amine, or other base leads to ionization of carboxylic functional
groups, followed by partial disentanglement of polymer chains and formation of irre-
versible agglomerates [78,79]. Very often the medium of carbomer gels contains, in addition
to water, polyethylene glycol (PEG 400) or glycerol, which may affect the rheological and
mucoadhesive properties [78]. In the current review, Carbopol® 934 was found to be most
commonly applied in order to prepare conventional physical gels. The concentrations
ranged from 0.5% to 3% w/w [80–84].
Gels 2023, 9, 352 8 of 36

One of the drawbacks in carbomer-based physical gels is the aqueous medium in

which they are prepared. On one hand, this raises the need for the addition of other
excipients such as preservatives [85] in order to prolong microbial stability. On the other
hand, there is a significant number of drugs that are not water soluble such as resatorvid,
which is used to treat skin cancer. This requires the addition of a suitable co-solvent
as suggested by Ruiz et al. [80]. Another work group of Osipitan et al. [81] compared
phenethyl isothiocyanate (a phytochemical, PEIT) formulated in 0.5% Carbopol® 940 to an
analogical gel containing 5-fluorouracil. The incorporation of the PEIT similarly required
its dissolving in DMSO prior to the gel preparation. DMSO can further potentiate the
effect because it is commonly used as a penetration enhancer. The conducted investigation
showed also that it is compatible with carbomer gel [81,84]. Recombinant heat shock
protein (Hsp70) was incorporated into 1% carbomer in the presence of 1% glycerol and
10% DMSO by Abkin and colleagues [82]. Their investigation showed that the protein
was prevented from undergoing denaturation and/or proteolysis during storage. The
lyophilized methanolic root extract of Annona reticulate was successfully incorporated into
Carbopol® 940 gel (1% w/w) by Bharadwaj et al. with the help of 10% glycerol [83]. The
authors showed the potential of the formulation for dermal anticancer treatment.
Photodynamic therapy (PDT) could also benefit from the application of physical
gels. Non-toxic chemicals called photosensitizers are applied either orally or locally to
produce visible fluorescence when activated through illumination with an appropriate
wavelength [86]. A classic example of a drug used in PDT is porphyrins and their precursor,
5-aminolevulinic acid (5-ALA). Even though 5-ALA is a small molecule, its hydrophilic
nature hinders penetration through the stratum corneum. A possible approach to resolve
the issue is via its chemical modification as a methyl or hexyl ester. An alternative could be
the use of penetration enhancers such as DMSO [87]. Merclin and co-workers investigated
the possibility of using carbomer physical gel containing 5-ALA or methyl-ALA by means
of iontophoresis [84]. Since hydrogels serve as contact gels between the skin and electrodes
in iontophoresis, they could be used as a vehicle to deliver APIs to the deeper skin layers.
Furthermore, carbomer is an anionic polymer and possesses good buffering capacity, which
can be beneficial in maintaining constant pH. Interestingly, the authors investigated this
and showed that the diffusion of uncharged drug in 1% w/w carbomer gel is similar to
that in water. At the same time, positively charged drugs are retained to some extent [84].
The given examples of carbomer-based physical gels show that this is a versatile
platform for the direct loading of hydrophilic and lipophilic substances, which can be
applied in combination with phototherapy, radiotherapy, and iontophoresis. Nevertheless,
the limitations to deeper penetration of the APIs into the skin layers still exist, which in these
types of gels depend significantly on the properties of the drug itself. Therefore, physical
gels produced by means of carbomer are suitable semisolid vehicles for the treatment of
surface skin cancer given suitable drug solubilization is achieved.

4.1.2. Cellulose Derivatives as a Gelling Agent

Different cellulose derivatives have been exploited in the preparation of various
hydrogels and there are already published reviews discussing their properties, preparation
techniques, and fields of application [88–90]. The current article focuses on their application
as a dosage form for topical chemotherapeutic delivery.
Cellulose is a polysaccharide obtained from various plants, animals, or bacteria. It
is renewable and abundant worldwide, which together with its biodegradability, biocom-
patibility, environment friendliness, and good mechanical properties, makes it suitable for
numerous areas of application. Cellulose is a semicrystalline linear polymer of glucose that
is tasteless and odorless but insoluble in water, like many organic solvents [88]. Its aqueous
insolubility hinders the biomedical application of cellulose. Therefore, chemical modifica-
tion of its hydroxyl group through etherification and esterification leads to the preparation
of substances with improved solubility [91]. Many cellulose derivatives are used in the
development of the vast majority of drug delivery systems including liquid, semisolid,
Gels 2023, 9, 352 9 of 36

and solid conventional dosage forms [92] and the relatively newer nanocomposites [93].
In addition, the cellulose derivatives can form physical hydrogels due to hydrogen bonds,
ionic interactions, and hydrophobic forces [90].
Hypromellose or hydroxypropylmethyl cellulose (HPMC) is an electroneutral water-
soluble derivative of cellulose to which methyl and hydroxypropyl side groups are attached.
The polymer provides a wide range of viscosity grades depending on the substitution
degree and ratios [94]. The systematic search retrieved four articles considering HPMC as a
gelling agent in physical hydrogels [95–98]. Two of them investigated the incorporation of
cyclodextrin complexes with APIs into a semisolid gel. Ceschel and co-workers showed that
the HPMC-based gel has its own solubilizing effect, as the release rate from a gel containing
the API and a gel containing the API-cyclodextrin complex is identical. Nevertheless, the
cyclodextrin complex showed better permeation. The authors hypothesized that this is
due to the presence of a diffusion layer on the skin surface and the cyclodextrin acts as
a carrier through it towards the lipophilic skin layer [95]. In another more recent study
performed by Doneda and colleagues, different cyclodextrin complexes of the lipophilic
flavonoid 3-O-methylquercetin were used to allow its incorporation into a hydrophilic
topical formulation [97]. HPMC was used as a gelling agent at 3.5% concentration in the
presence of 1% propylene glycol. All of the proposed gels showed suitable characteristics
for dermal application such as pH in the range of 4.49 to 4.87 and pseudoplastic rheological
behavior. Bioadhesion was also established for the formulations even though the presence
of β-cyclodextrin or hydroxypropyl-β-cyclodextrin complex leads to some reduction in
their bioadhesive capacity due to interaction with HPMC.
Carboxymethyl cellulose (CMC) possesses carboxylate moiety which is pH-sensitive
and provides the polymer with in situ gelling properties as well as bioadhesive ability [99].
However, physical gels prepared by means of CMC are characterized by low mechanical
stability. Except by chemical cross-linking, this issue can be overcome by the addition of
naturally available nano-clays such as sepiolite. Palem et al. used simple moisture heat
treatment to prepare a physical gel of CMC, agar, PVP, and sepiolite. The platform was
non-toxic and showed stable and sustained release of 5-fluorouracil.
Another cellulose derivative used in the delivery of 5-ALA or glycoalkaloids is hydrox-
yethyl cellulose (HEC) in the concentration range of 2–3%. HEC is non-ionic cellulose ether
that is water-soluble [94]. A study performed by Maisch et al. showed that the depth of
5-ALA penetration from 3% HEC gel containing 40% DMSO as an absorption enhancer was
higher in comparison to hydrophilic ointment, lipophilic ointment, or w/o gel containing
DMSO. Nevertheless, low chain alcohols were shown to act better as penetration enhancers
in the case of 5-ALA. Its solution in the mixture of ethanol, isopropanol, and polyethylene
glycol with tetraethylene glycol ether is superior to the newly proposed physical gel in
terms of penetration. Tiossi and co-workers used commercial 2% physical hydrogel of HEC
to deliver glycoalkaloids from Solanum lycocarpum fruits for the treatment of non-melanoma
skin cancer [100]. In order to promote skin permeation, different penetration enhancers
were used and it was proven that 5% monoolein, alone or in combination with 10% ethanol,
is most suitable to achieve permeation to the target site. These absorption enhancers are
compatible with HEC gel and could be used for the delivery of other chemotherapeutics.
The results shown in the discussed articles suggest that cellulose derivatives alone
are not ideal as a delivery platform for chemotherapeutics in the treatment of skin cancer.
There is a need for the addition of excipients such as cyclodextrins or penetration enhancers
in order to achieve the desired depth of penetration.

4.1.3. Poloxamer as Gelling Agent

Poloxamers known by their trade name Pluronics (BASF, Ludwigshafen, Germany) are
a group of synthetic triblock copolymers of poly(ethylene oxide) (PEO) and poly(propylene
oxide) (PPO) in the arrangement [PEO]n -[PPO]m -[PEO]n , with varying numbers of monomers
(n and m) from each block [101]. They are thermoresponsive and their micellization, aggrega-
tion, and gelation depend on temperature [102]. The micellization is due to the dehydration
Gels 2023, 9, 352 10 of 36

of PPO blocks, which are then located in the core and the hydrated PEO chain forms an outer
shell [103]. The critical gelation concentration and gelation temperature of poloxamers de-
crease with the increase in their molecular weight. Poloxamer 407 (Pluronic® F127) is known
to form a reversible gel at a concentration above 20% and temperature of about 19 ◦ C. The
higher the polymer concentration, the lower the gelation temperature will be [86,104]. One of
the first investigations of poloxamer gel for dermal delivery of 5-fluorouracil or doxorubicin
dates back to 1984 [105]. The authors found that the apparent release of the APIs from the
gels depends on the concentration of the gelling agent. The released amount was improved
with an increase in the temperature of the in vitro dissolution test. These findings suggest
that the release happens through the aqueous channels around the polymer micelles. The
more polymer is used for gelling, the smaller those channels are, while with the increase in
temperature the micro-viscosity in the channels decreases. Redpath and co-workers found
that 30% blank poloxamers 407 gel without API being loaded slightly inhibited the cell mi-
gration in C8161 melanoma cell lines without affecting the cell viability, but did not further
investigate the observation. Furthermore, their study showed that the release of silybinin
from the gel is somewhat retarded due to the slow diffusion of the drug in the gel and the
diffusion is the rate-limiting step. The gel crystalline structure is less permeable than the
liquid crystalline one and the results showed that Poloxamer 407 gel had limited drug flux
into the skin. The polymer did not affect the skin’s lipid integrity and lower penetration
was observed [104]. Another study investigated the possibility of forming an in situ gelling
formulation consisting of 7% poloxamer 407 and 40% poloxamer 188. In situ gels possess
several advantages, such as easy application simultaneous with prolonged adhesion on the
skin surface and good permeability of therapeutic agents. Nevertheless, the investigation of
Sun and colleagues showed that for lipophilic APIs such as curcumin the release rate was
limited by the drug dissolution. Applying the cyclodextrin complex significantly improved
the potential to effectively deliver curcumin to melanoma cells [103].
Batista and team investigated the stability of a poloxamer 407 gel in the case of
incorporation of hydroalcoholic extract. Evidently, the gelling agent is compatible with
ethanol in comparison to HEC-based gel [106]. Nevertheless, poloxamer 407 gels possess
some disadvantages such as low mechanical strength, low durability, and very fast drug
release [107]. As shown by Sun and co-workers, the erosion of in situ gel based on both
poloxamer 188 and 407 was about 40% within 3 h [103]. Therefore, it is common to blend
poloxamers with other gelling polymers. In the current review, mixtures of poloxamers
and carbomer were identified for the topical delivery of anticancer drugs [86,108]. The
addition of carbomer could improve the stability and consistency of the poloxamer gel
and further provide it with bioadhesive properties. This could prolong the contact time
and improve the drug delivery. Borghi-Pangoni and colleagues showed that the required
concentration of a combined poloxamer/carbomer gel is 20%/0.15%, respectively, in order
to achieve appropriate in situ gelation without runoff upon application. The poor aqueous
solubility of hypericin could be overcome to some extent in the proposed gel. Even though
a rapid release of the drug was present (within 2 h), no permeation was evident. Therefore,
the proposed dosage form could be suitable for photodynamic therapy [86]. The study
of Campanholi and colleagues also supports these conclusions. The authors showed the
solubilizing capacity of the combined poloxamer 20% and carbomer 0.2% gel for chlorophyll
used in photodynamic therapy [108].
Poloxamer gels could be used in the chemotherapy of skin cancer, providing that
suitable measurements are taken in order to improve the gel stability and solubilization of
lipophilic APIs. Furthermore, prolonging the contact time by adding bioadhesive polymers
such as carbomer could further positively affect the properties of such drug delivery
systems. Otherwise, the drugs are superficially released without penetration. This could be
desirable in the scope of photodynamic therapy.
Gels 2023, 9, 352 11 of 36

4.1.4. Other Physical Hydrogels

Chitin is another polysaccharide which forms physical hydrogels upon desolvation or
physical cross-linking [109]. Chitin is a natural co-polymer of glucose and acetamide. In the
case where the degree of acetylation is lower than 50%, the biopolymer is called chitosan.
The formation of the physical hydrogel by means of chitin first requires its dissolving in a
suitable solvent as it is not water-soluble. The increase in the gelling agent concentration
leads to more pronounced entanglement and an increase in the hydrogen bonding, followed
by a transition from sol to gel. Furthermore, the stability of the hydrogel can be increased by
curing at various temperatures or by coagulation in a specific antisolvent. The antisolvent
approach was used by Nair and co-workers in order to prepare a 0.5% chitin hydrogel
loaded with plumbagin [110].
Another natural polymer found to form physical gels is iota-carrageenan. The 3D
structure formation is due to the aggregation of the macromolecules through electrostatic
interactions and hydrogen bonds. Successful loading of methotrexate cyclodextrin inclusion
complex into 1% iota carrageenan was presented by Kochkina et al. [111]. The cyclodextrin
complex did not influence the gel rheology and mechanical stability.
The literature search provided the information that scientific efforts have been made
to synthesize novel polymers that can form physical hydrogels and deliver lipophilic APIs
to skin cancerous cells. Such is the case with the synthesized ABA type cationic triblock
polymer developed by Taktak et al. [112]. The amphiphilic nature of the polymer and
its positive charge could lead to interaction with the stratum corneum by promoting the
penetration of lipophilic drugs such as paclitaxel.

4.2. Chemical Hydrogels

Covalently cross-linked hydrogels are 3D swollen networks which are prepared by
hydrophilic polymers containing various functional groups, such as -OH, -SO3 H, -COOH,
-CONH-, and -CONH2 . These groups are either embedded or grafted in their structure,
allowing them to absorb and retain large amounts of water and biological fluids. They do
not dissolve in water but rather swell and hold up the medium [70]. Their structure can
be tuned by varying the degree of chemical cross-linking and the affinity of the hydrogel
towards the aqueous medium [9]. Examples of chemical hydrogels investigated for the
treatment of skin cancer are given in Table 1.
Carboxymethyl cellulose (CMC) can be efficiently cross-linked with citric acid in
order to prepare biocompatible hydrogel with no cytotoxicity [9,113,114]. A prodrug
conjugate between CMC and doxorubicin was prepared and afterwards cross-linked with
the acid [9,114]. The study shows promising sustained release of the drug as the covalent
bondamide bonds will be cleaved predominantly in the lysosomes after cellular uptake
in the melanoma cancer. The authors further explored the possibility of preparing hybrid
hydrogel containing CMC-silver nanoparticles electrostatically associated with the same
API and further cross-linked with citric acid to form the gel [113]. This newly proposed
formulation showed synergistic anti-tumor effect between doxorubicin and the silver
nanoparticles and in addition possessed antibacterial activity.
Oktay and Alemdar prepared an electro-responsive hydrogel based on gelatin for
stimulus triggered release of 5-fluorouracil [115]. Gelatin was modified with methacrylic
anhydride and further subjected to UV cross-linking. They encapsulated a conductive poly-
mer which controlled the drug release, and the application of 1.5 V led to anisotropic
gel deformation and the amount of 5-fluorouracil was sufficient for the treatment of
skin cancer.
Gels 2023, 9, 352 12 of 36

Table 1. Examples of APIs formulated in chemical hydrogels and the corresponding excipients used.

Polymer Cross-Linker API Method of Preparation Ref.

Gelatin Metacrylic anhydride 5-fluorouracil UV cross-linking [115]
Citric acid Doxorubicin “green” method [9,114]
CMC Citric acid Doxorubicin “green” method [114]
METAC 1 , DEGDMA 2 curcumin Free radical polymerization [116]
Carboxymethyl chitosan Glutaraldehyde 5-fluorouracil Gelled deoxycholic acid micelles [117]
Poly(acrylamide-co-
diallyldimethylammonium BisAA 3 , APS 4 /TEMED 5 Indocyanine green Free radical polymerization [118]
chloride)
Chitosan PEGDA 6 Aloe vera juice UV cross-linking [119]
1 2
METAC-[2-(metacryloyloxy) ethyl] trimethyl-ammonium chloride; DEGDMA-diethylene glycol dimethacry-
late; 3 BisAA-N,N’-methylenebisacrylamide; 4 APS- ammonium persulfate; 5 TEMED-N,N,N0 ,N0 -
tetramethylethylenediamine; 6 PEGDA-diacrylate poly(ethyleneglycol).

A hydrogel-based transdermal system for the potential treatment of skin cancer

and radiotherapy-induced burn wounds was prepared and characterized by Kudłacik-
Kramarczyk et al. The formulation was based on chitosan and cross-linked with PEGDA
(diacrylate poly(ethyleneglycol)). Chitosan hydrogels need an alkaline medium to coagu-
late and provide the characteristic rheological behavior. Their strength can be improved by
ionic cross-linkers such as sodium citrate or tripolyphosphate, which also provide them
with pH sensitivity [109]. The authors performed intensive physico-chemical characteriza-
tion of the prepared gel and proved its biocomparibility.
The hydrophilic properties of the hydrogels significantly limit their ability to deliver
hydrophobic drugs. In such a case, the loaded amount is lower and unevenly distributed
in the gel structure, and shows inadequate release. In order to overcome this issue, Pour-
manouchehri et al. proposed incorporation of desoxucholic acid micelles containing 5-
fluorouracil in a hydrogel. Carboxymethyl chitosan cross-linked with glutaraldehyde was
shown to be less soluble at pH = 9 in comparison to the unmodified polymer [117]. There-
fore, the authors found a better and more complete release of 5-fluorouracil in an acidic
medium (pH = 6.8 and pH = 5). Furthermore, the prepared hydrogel prevented deoxycholic
acid micelles’ destabilization and had no burst effect. Altogether, these measurements
improved the cytotoxic effect of the API five-fold compared to free 5-fluorouracil and
proved the efficiency for the treatment of melanoma
Hwang and Jin synthesized a polymer for the preparation of a chemical hydrogel
which can be loaded with indocyanine green and used in combination with photodynamic
treatment of melanoma [118]. This type of skin cancer is especially difficult to treat due
to its fast spreading to the adjacent skin tissue. The produced hydrogel is mechanically
stable and can be attached to the skin. The proposed formulations appear to be superior for
the PDT in comparison to an injectable hydrogel, as they offer irradiation protection of the
loaded indocyanine green and exert less irritation at the site of application. The authors
demonstrated complete elimination of the melanoma cells in the tested mouse model.
A different strategy for topical antineoplastic drug delivery by means of chemically
cross-linked hydrogel has been proposed by Oktay and Alemdar [115]. The authors
prepared electro-responsive hydrogel loaded with 5-fluorouracil. Gelatin was modified
with methacrylic anhydride and further subjected to UV cross-linking. They encapsulated a
conductive polymer which controlled the drug release and the application of a 1.5 V electric
current led to anisotropic gel deformation. Thus, the released amount of 5-fluorouracil was
sufficient for the treatment of skin cancer.
The limited number of articles in this category of hydrogels is possibly due to the
fact that they usually do not possess the typical rheological properties for topical applica-
tion. Thus, they are applied as plasters or after being injected directly into the cancerous
cells [120].
Gels 2023, 9, 352 13 of 36

4.3. Nanogels
Nanogels are a category of hydrogels characterized by a 3D porous structure and
particle size in the range from 20 to 250 nm [121]. Other definitions put nanogel particles
in the range from about 10 nm to 1000 nm [38]. Similarly, they can be either physically or
chemically cross-linked. The second can be prepared either by polymerization of monomers
or by cross-linking of preformed polymers [122]. In comparison to typical nanoparticles,
nanogels possess tunable particle size and particle shape, and sensitivity to various external
stimuli (pH, temperature, ionic strength, etc.) [121]. Therefore, they mostly present drug
delivery carriers for systemic therapy. Nanogels can also be used for topical delivery, as
their unique structure and mechanical properties resemble those of the skin’s extracellular
matrix [14]. However, this route of administration encounters a major hurdle, which is
the limited drug diffusion across the stratum corneum together with the possibility of
spilling and aggregation over time [14,38]. Therefore, surface modification is often needed
in order to overcome these obstacles [38,43,123]. Examples of such formulations can be seen
in Table 2.

Table 2. Examples of APIs formulated in nanogels and the corresponding excipients used.

Specific Features
Composition Additives API Particle Size [nm] Ref.
and/or Comments
PLGA 1 (0.1%), chitosan
(0.4%), Poloxamer 108 and Eucalyptus oil coating 5-fluorouracil 190–220 - [38]
407, PVA 2 (0.4%)
Chitin - 5-fluorouracil 125–140 - [124,125]
Cross-linked chitosan
Bleomycin 140–170 pH sensitive [126]
Poloxamer 407
Chitosan, TPP 3 ,
Transcutol® coating Capecitabine 120–160 pH sensitive [123]
Poloxamer 407
Chitosan, TPP 3 ,
Transcutol® coating Temozolomide 170–200 pH-sensitive [43]
Poloxamer 407
Syzygium
Deacetylated-β-chitosan - Newly extracted
aromaticum 200–460 [127]
grafted with ρ-coumaric acid squid β
essential oil
Layer by layer
CMC 4 -casein Casein and folic acid coating Curcumin - coating; folic acid [14]
active targeting
1 PLGA—Poly(lactic-co-glycolic acid); 2 PVA—Polivinylalcohol, 3 TPP—sodium tri-polyphosphate; 4 CMC—
carboxymethyl cellulose.

Transcutol® (di-ethylene glycol monoethyl ether) can interfere with cell membranes in
the stratum corneum and thus acts as a penetration enhancer. It can be added to simple gel
formulations in concentrations ranging from 1 to 50% and promotes drug permeation [128].
The usual concentration of 22% v/v guarantees diffusion through the skin’s lipid matrix.
Combining poloxamer 407 with Transcutol® results in a stable nanogel formulation and
avoids the irritation potential of the penetration enhancer [123]. Another strategy to limit
irritation, edema, and inflammation is the application of natural penetration enhancers, as
suggested by Sahu et al. [38]. Such substances are terpenes and terpenoids, constituents in
eucalyptus and chenopodium essential oils. They can significantly improve the penetration
depth and therefore increase the therapeutic potential of the formulation.
Chitin and chitosan-based nanogels showed improved drug release in an acidic en-
vironment (pH = 4.5–6), which is very suitable for the skin delivery of APIs. The main
reason for this phenomenon is the possible protonation of free amino groups in the polymer
molecule [43,123–126]. This is additionally helpful in regard to the possibility of ionic
bonding with the tumor cells because of their acidic nature (pH = 5.5–6.5), and thus release
in a controlled manner can be expected [123].
 reason for this phenomenon is the possible protonation of free amino groups in the poly-
mer molecule [43,123–126]. This is additionally helpful in regard to the possibility of ionic
bonding with the tumor cells because of their acidic nature (pH = 5.5–6.5), and thus release
in a controlled manner can be expected [123].
Gels 2023, 9, 352 An alternative approach has been proposed by Priya et al. [14]. In the study, a layer- 14 of 36
by-layer technique is applied. First, self-assembled CMC-casein nanogel as a core is for-
mulated and loaded with curcumin. Afterwards, alternating layers of casein and folic acid
are applied. The relatively simple procedure resulted in a formulation with better cellular
An alternative approach has been proposed by Priya et al. [14]. In the study, a
uptake and enhanced cytotoxic and apoptic potential.
layer-by-layer technique is applied. First, self-assembled CMC-casein nanogel as a core is
formulated and loaded with curcumin. Afterwards, alternating layers of casein and folic
4.4. Nanocarrier-Loaded Gels
acid are applied. The relatively simple procedure resulted in a formulation with better
Thisuptake
cellular type ofanddrug deliverycytotoxic
enhanced system andsimultaneously combines two technological ap-
apoptic potential.
proaches, namely, gel formulations and nanotechnology. Gel supports the nanocarriers
and
4.4. guarantees their application
Nanocarrier-Loaded Gels and sustained release. The nanocarriers can further pro-
vide modification
This type of drug delivery due
of drug release to their
system specific properties
simultaneously combinesand two
characteristics.
technologicalThus,
ap-
the
proaches, namely, gel formulations and nanotechnology. Gel supports the nanocarriersand
combinatorial approach can improve the therapeutic efficacy of various drugs and
routes of administration
guarantees [129].and
their application In the presentrelease.
sustained review,The
thenanocarriers
focus is on the
cantopical
furtherdelivery
provide
ofmodification
chemotherapeutics. According
of drug release dueto tothe systematic
their search, it was
specific properties andevident that for the
characteristics. treat-
Thus, the
ment of skin cancer
combinatorial approachdifferent nanocarriers
can improve can be loaded
the therapeutic efficacyonto physical
of various hydrogels.
drugs and routesTheof
predominant
administrationtypes ofIn
[129]. nanocarriers are lipid-based,
the present review, the focus as canthe
is on betopical
seen from Figure
delivery 4. This is
of chemother-
expected
apeutics. According to the systematic search, it was evident that for the treatment ofskin
due to the characteristic structure of the stratum corneum and the other skin
layers.
cancer different nanocarriers can be loaded onto physical hydrogels. The predominant types
of nanocarriers are lipid-based, as can be seen from Figure 4. This is expected due to the
characteristic structure of the stratum corneum and the other skin layers.

Figure 4. Nanocarrier-loaded gels: distribution of nanocomposites (SLN—solid lipid nanoparticles;

Figure 4. Nanocarrier-loaded gels: distribution of nanocomposites (SLN—solid lipid nanoparticles;
NLC—nanostructured lipid carrier).
NLC—nanostructured lipid carrier).
The mechanical properties of the gel can be significantly influenced upon addition of
nanoparticles, and depend on the additive concentration, modulus, and extent of additive–
gel matrix interactions [130]. Therefore, in the following section the different types of
nanocomposites and their effect on the formed gels are discussed.

4.4.1. Nanovesicles
Liposomes are intensively studied nanosystems, often developed for use in anti-tumor
therapy. They consist of concentric two-layer vesicles in which the hydrophilic core is sur-
rounded by a dual phospholipid layer [131]. The drugs can be included in liposomes according
to their relations, with hydrophilic drugs incorporated inside and hydrophobic in the phospho-
lipid layer (Figure 5). Two-layer membranes can consist of natural or synthetic amphiphilic
lipids and phospholipids. Liposomes can be formed with different diameters, from about
20 nm to several micrometers. The small single-layer vesicles are about 20 to 100 nm in size.
They are relatively easy to prepare, with a unique size compared to other types of vesicles,
and are found to be widely used. Compared to the standard formulation, some types of
liposomes show a higher maximum penetration depth. The scientific literature describes
various approaches in which liposomes intended for skin anti-tumor therapy are incorporated
in gels that are used as suitable carriers for dermal administration.
 ameters, from about 20 nm to several micrometers. The small single-layer vesicles are
about 20 to 100 nm in size. They are relatively easy to prepare, with a unique size com-
pared to other types of vesicles, and are found to be widely used. Compared to the stand-
ard formulation, some types of liposomes show a higher maximum penetration depth.
The scientific literature describes various approaches in which liposomes intended for
Gels 2023, 9, 352 skin anti-tumor therapy are incorporated in gels that are used as suitable carriers for15der-
of 36

mal administration.

Figure 5. Schematic representation of nanovesicles incorporated within topical gel.

Figure 5. Schematic representation of nanovesicles incorporated within topical gel.

Elastic
Elasticliposomes
liposomes were
were used
used by Hussain et
by Hussain et al.
al. as
as aa 5-fluorouracil-delivery
5-fluorouracil-deliverysystem systeminina
agelgelbased
basedon onCarbopol
Carbopol980.980.The
Theincorporation
incorporationofofliposomes
liposomesinin the gel resulted in in
the gel resulted a sig-
a signifi-
nificant (double)
cant (double) increase
increase in thein concentrations
the concentrationsof theofdrugthe (300
drugrelatives
(300 relatives to 150 mi-
to 150 micrograms)
crograms)
comparedcompared
to the free to thegel-incorporated)
(not free (not gel-incorporated)
liposomes. liposomes.
In addition,Inreduced
addition, reduced
side effects
side effects were observed [132]. The result clearly shows that incorporating
were observed [132]. The result clearly shows that incorporating the nanoparticles in an the nanopar-
ticles in an appropriate
appropriate base such as base such
a gel as aimprove
could gel could theimprove
liposome thenanoparticles’
liposome nanoparticles’
advantages.ad-
vantages.
Another use related to the incorporation of liposomes in the anti-tumor therapy gel is
Another use
the inclusion related to
of different the incorporation
types of liposomes
of photosensitizers in the anti-tumor
for photodynamic therapytherapy gel
of different
istypes
the inclusion of different
of skin cancer. types et
Nekvasil of photosensitizers for photodynamic
al. presented a preclinical study of therapy of differ-
gels containing
ent types ofwith
liposomes skinhydrophobic
cancer. Nekvasil et al. presented
photosensitizers a preclinical study of gels containing
(meso-tetrakisporphylporphyrin or hydroxy-
liposomes
aluminum with hydrophobic
phthalocyanine) photosensitizers
for photodynamic (meso-tetrakisporphylporphyrin
therapy in various types of skin cancers or [133].
hy-
droxy-aluminum phthalocyanine) for photodynamic therapy in various
It can be concluded that the liposomal gel formulations of the photosensitizers used could types of skin can-
cers
be an[133]. It can be
optimum concluded
dermal that the enabling
preparation liposomalagel wideformulations of the photosensitizers
range of topical applications for
numerous
used could cancer indications,
be an optimum especially
dermal for nonmelanoma
preparation enabling a wide skinrange
cancer.ofIn another
topical study,
applica-
temoporfin
tions (potentcancer
for numerous second-generation synthetic photosensitizer)
indications, especially for nonmelanoma is included
skin cancer.in hydrophilic
In another
gels for
study, photodynamic
temoporfin (potenttherapy with a different
second-generation concentration
synthetic of carbomer
photosensitizer) [134].
is included The
in hy-
resulting gels
drophilic gelsforshow very good stability
photodynamic therapyinwith
the astudies
different conducted for 6 months.
concentration of carbomer [134].
Similar systems
The resulting gels showwere
veryalso proposed
good stabilityfor
in combination therapy, including
the studies conducted for 6 months.anti-tumor
agents curcumin and STAT3 Si-RNA in liposomes included in 0.4% agarose gel [20]. Studies
have shown that the topical ionophoretic administration of the developed gel shows a tumor
suppression comparable to the invasively applied liposomes. In addition to curcumin, in
another study neringenin (an anti-tumor agent with a pronounced antioxidant effect) was
included in deformable liposomes dispersed in hydrophilic gels based on hydroxyethyl
cellulose (HEC) and hydroxypropyl methylcellulose (HPMC) [135]. The results show that
the incorporation of liposomes in the gel leads to a further delay in the release of the drug,
with a difference in release in gels based on HEC and HPMC.
Along with the inclusion of liposomes in conventional topical gels, Famta et al. in-
cluded niclosamide in liposomes and incorporated it based on the Pluronic® F127 and
Pluronic® F68 (3:1 Ratio) heat-sensitive gels characterized by the sol-to-gel transition tem-
perature of 33 ◦ C [136]. Their research shows that the developed compositions significantly
increase the cytotoxicity of niclosamide to melanoma cells, with their subsequent inclusion
in thermogel providing the ability to control release kinetics.
Other vesicular nanocarriers are transferosomes. Transferosomes are similar to lipo-
somes in their morphology, but according to their functionality, they can deform enough
to go through pores much smaller than their own size. This is due to the great flexi-
bility of the vesicle membrane, which causes the vesicles to be highly deformable [137].
Therefore, typical transferosomes are characterized by a more elastic membrane than con-
ventional liposomes. Another specific difference between transferosomes and liposomes is
Gels 2023, 9, 352 16 of 36

the great hydrophilies of the former, which allow the transferosome membrane to swell
more than the conventional lipid vesicle bilayer [138]. Because of these advantages, trans-
ferosomes are one of the most commonly studied representatives of nanosystems used
for dermal administration, with scientific data gathered regarding their inclusion in gels.
One specific representative of the group is protransferosome, which is a liquid crystalline
pro-ultra-flexible vesicle with a lipid structure and is in situ convertible to an ultra-flexible
transferosome by absorbing water from the skin [139].
Gupta and Trivedi developed a Carbopol® 940 gel, including protransferosomes
containing cisplatin [140]. The authors compared the kinetics of the release and skin
permeation of the prepared gel, as well as the free protransferosomes. The results show that
including the vesicles in the gel improves the ability to control release and improve skin
permeation. The Carbopol-based gel was used as a vehicle for transferosomes loaded with
5-FU [141], paclitaxel [142], methotrexate [143], tofacitinib [144], tamoxifen citrate [145],
and others. An interesting study was presented by Shamim et al., which includes carvedilol
in transferosomes for topical administration to prevent UV-induced skin cancer [146].
Using the system proposed, unwanted systemic cardiovascular effects are prevented while
maintaining the efficiency of carvedilol.
Biologically active substances of natural origin are of great interest in many areas of
modern pharmaceutical practice. For this reason, many scientific teams have explored the
possibilities of incorporating non-synthetic substances into dermal anti-cancer systems.
In the group of natural substances can be classified apigenin, included by Jangdey et al.
in transferosomes [147], as well as Green Tea catechins [148], subsequently dispersed in
carbomer gel. Both gel systems showed good potential for use in skin cancer. Furthermore,
as has been often studied in recent years, curcumin has been used as a biologically active
component in a transferosomal system included in a Poloxamer 407 gel aimed at improved
skin penetration and dermal localization [149].
Another example of nanosystems often included in dermal gels for the therapy of
various types of skin cancer is ethosomes (Figure 5). Ethosomes are lipid vesicular carriers
formed with ethanol in relatively high concentrations, phospholipids, and water. The high
ethanol concentration, which significantly distinguishes the ethosomes from other vesicles,
improves skin penetration [150]. Ethosomes pass the stratum corneum to a significantly
greater extent than classic liposomes [151]. The effects of combining phospholipids and a
high ethanol concentration lead to greater distribution and penetration through the skin
lipid pots. They are designed to improve the penetration of drugs through the skin by
fluidizing the lipids into the stratum corneum.
Gels with incorporated ethosomes were prepared for dermal drug delivery of 5-
FU [152], curcumin [13], vismodegib [153], brucine [15], sonidegib [154], itraconazole [155],
etc. Puri et al. offer the use of ethosomes for improved dermal administration of 5-FU, thus
overcoming the limiting factors of the drug, such as limited skin permeation, retention
at the target site, and possible skin irritation [152]. Ethosomal systems are subsequently
included in Carbopol® 934P-based gel and have been tested in terms of skin permeation
and deposition, showing significantly increased skin permeation (5.9 to 9.4 times) and
anti-tumor potential compared to cream (commercial product), in addition to reduced
skin irritations. The possibility of incorporating ethosomes loaded with vismodegib into
the carbomer gel has also been studied, providing data on increased anti-tumor activ-
ity, compared to oral drug forms of the same active substance [10,153]. Similar results
(threefold increased bioavailability and significantly increased anti-tumor activity) have
been observed by other authors regarding the drug sonidegib, included in the ethosomes
system in the gel based on carbomer [154]. The same polymer has also been used in the
inclusion of fisetin-containing binary ethosomes, with the results being positive in terms of
achieving better release control and improved skin penetration compared to a conventional
gel containing the same drug [156].
Although most ethosomes tests have been conducted in carbomer-based gels, a study
by Abdellateif et al. displays better controlled drug release from a hydroxypropyl methyl-
Gels 2023, 9, 352 17 of 36

cellulose (HPMC) 2.5% w/w gel system, containing ethosome-loaded celecoxib, compared
to the same ethosome dispersion [157]. In the same study, the data were compared to
the carbomer-based gel, taking into account different release kinetics depending on the
polymer used.
Another type of nanovesicle is the emulsomes (Figure 5). These were used by Sahu
et al. as methotrexate carriers and were further incorporated in a Carbopol® 934 gel for
the management of skin cancer through topical delivery. The gel shows a delayed release
of the drug for a period of 12 h, as well as a good profile of stability, examined during
45 days period of testing [158]. In addition, a different type of hydrogel containing vesicular
structures—glycerosomes loaded with plumbagin—showed increased anti-tumor activity
and improved skin penetration [159].

4.4.2. Lipid Nanoparticles

In recent years, lipid nanoparticles have been of great interest in the field of pharmaceu-
tical technology. They are colloidal carriers, characterized by a solid lipid core consisting of
a mixture of hard and liquid lipids and having particle dimensions in the nanometer range.
They consist of a lipid matrix with a special nanostructure. These nanostructures improve the
drug loading and firmly retain the drug during storage. Nanostructured lipid carriers weaken
the barrier function of the stratum corneum and improve the penetration of drugs through the
skin. There are data on topical gels containing lipid nanoparticles for the skin drug delivery of
silymarin [160], topotecan [161], and others. The prepared lipid particle-containing gels are
characterized by improved anti-tumor activity after dermal administration.
EL-Sheridi et al. used the antifungal agent with good anticancer activity, itracona-
zole (ITC), unmodified or modified with the amphiphile miltefosine or the lipopeptide
biosurfactant surfactin lipid systems for low-risk cancers of the skin [162]. The prepared
lipid nanosystems were subsequently included in the gel, comparing the tumor-inhibitory
capacity of a conventional gel with itraconazole and the gel-containing nanoparticles, with
better results achieved with the gel containing lipid nanoparticles.
Khallaf et al. showed that 5-FU-loaded SLNs (mean size of 137 ± 5.5 nm and zeta
potential of −19.70 ± 0.40 mV) based on lecithin and poloxamer 188 could deliver the drug
topically and treat tumors when loaded on a negatively charged physical hydrogel vehicle
(CMC). The results show that a repulsion of charged particles and the gel charges may be
the reason for higher dermal permeability [163].
Some authors expanded the studies of gels loaded with lipid nanoparticles, and of-
fered dual load systems, aiming to synergize the effect of the biologically active substances
involved. As an example, there is the simultaneous inclusion of cannabidiol and 5- flu-
orouracil in lipid nanoparticles, followed by incorporation in a gel based on Carbopol®
934 [164]. The dermal administration system shows a good toxicological profile and
improved penetration through the skin barrier compared to conventional drug delivery
systems. Other examples of similar systems are lipid-based gel for the co-delivery of
quercetin and resveratrol [165], and 5-FU and resveratrol [166].

4.4.3. Inorganic Nanoparticles

Inorganic nanoparticles are presented by drug delivery systems based on different
inorganic materials such as metals, silica, and carbon materials (Figure 6). Metal nanoparti-
cles, most often silver (AG) and gold (AU), are examined as potential transdermal carriers
due to their easy preparation, ability to modify their surface, and adjustable size. It is
assumed that the transdermal transport of gold nanoparticles is related to their ability to
interact with skin lipids by changing the stratum corneum by inducing transitional and
reversible openings. One of the fastest developing areas in the field of inorganic nanoparti-
cles is the development of mesoporous silicate nanoparticles. The key properties of this
versatile material are due to the arranged structure of the pores (sizes from 2 to 50 nm)
and surface chemistry, which allows insertion in a controlled manner of new functional
groups [167]. The interest in these nanoparticles is explained by their high specific surface
 assumed that the transdermal transport of gold nanoparticles is related to their ability to
interact with skin lipids by changing the stratum corneum by inducing transitional and
reversible openings. One of the fastest developing areas in the field of inorganic nanopar-
ticles is the development of mesoporous silicate nanoparticles. The key properties of this
Gels 2023, 9, 352
versatile material are due to the arranged structure of the pores (sizes from 2 to 50 nm)
18 of 36
and surface chemistry, which allows insertion in a controlled manner of new functional
groups [167]. The interest in these nanoparticles is explained by their high specific surface
area (>1000 m2/g) and large volume (~1.0–2.0 cm3/g), as well as the high capacity of sorp-
area (>1000 m2 /g) and large volume (~1.0–2.0 cm3 /g), as well as the high capacity of
tion of drug molecules, the relatively simple, cheap, environmental, and controllable pro-
sorption of drug molecules, the relatively simple, cheap, environmental, and controllable
cedure of synthesis, their biocompatibility, and their lack of toxicity. Mesoporous silica
procedure of synthesis, their biocompatibility, and their lack of toxicity. Mesoporous silica
particles have been shown to increase the aqueous solubility of poorly water soluble
particles have been shown to increase the aqueous solubility of poorly water soluble drugs,
drugs, which significantly improves their transdermal administration [168].
which significantly improves their transdermal administration [168].

Figure 6. Schematic representation of inorganic nanoparticles incorporated within topical gel.

Figure 6. Schematic representation of inorganic nanoparticles incorporated within topical gel.

Safwat et
Safwat et al.
al. used
used gold
gold nanoparticles covered with
nanoparticles covered with CTAB
CTAB (cetyltrimethyl
(cetyltrimethyl ammonium
ammonium
bromide) as
bromide) as aa possible
possible carrier
carrier for
for 5-FU.
5-FU. The
The prepared
prepared nanocarriers
nanocarriers with
with aa mean
mean size
size of
of
16.02 ± 0.22 nm and positive zeta potential (+47.81 ± 0.43 mV) were additionally
16.02 ± 0.22 nm and positive zeta potential (+47.81 ± 0.43 mV) were additionally dispersed dispersed
in the
in the Pluronic
Pluronic®F127
®
F127gel
gelfor
fortopical
topicalapplication
application onontumor
tumor xenografs
xenografs [6].[6].
TheThegel gel
thusthus
ob-
tained showed twice as high permeability through mice skin compared
obtained showed twice as high permeability through mice skin compared with conven- with conventional
5-FU gel.
tional 5-FUCapanema et al. synthesized
gel. Capanema hydrogel
et al. synthesized for doxorubicin
hydrogel delivery
for doxorubicin based
delivery on em-
based on
bedded silver
embedded nanoparticles
silver nanoparticles within
withincross-carboxymethylcellulose
cross-carboxymethylcellulose[113]. [113]. Interestingly, in
Interestingly, in
this case,
this case, aa green
green process
process involving
involving the
the in
in situ
situ reduction
reduction ofof Ag+
Ag+ by
by the
the polymer, followed
polymer, followed
the electrostatic
by the electrostaticconjugation
conjugationwith with DOX,
DOX, waswas used
used to form
to form colloidal
colloidal nanocomplexes.
nanocomplexes. The
nanostructures obtained were further chemically cross-linked using citric acid under mild
conditions. The predecessor of mesoporous silica—inorganic zeolites—have been used as a
skin delivery system for carmustine after their inclusion in the HPC gel [169].

4.4.4. Other Nanocarriers

Nasr et al. studied gel formulation based on 2% Carbopol® 934, including ethosomes
and lipid-coated chitosan nanocarriers loaded with ferrous chlorophyllin, designed for
photodynamic therapy for squamous carcinoma [170]. Sun et al. reported a better effect
of curcumin-loaded PLGA included in the gel compared to free-drug-loaded hydrogel in
a mouse model [103]. The carboxymethylcellulose polymer nanoparticles included the
anticancer drug doxorubicin. Specifically in this case, the polymer available in the synthe-
sized nanocomposites was further chemically modified to obtain a hydrogel showing good
effectiveness against melanoma cancer cells with reduced toxicity to healthy cells [114].
A dual mucoadhesive topical gel containing gellan gum nanoparticles with cisplatin and
liposomes with paclitaxel was prepared by Bhardwaj et al. [171]. Interestingly, the gel was
prepared after dispersing the pre-prepared nanoparticles in the high acyl gellan solution.
Chitosan hydrogel was used in the system consisting of the immune adjuvant im-
iquimod in the form of polydopamine-coated nanocrystals in order to achieve an im-
munomodulation effect as well as immunogenic cell death induction [172]. In addition,
using the prepared system resulted in inhibited melanoma growth and metastatic processes.
A new drug delivery system for the local treatment of dermal cancer, based on highly
elastic and deformable nanostructures with a size of about 100 nm and positive zeta
potential, was proposed to enhance the skin therapy with an antioxidant diindolylmethane
Gels 2023, 9, 352 19 of 36

derivative [173]. The authors hypothesized that the positively charged nanostructures
could interact with the stratum corneum due to its negative charge. Based on the results, it
was also suggested that incorporating the nanovesicles in a hydroxypropyl methylcellulose
physical hydrogel may contribute to its increased deposition within the skin. The hydrogel
probably leads to hydration and disruption of the stratum corneum, followed by an opening
of channels within the lipid lamellae domain. The nanoparticles could then use the gap to
penetrate into the skin.

4.5. Other Gels

Here, some other types of gels were identified that do not belong to the previously
discussed classes, as can be seen from the examples in Table 3. The search found 10 articles
that discuss nanoemulgels, bigels, emulgels, or microgels, or in which the type of gel is
not clear due to the unavailability of the full texts. Microgels can be defined in a similar
way as nanogels, but the difference arises from their bigger sizes, which fall into the range
of 100 nm to 1 µm [70]. Even though clear definitions based on the particle size exist
for the macrogels, microgels, and nanogels [70], it can be seen that different researchers
apply the terms interchangeably to some extent (Tables 2 and 3), and these size ranges are
only approximate.

Table 3. Examples of APIs formulated into other types of gels and the corresponding excipients used.

Specific Features and/or

Type of Gel Gelling Agent API Particle Size [nm] Ref.
Comments
Chitosan coated with
Microgel 5-fluorouracil 200–600 nm pH-sensitive [174]
pectin
Carbopol® 940 (3%) and Hydrogel + oleogel based on
Bigel Imiquimod - [175]
beeswax (10%) fish oil mixed at 50:50 ratio
Self-nanoemulsifying
Nanoemulgel Poloxamer 407 (20%) Chrysin 157 nm preconcentrate was further [17]
dispersed in gel
Nanoemulgel Protasan™ UP G 213 Daidzein 190–210 nm Nanoemulsion-based gel [18]
Mentha spicata
Nanoemulgel CMC (3.5%) 189–464 nm Gelled nanoemulsion [176]
essential oil

One example is the microgel prepared by Puga et al. based on chitosan and cross-
linked with glutaraldehyde with particles in the size range 200–600 µm [174]. This proposed
formulation is suggested for oral or dermal delivery of the chemotherapeutic agent 5-
fluorouracil. They showed pH-dependent release, with delayed release of an acidic medium
with a limited burst effect due to the pectin coating. This study showed promising results
as a topical treatment of malignant melanoma.
Bigels are intimate hydrogel/oleogel colloidal mixtures in which each of the corre-
sponding liquid phases is independently stabilized by means of a suitable gelling agent. One
significant advantage of these gels is the decreased expenditure required for preparation
in comparison to the formulation of gels containing liposomes or other nanoparticles and
nanovesicles [70]. In this review, one article was identified dealing with the preparation
of a bigel for topical delivery of imiquimod [175]. This study investigated the possibility
of dissolving the chemotherapeutic drug in fish oil, gelling it with beeswax and mixing it
with previously prepared physical carbomer hydrogel. The results showed that the skin
permeation was superior in a simple oleogel, and in the bigels, it depended on the ratio be-
tween the two corresponding gels. It was found that the fatty acids in the fish oil modify the
stratum corneum permeability for the lipophilic API. Once again, it was confirmed that the
drug’s solubility and the stratum corneum’s barrier function are of utmost importance for
the depth of drug delivery. At the same time, the rheological and mechanical characteristics
Gels 2023, 9, 352 20 of 36

of the bigels are better than those of an oleogel. It can be said that a compromise needs to be
met between the ideal penetration and optimal application formulation.
As shown by different researchers, incorporating lipophilic APIs in various lipids can
improve their solubility and permeability [17,18,176]. Nagaraja et al. developed an emulgel
for the delivery of chrysin, a phytochemical with broad therapeutic activity but with limited
solubility and bioavailability [17]. Emulgels are emulsion-based gels and can be of the type
o/w or w/o emulsion that is further gelled by a suitable gelling agent [70]. Their properties
provide them with significant advantages for the dermal application of drugs. Some of the
most important are the thixotropic behavior, spreadability, lack of greasiness, emollient
action, and longer shelf life. The approach for improving drug delivery to cancerous skin
proposed by Nagaraja et al. [17] proved to be versatile for hydrophobic constituents. It
leads to a decrease in overall dose and thus can guarantee lower systemic penetration and
limit the associated side effects.

5. Methods for Characterization of Gels

Gels, as presented above, can be synthesized from various materials—organic, inor-
ganic, and hybrids. Moreover, they can vary from semi-fluid and semisolid to solid-like
substances such as hydrogels or xerogels, which form a powder after drying. Therefore, var-
ious techniques are used to characterize gels’ chemical and physical structure, morphology,
and overall properties, as well as rheology. A summary of the characterization techniques
is presented in Table 4, and these are briefly discussed in the following subsections.

Table 4. Summary of methods for gel characterization and their application.

Type of Characterization Method Application

The method is used for determination of the
crystalline structure of polymers including crystal
X-ray
size, crystalline phases and their amount,
crystallinity level and texture [177–179].
Gel sample is diluted in purified water to obtain a
concentration of 10% w/v. A potentiometric
pH
measurement of the pH could be used to elucidate
skin tolerability and possible stability issues [106].
It can be a useful tool for studying functional
groups present in chemical gels, or molecular
arrangement, such as π stacking, between aromatic
UV-vis spectroscopy rings in physical gels [179–181]. It can be also
applied for the determination of lower critical
solution temperature (LCST) related to the sol–gel
transition properties [182]
Physico-chemical characterization IR spectroscopy is one of the most used
confirmation methods to prove the structure of
newly synthesized or already known polymers as
Infrared (IR) spectroscopy a basis for gel preparation [13,17,18]. New
functional groups or their absence are accounted
for based on the bond energies that can be
determined by the method [180]
The specific transitions detected in the peaks can
imply what kind and how many atoms are there in
the structure. The chemical shifts are dependent on
temperature and concentration, and thus, the NMR
Nuclear magnetic resonance (NMR) technique can be applied in gel characterization.
Molecules come closer together in more
concentrated solutions and this fact can be used to
investigate the sol–gel transition in gel
formulations [183]
Gels 2023, 9, 352 21 of 36

Table 4. Cont.

Type of Characterization Method Application

In case of gels this method presents information
Thermogravimetric analysis (TGA) regarding the thermal stability and the phase
transitions of the gels [184,185].
It can be used to determine compatibility between
various polymer blends, interaction of the gelling
Thermal characterization agent with the API, thermal stability, etc. [99]. It
can be also applied to determine the interaction of
Differential scanning calorimetry (DSC) the skin with the formulation as the thermogram
of untreated skin shows one endothermic peak at
78 ◦ C due to melting of stratum corneum lipid. If
interaction is observed there would be a change in
this peak [185].
Dried gel samples can be observed for their surface
morphology at significant magnifications
(300,000×). In addition, the high resolution allows
detection of nanostructures with the gel base [186].
Scanning electron microscopy (SEM)
The data about surface roughness can be related to
cell adherence and sustained drug release [186]. A
confirmation of size could also be derived from
this method [126]
The technique could be used in the chemical
hydrogels and nanogels characterization,
Transmission electron microscopy (TEM)
Morphological characterization providing a very thin layer can be produced;
otherwise, they are not visible on TEM [187].
Direct observation of gel surface in water is
possible providing specific conditions of the
measurement are selected [188]. Usually the
method is performed in non-contact mode for the
Atomic force microscopy (AFM) evaluation of surface roughness. Furthermore,
using force–distance curves, the elastic modulus of
the sample can be determined. Adhesion to
substrates (such as cells) can be another parameter
determined by the method [189].
Gel formation can be measured by monitoring
their elastic (G0 ) and viscous (G00 ) moduli. When
Viscosimetry the value of G0 exceeds the one of G00 , a gel is
formed [190]. Furthermore, the gel kinetics can be
observed [22].
The method allows evaluation of various
parameters such as cohesiveness, adhesiveness,
hardness, and extrudability [106,175]. They
Texture analysis
determine the ability to spread on the skin, the
Mechanical characterization bioadhesion, and the ability to be evacuated from
the packaging [106].
It is evaluated by the parallel plate method. A
definite amount of the gel is placed on a glass plate.
Another plate with known weight is positioned on
Spreadability top. After predetermined intervals additional
weights are applied. The radius of spreading is
measured and further used to calculate the
spreadability factor [106,191,192].
Gels 2023, 9, 352 22 of 36

Table 4. Cont.

Type of Characterization Method Application

Test for the ability of chemical hydrogels and
nanogels [14] to imbibe water upon immersion in
different liquid media (deionized water, phosphate
buffer with various pH). The increase in weight of
Swelling
the gel sample over time is a measurement of its
swelling ability. The results are usually directly
related to the release of the loaded API [14,126]
and the mechanical stability of the gel [114,193].
A beaker is filled with water, covered by cellulose
acetate filter, and sealed with Teflon tape. A
predetermined amount of the gel formulation is
evenly placed on top. These samples are kept in
Occlusion in vitro skin-mimicking conditions (temperature 32 ◦ C)
and constant humidity for 48 h. As a reference, a
sample covered with filter paper only is used. The
occlusion factor is calculated based on the change
in weight of the samples [83,194–196].
The test is performed on healthy volunteers with
an established protocol of application. At the
beginning and after one week of application the
Occlusion in vivo
skin hydration is determined based on capacity
measurements with specific probes of Soft Plus
apparatus (Callegari Srl, Parma, Italy) [196,197]
This is an acellular assay in phosphate buffer with
Performance characterization different pH [114] through a dialysis membrane
In vitro release [157] or with a membrane attached to a
Franz-diffusion cell [137,143] which measures the
amount of drug released over time.
Ex vivo hairless animal skin is used together with a
Franz-diffusion cell to measure the amount of drug
that passes through the membrane [38,123,124].
Artificial membranes can be applied such as
Permeation studies
Strat-M® membrane or keratinocytes culture
(EpiDermTM ) in a Franz-diffusion set-up [80]. They
are standard and thus provide better
reproducibility of the results [198,199].
Confocal laser scanning microscopy (CLSM) is
used in combination with permeation studies in
order to evaluate the depth of penetration, cell
internalization, and formulation factors affecting
them. Usually, rhodamine B or other fluorescent
dye is loaded in the tested sample. A substrate is
treated with the gel formulation and optically
Skin deposition studies
scanned with fluorescent microscope. The
substrate could present in vitro grown cells [156],
excised skin sample used in a Franz-diffusion
set-up [165,200], or in vivo observed skin [201]
Tape stripping technique can non-invasively
measure the amount of drug penetrated in the
stratum corneum [201–203].

5.1. Physico-Chemical and Thermal Characterization Methods

The complex nature of the topical gels is reflected in a significant number of parameters
that can be evaluated. The most important ones based on their frequency of utilization and
informative value for dermal gels are summarized in Table 4. It can be seen that there are
various aspects regarding the chemical, physical, morphological, and performance proper-
ties of the topical formulations. Some of the methods are well-established techniques (X-ray
diffraction, UV-vis and IR spectroscopy, NMR, pH measurement, TGA, DSC, etc.) applied
in the characterization of diverse materials and nanoformulations including gels. There
are current reviews that elucidate in more details the principles and application of those
methods [204,205]. As the focus of the current review is on topical administration of the
gel-based formulations, more details are discussed about the mechanical and performance
characterization techniques that are directly related to their application.
Gels 2023, 9, 352 23 of 36

5.2. Rheology Studies

Gels possess specific properties from a physical point of view as they are neither solid
nor liquid. Their behavior is complex; therefore, the deformation and flow pattern are studied
by rheology. Viscosity can be affected by various factors including polymer concentration,
pH and ionic strength of the medium, temperature, and particle size of the polymer [22]. Its
evaluation is of paramount significance as it provides information regarding the ability of
the gel formulation to spread on the skin. The drug release is also affected by the rheological
behavior of the gel [141,175,176]. Most of the performed studies indicate that gels are non-
Newtonian systems and possess pseudoplastic rheology [100,111,191]. This indicates that the
viscosity decreases in high shear, thus facilitating the gel application. Typical yield stress for
semisolid formulations is in the range 20–50 (80) Pa and varies according to the method used
for its determination [153]. The incorporation of cyclodextrin complexes within the HPMC
gel matrix could lead to a decrease in the apparent viscosity, possibly due to hydrophobic
interactions between the cyclodextrins and the polymer chains [97]. The composition and
type of liposomes also affect, in a different manner, the rheology behavior of a carbomer gel,
and can either increase or decrease its yield stress, apparent viscosity, and elasticity [206].
In the case of ethosome-loaded carbomer gels, a slight decrease in viscosity is observed,
most likely due to the presence of ethanol in the nanovesicle structure [153,154,207]. On
the contrary, the loading of a hydrogel with NLC leads to an increase in the viscosity in
comparison to a corresponding gel with no nanostructures embedded within it [44]. Therefore,
the incorporation of nanoparticles may affect the rheological behavior of the gel, and different
release and skin retention can be observed. The effect of the nanocomposites in gels is not
always studied in the articles identified in the current review. It would be beneficial to compare
the conventional gel and the nanocarrier-enriched gel in terms of viscosity, as this is directly
related to the applicability of the formulation and the drug release.

5.3. Morphology Charcaterization

Gels’ morphology can be studied by transmission electron microscopy (TEM) and
scanning electron microscopy (SEM). They can be used to study amorphous, crystalline,
organic, and inorganic specimens. Examples of the observed differences in morphology of
a chemical hydrogel can be seen in the images taken with SEM and presented in Figure 7.
The images were obtained in another study of ours and have not been published elsewhere.
Gels 2023, 9, 352
The polymer’s morphology itself (Figure 7A) differs from the appearance of the polymer in
24 of 37
gelled form. Figure 7B shows the lyophilized hydrogel and there is the clear presence of
large interconnected pores.

SEMimages
Figure 7. SEM imagesshowing
showing
thethe application
application of the
of the technique
technique for evaluation
for the the evaluation of hydrogel
of hydrogel mor-
phology: (A) polymer powder; (B) lyophilized gel sample at ×250 magnification.
morphology: (A) polymer powder; (B) lyophilized gel sample at ×250 magnification.

Das et al. [208]

[208] obtained
obtained cryo-SEM
cryo-SEM micrographs of three samples of successfully
successfully
grafted
grafted hyperbranched poly(acrylic acid) chains from the surface of guar They
hyperbranched poly(acrylic acid) chains from the surface of guar gum. gum.found
They
found deformations in their structures in the swollen conditions compared with the dried
samples’ SEM images. The authors expect the pores in these samples to enlarge upon
swelling in water. It is a common phenomenon that, whenever a hydrogel swells in an
aqueous medium, the polymer deforms, i.e., the pores in the polymer become bigger and
Gels 2023, 9, 352 24 of 36

deformations in their structures in the swollen conditions compared with the dried samples’
SEM images. The authors expect the pores in these samples to enlarge upon swelling
in water. It is a common phenomenon that, whenever a hydrogel swells in an aqueous
medium, the polymer deforms, i.e., the pores in the polymer become bigger and distorted.
Typically, in a cryo-SEM image that captures the cross-section of a frozen swollen polymer,
deformation of the pores is depicted.

5.4. Performance Characterization

The performance characterization is related to the properties of the formulations
directly affecting their ease of administration, residence time on site of application, release
of the active constituents, and permeation through the skin and reaching the site of action.
These settings are discussed in the following subsections.

5.4.1. Occlusion
The occlusion properties of any semisolid formulation are of compelling significance
for the normal transepidermal water loss of human skin. It is directly related to the skin
hydration and especially that of the stratum corneum. Consequently, the occlusion effect
can promote the percutaneous absorption [83,194–196,209]. At the same time, occlusion
may produce unwanted effects. In the case of transferosome-loaded dermal gels, it was
established that the transepidermal osmotic gradient is crucial as a driving force for the
elastic transport into the skin [210]. Some adverse effects may also be attributed to signifi-
cant occlusion [211]. The occlusion factor is strongly dependent on the crystallinity in the
case of solid lipid nanoparticles or nanostructured lipid carriers [212]. The data suggest
that the higher the crystallinity level, the higher the occlusion factor.

5.4.2. In Vitro Release

The in vitro release can be an acellular technique, i.e., a dissolution test study with
proper modifications such as applying membranes between the donor and receiver com-
partment. It is applied for a preliminary evaluation of the properties of the formulation and
the factors affecting them. The conditions of the experiment should mimic the physiological
ones of the administration route. This means that a temperature of 32 ◦ C and pH of the
medium between 5.0–6.0 would ideally be used to reflect the healthy skin conditions [213].
Nevertheless, the results of the current review show that various parameters of the release
set-up are applied, i.e., varying temperatures: 25◦ [137], 32◦ [4], and 37 ◦ C [4,143,144,157]
and varying pH values: 5.5 [4], 6.8 [137,157], and 7.4 [4,143,144]. In addition, the medium
can contain surfactants such as Tween 80 [137] or sodium lauryl sulfate [157] to maintain
sink conditions. These variations in performing the tests yield different results which are
hard to compare in terms of efficiency of the proposed formulations.

5.4.3. Drug Penetration

Evaluation of the drug level within the skin (penetration evaluation) plays a key
role in the formulation of transdermal and topical drug dosage forms. Depending on the
conditions, drug permeability study can be performed in vivo, ex vivo, and in vitro.

In Vivo Methods
The in vivo methods can provide the most accurate information regarding the drug
penetration. Nevertheless, those methods are characterized by complexity and variability,
and require living species. The “gold standard” in determining drug penetration through
the skin is by application of the tested dosage form to a particular subject and evaluating
drug levels on the target skin tissue [202]. Unfortunately, clinical trials are too expensive
and can lead to harmful outcomes. The in vivo methods can be further classified as invasive
and non-invasive, as the latter are preferable [214].
Gels 2023, 9, 352 25 of 36

Pharmacokinetic Studies
Pharmacokinetic studies are of high importance for the evaluation of transdermal
delivery since they can fully resemble the processes in the human organism. In general,
the pharmacokinetic evaluations use the drug’s plasma concentrations and the parameters
of interest such as the area under the curve (AUC) and Cmax . Unfortunately, detection of
these parameters after topical and transdermal delivery is not always possible due to the
very low concentrations achieved [202].

Skin Biopsy and Suction Blister Methods

Skin biopsy and suction blister are invasive methods for evaluation of drug pene-
tration [202]. Even though they give precise information of drug deposition in skin, due
to the tissue damages they are not a preferable approach for a regular evaluation of skin
penetration [214].

Microdialysis
The microdialysis technique is a less invasive (semi-invasive) in vivo technique that
measures the drug concentration directly in the target tissue, giving full information about
the drug penetration through the skin [215]. This method uses a semi-permeable tube
(catheter), representing a dialysis membrane, inserted underneath the skin [216]. After
application of a dosage form on the skin, the API passes through its layers, reaches the
catheter and accumulates in the perfusate. The samples are taken at different time intervals
and the amount of drug is measured by the usual analytical methods [214].

Tape Stripping
Tape stripping is an inexpensive, efficient, quick, and minimally invasive technique
used to determine the skin penetration and bioavailability of topically applied drugs whose
target is viable skin tissue [201–203]. This procedure can be performed in vivo and ex
vivo using skin model membranes instead of human volunteers and animals. The method
includes repeated application and subsequent removal of an adhesive film on the skin
surface after administration of the tested topical dosage form [215] (Figure 8). Upon re-
moval, cells from the stratum corneum are also removed. The sample contains corneocytes
Gels 2023, 9, 352 and a certain quantity of drug molecules, which can be extracted by selective solvents 26 and
of 37
determined by the classical analytical method [203]. In order to achieve representative
results, all remnants of the applied formulation should be removed. Therefore, the first
piece of tape
the first pieceisofdiscarded [215,216].[215,216].
tape is discarded Moreover, the teststhe
Moreover, should
tests be performed
should under the
be performed un-
same conditions, regarding skin area and velocity of tape removal [214].
der the same conditions, regarding skin area and velocity of tape removal [214].

Figure8.8.Schematic
Figure Schematicrepresentation
representationofoftape
tapestripping
strippingtechnique.
technique.

Confocal Laser Scanning Microscopy (CLSM)

Unlike the previously mentioned techniques, confocal laser scanning microscopy
(CLSM) is a non-invasive method that uses fluorescence phenomenon in order to examine
the drug distribution throughout the skin [215]. Usually, rhodamine B or other fluorescent
dye is loaded in the tested sample. A substrate is treated with the gel formulation and
Gels 2023, 9, 352 26 of 36

Confocal Laser Scanning Microscopy (CLSM)

Unlike the previously mentioned techniques, confocal laser scanning microscopy
(CLSM) is a non-invasive method that uses fluorescence phenomenon in order to examine
the drug distribution throughout the skin [215]. Usually, rhodamine B or other fluorescent
dye is loaded in the tested sample. A substrate is treated with the gel formulation and
optically scanned with a fluorescent microscope. Therefore, CLSM has potential in ana-
lyzing the localization of different nano- and micro-sized structures in the skin delivery.
However, the main disadvantage of this technology is the limited number of fluorescence
markers [214].

In Vitro Methods
Even though in vitro assay cannot completely resemble the complexity of the human
skin structure, it is an essential tool for assessing drug release behavior as well as measuring
in vivo skin absorption [215].
The Franz-diffusion cell is well-established experimental set-up with a structure de-
signed to mimic skin conditions [217]. This tool consists of a cell that holds a chamber
for drug application (donor compartment), a membrane within which the drug can dif-
fuse, and an acceptor media chamber (receptor compartment) from which samples can
be collected [201] (Figure 9). Measurement of the amount of drug into the receptor com-
Gels 2023, 9, 352 partment by a suitable analytical method is used to evaluate the drug diffusion in the 27 of 37
skin
over time [214].

Figure 9. Schematic representation of Franz-diffusion

Franz-diffusion cell.

Different techniques
Different techniquesevaluating
evaluating thethe
API permeation
API permeation usually estimate
usually the drug
estimate the flux,
drugwhich
flux,
is expressed as the amount released through a definite surface area over time (mg/cm 2 /h).
which is expressed as the amount released through a definite surface area over time
Based on
(mg/cm theBased
2/h). flux value,
on thethe fluxpermeability coefficient can
value, the permeability also be can
coefficient determined, taking into
also be determined,
accountinto
taking the account
drug concentration in the donor in
the drug concentration compartment [143]. These set-ups
the donor compartment utilizeset-ups
[143]. These Franz-
diffusion
utilize cells with a membrane
Franz-diffusion cells with aseparating
membranethe donor and
separating the acceptor
donor and compartments.
acceptor compart- The
membrane can be either an excised hairless animal skin (such as
ments. The membrane can be either an excised hairless animal skin (such as goat [143], ratgoat [143], rat [12,218],
or pig [38,84,97,219]) or an artificial skin (StratM ® , EpiDermTM ). The choice of the media
[12,218], or pig [38,84,97,219]) or an artificial skin (StratM ®, EpiDermTM). The choice of the

for the receptor compartment depends on the

media for the receptor compartment depends on the solubility solubility of the API,
of thebutAPI,aqueous buffers
but aqueous
with
buffers with physiological pH values are preferred. To increase the API solubility sink
physiological pH values are preferred. To increase the API solubility and achieve and
conditions,
achieve sinksurfactants
conditions, (such as Tween)
surfactants andas
(such co-solvents
Tween) and (such as ethanol)
co-solvents (suchare also allowedare
as ethanol) to
be added.
also allowed Thetofactor that has
be added. The the strongest
factor influence
that has on accurate
the strongest and representative
influence on accurate and results
rep-is
the choice of an appropriate membrane [201]. Even though human
resentative results is the choice of an appropriate membrane [201]. Even though human skin is the most relevant
model
skin is for
the the
most evaluation of in vitro
relevant model for skin permeationofstudies,
the evaluation in vitroits usepermeation
skin is usually replaced
studies, by its
use is usually replaced by animal models such as pigs, rats, mice, and snakes [220]. ear
animal models such as pigs, rats, mice, and snakes [220]. Among these, porcine Amongskin
is thought
these, to most
porcine resemble
ear skin normal
is thought to human skin, due
most resemble to its human
normal thickness,skin,follicular
due to structure,
its thick-
ness, follicular structure, vascularity, and lipid content [38,84,97,219]. Unfortunately, due
to ethical considerations, today there are many regulatory restrictions on the use of ani-
mals [216,221]. For these reasons and taking into account the advances in tissue engineer-
ing, the development of artificial in vitro human skin models that resemble both healthy
Gels 2023, 9, 352 27 of 36

vascularity, and lipid content [38,84,97,219]. Unfortunately, due to ethical considerations,

today there are many regulatory restrictions on the use of animals [216,221]. For these reasons
and taking into account the advances in tissue engineering, the development of artificial
in vitro human skin models that resemble both healthy and diseased skin have been explored
widely [216,220]. The artificial skin membranes can be made of simple homogeneous polymer
materials, such as poly(dimethoxysilane), silicone membranes, or even lipid-based parallel
artificial membrane-permeability assay (PAMPA) or phospholipid vesicle-based permeation-
assay membranes [216]. Their main advantage is their easy reproducibility, which allows
studying the basic mechanisms controlling skin permeation [221]. Moreover, they can be
modified according to the acquired specific disease characteristics. For example, skin cancer
models were constructed by incorporating various tumor entities within the three-dimensional
(3-D) matrix, including cultured melanoma cells, melanoma tumor spheroids, and various
cutaneous squamous cell carcinoma cell lines [220].
The controversy surrounding all characterization methods and the information they
provide once again prove the complexity of the dermal route of administration. The skin
is an easily accessible and non-invasive application site. However, the skin’s properties,
together with the effects of the formulations on the skin, explain the intensive scientific
research in the area and the continuously growing number of research articles.

6. Conclusions and Future Aspects

The current review evaluated the achievements and hurdles in the development of
suitable topical formulations for the delivery of chemotherapeutic substances of various
properties in the treatment of skin cancer. The review showed the complexity of the matter.
Knowledge from a large number of scientific areas is needed in order to be able to prepare
and characterize an efficient drug delivery system. It is evident that a large amount of
scientific effort has been put into improving the penetration, stability, and efficacy of the
APIs. Various approaches have been implemented, such as the addition of penetration
enhancers, preparation of different types of gel carriers, loading with nanocomposites, and
other strategies. However, the results from the current review showed that there is a wide
variety of terms used to classify these complex systems. The lack of clear, uniform, and
accepted terminology makes investigating and understanding the mechanisms behind
some of the findings difficult. Therefore, in our opinion, the general classification of gels
used in this article could be convenient for future studies and distinguishing between
different formulations. It can also be noted that a significant number of characterization
tests exist for the explanation of the gels’ various properties. There are a large number of
variations in the penetration tests, and the results from in vivo, in vitro, and ex vivo studies
vary. This is most likely due to the skin’s complex structure and physiological properties.
Therefore, the mechanism by which these processes occur requires further clarification.
Nevertheless, it is possible to deliver both hydrophilic and lipophilic drugs by combining
the nanotechnological formulations together with the gel supporting system. The latter
can provide an easy, acceptable, and versatile carrier in which various nanoparticles and
nanovesicles can be loaded.

Author Contributions: Conceptualization, M.S.; methodology, M.S.; investigation, M.S., B.T., T.P.,
C.V.; writing—original draft preparation, M.S., B.T., T.P., C.V.; writing—review and editing, M.S.,
B.T., T.P., C.V.; visualization, M.S., B.T., T.P., C.V.; supervision, M.S.; project administration, B.T., C.V.;
funding acquisition, M.S., B.T., T.P., C.V. All authors have read and agreed to the published version of
the manuscript.
Funding: The authors would like to acknowledge the financial support by the European Union-
NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria,
project № BG-RRP-2.004-0004-C01.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Gels 2023, 9, 352 28 of 36

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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