International Journal of Pharmaceutics 614 (2022) 121439

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Skin interaction, permeation, and toxicity of silica nanoparticles:

Challenges and recent therapeutic and cosmetic advances
Renata Pinho Morais a, *, Sabrina Hochheim b, Carolina C. de Oliveira c, Izabel C. Riegel-Vidotti b,
Cláudia E.B. Marino a
a
Department of Mechanical Engineering, Universidade Federal do Paraná, Curitiba, Brazil
b
Department of Chemistry, Universidade Federal do Paraná, Curitiba, Brazil
c
Department of Cell Biology, Universidade Federal do Paraná, Curitiba, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Silica nanoparticles (SNPs) received more attention with the emergence of nanotechnology with the aim and
Silica nanoparticles promise of becoming innovative drug delivery systems. They have been fulfilling this objective with excellence
Topical drug delivery and nowadays they play a central role in biomedical applications. New SNPs application routes are being
Skin permeation
explored such as the epidermal, dermal, and transdermal routes. With that, novel models of synthesis, func­
Skin toxicity
tionalization, and applications constantly appear. However, it is essential that such innovations are accompanied
Topical formulations
by in-depth studies on permeation, biodistribution, metabolization, and elimination of the generated by-
products. Such studies are still incipient, if not rare. This article reviews significant findings on SNPs and
their skin interactions. An extensive literature review on SNPs synthesis and functionalization methodologies was
performed, as well as on the skin characteristics, skin permeation mechanisms, and in vivo toxicity assessments.
Furthermore, studies of the past 5 years on the main therapeutic and cosmetic products employing SNPs, with
greater emphasis on in vivo and ex vivo studies were included.

1. Introduction and motivation
There is a long history of substances application on the skin for either
cosmetic or skin treatments, disclosed in the oldest medical records and
in all periods of human evolution (Khavkin and Ellis, 2011; Kolarsick
et al., 2011). Today, the market for transepidermal products is on the
rise, as it is a comfortable, safe, and non-invasive route for patients
(Jepps et al., 2013; Zsikó et al., 2019; Bakshi et al., 2020). In addition,
the skin is a social organ, as it reflects our contact with society. In­
dividuals who suffer from skin disorders can develop mental disorders
and poor quality of life due to low self-esteem (Cortés et al., 2021; Dreno
et al., 2021). In this way, cosmetic care increasingly co-emerges with
dermatocosmetic technology as another treatment option. (Khavkin and
Ellis, 2011).
However, due to a complex structure of multiple layers, the skin acts
as a barrier between the body and the external environment, regulating
the transit of substances in a highly selective manner (Kolarsick et al.,
2011; Wong et al., 2016). When planning a dermatological product, its
purpose must be very clear, thus from the beginning of development the
right direction can be taken. Skin administration of active compounds
generally has three different goals: non-absorption, local absorption
(epidermis and dermis), and transdermal absorption. Cosmetics, insect
repellents, antifungals or disinfectants are examples of common for­
mulations designed to maintain the active compound on the skin sur­
face. Topical formulations allow the active compounds to penetrate into
the skin deepest regions, and transdermal formulations aim to supply
active compounds to systemic circulation (Lane, 2011).
Different strategies have been developed to overcome the skin
outermost layer limiting barrier, the stratum corneum, to improve drugs
permeation, which include chemical enhancers (ethanol, fatty acids, and
polysorbates) and physical methods (iontophoresis, electroporation,
sonophoresis, and microneedles). These penetration enhancers, in gen­
eral, promote drug diffusion by disturbing stratum corneum and/or
deeper layers structure, which can attack skin causing irritation and
even toxic adverse effects (Alexander et al., 2012; Foldvari, 2000; Goyal
et al., 2016; Medi et al., 2017). In addition, drugs classified by BCS

* Corresponding author at: Grupo de Biomateriais, Eletroquímica e Corrosão, Universidade Federal do Paraná, ZIP Code: 81531-980, Curitiba, Brazil.
E-mail addresses: renata.morais@ufpr.br (R.P. Morais), sabrina.hochheim@ufpr.br (S. Hochheim), krokoli@ufpr.br (C.C. de Oliveira), izabel.riegel@ufpr.br
(I.C. Riegel-Vidotti), claudiamarino@ufpr.br (C.E.B. Marino).

https://doi.org/10.1016/j.ijpharm.2021.121439
Received 23 September 2021; Received in revised form 16 December 2021; Accepted 28 December 2021
Available online 3 January 2022
0378-5173/© 2021 Elsevier B.V. All rights reserved.
R.P. Morais et al.
(Biopharmaceutical Classification System) as belonging to class II (low
solubility and high permeability) and class IV (low solubility and low
permeability) are considered the most problematic drug types in the
pharmaceutical formulation (Teixeira et al., 2017). This is because
taking into account the natural skin selectivity, drugs must be lipophilic
enough to cross the stratum corneum, but also have the necessary hy­
drophilicity to be able to cross the viable epidermis, dermis (more hy­
drophilic regions), and reach the bloodstream (in the case of
transdermal systems) (Lane et al., 2012). Another problem is that
insufficiently solubilized drugs can undergo crystallization and cause
acute toxicity (Zhu et al., 2018). Thus, an alternative found by re­
searchers to overcome these difficulties was to load these drugs in drug
release nanosystems, which are applicable both in cosmetic and thera­
peutic areas.
In this context, nanoparticles have emerged to improve drug
apparent solubility, permeability, and decrease toxicity to skin. They not
only achieve a deeper drug penetration, but also are also able to create
reservoirs, which increase stability and permanence on the target site.
These nanoparticulate systems promote the delivery and sustained
release of drugs, increasing their effectiveness and reducing their
adverse effects (Carazo et al., 2018; Goyal et al., 2016).
Among the various nanoparticles used as drug carriers are silica
nanoparticles (SNPs). Their excellent properties, such as large surface
area, biocompatibility, porosity, versatility for surface modification,
control of parameters such as size and shape, ease of large-scale syn­
thesis and low production costs make them promising tools for appli­
cation in dermatology and cosmetology (Esim et al., 2019; Gonçalves,
2018; Jeelani et al., 2020). The porosity of SNPs allows the loading of
therapeutic agents in large quantities. In addition, the size and volume
of the pores can be adjustable. Therefore, optimizing the pore size ac­
cording to the size of the load and limit of controlled release is highly
essential (Bharti et al., 2015; Selvarajan et al., 2020). Many researchers
have reported the successful application of SNPs in topical drug
administration (Jadhav et al., 2017; Mo et al., 2020; Montazeri et al.,
2019; Nafisi et al., 2018; Sapino et al., 2017, 2015). For example, in the
research carried out by Berlier et al. (2013), rutin immobilization, a
highly unstable flavonoid that is poorly soluble in aqueous medium, in
mesoporous SNPs functionalized with aminopropyl groups resulted in
active compound better performance in terms of photostability and skin
accumulation. However, despite the advances, the mechanisms involved
in SNPs interaction, transport, and fate in the skin have not yet been
fully understood.
Therefore, this article aims to review significant findings related to
SNPs preparation and functionalization and their skin interactions. First,
this review addresses SNPs synthesis and superficial modification stra­
tegies, their skin permeation capacity, and findings on these systems
toxicity. Finally, the most relevant advances and evidence in the cuta­
neous use of SNPs for therapeutic and cosmetic applications are pre­
sented, focusing on in vivo and ex vivo studies. For this, electronic
searches were conducted through the PubMed, ScienceDirect and Web
of Science databases and studies from the last 5 years were selected
combining the term ’silica nanoparticle’ with the terms ‘drug delivery’,
’skin’ and ‘cosmetic’.
2. Silica nanoparticles as drug carriers
Worldwide, nanotechnology is being used in drug delivery systems
development to prevent, control, and treat diseases. Thanks to their
unique nanoscale properties (usually in the range from 1 up to 100 nm)
and specific biological functions, nanosystems are able to transport
drugs more effectively and to release them in a controlled, targeted or
on-demand manner at the target site, thus promoting an increased
therapeutic efficacy and reducing side effects (Esim et al., 2019).
Silicon (Si) is one of the inorganic chemical elements found in the
earth crust. Its oxide forms are silicate (SiO4) and silica (silicon dioxide,
SiO2). Si is often used in industry, while its oxide forms are often used for
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International Journal of Pharmaceutics 614 (2022) 121439
biomedical applications. There are two basic silica structures: crystalline
and amorphous. Both forms have the same molecular formula, but their
structural arrangements are different (F. Chen et al., 2018; L. Chen et al.,
2018). However, amorphous silica is generally considered less harmful
to health than crystalline silica (Arts et al., 2007). Despite of this,
opinions about this issue are still very contradictory. Amorphous silica is
accepted by regulatory agencies such as the Food and Drug adminis­
tration (FDA) and is used as an ingredient in oral administration in an
amount not to exceed 2 percent by weight of the food (Food & Drug
Administration, 2020). However, the FDA does not have an official
document that prohibits or express opinion about silica in topical and
transdermal products. On the other hand, the Scientific Committee on
Consumer Safety (SCCS) from European Commission, presented an
extensive document analyzing studies about many types of silica forms
indicating that due the lack of research methods standardization, the
unique characteristics of each material must be well evaluated to
guarantee safety and biocompatibility (Scientific Committee on Con­
sumer Safety, 2015).
Since the 1980s, silica has been used in controlled drug delivery
systems (Unger et al., 1983), but it was after first report (Vallet-Regi
et al., 2001) on mesoporous silica nanoparticles (MCM-41 - mesoporous
silica with two-dimensional straight channel pore) as drug delivery
systems, that SNPs began to be extensively explored within biomedical
research (Arriagada et al., 2019). Researchers have successfully worked
with SNPs as carriers to deliver a variety of therapeutic agents, ranging
from small molecules (e.g., drugs) to macromolecules (e.g., proteins,
DNA and RNA) (Lio et al., 2019; Ren et al., 2020; Sun et al., 2013; Zhang
et al., 2014).
SNPs have been gaining prominence because of their differential
properties, which include stability, hydrophilicity, biocompatibility,
ease of functionalization/surface modification, large specific surface
area, high pore volume, controlled particle size, and high loading ca­
pacity for drugs/therapeutic molecules associated with ease of synthesis
and processing (Esim et al., 2019; Gonçalves, 2018; Jeelani et al., 2020).
In addition, due to the strong Si-O bond, SNPs are more stable to external
response, such as biological degradation and mechanical stress,
compared to other nanosystems, such as liposomes, nanoemulsions and
dendrimers, which excludes the need for any external SNPs synthesis
stabilization (Bharti et al., 2015; Karimi et al., 2016). Other advantages
are that SNPs pore size and porosity can be adjusted, as well as SNPs
surface functionalization can allow the control of drug loading and
release, a process that is necessary to properly load various drug mole­
cules, whether hydrophobic, hydrophilic, or having a positive or nega­
tive charge (Bharti et al., 2015).
SNPs used for drug delivery can be classified into two main types:
porous or non-porous (solid) SNPs (Tang and Cheng, 2013). Mesoporous
SNPs are the most common form of porous SNPs. Mesoporous SNPs are
characterized by their mesopores (pore size 2–50 nm), which can be
filled with drugs through physical or chemical adsorption. In contrast,
non-porous SNPs do not have a porous structure, thus drugs are
encapsulated or conjugated through various chemical ligands. Drug
release in mesoporous SNPs can be controlled using the “gatekeepers”
strategy, for example, metallic macromolecules or nanoparticles can be
attached to SNPs mesoporous surface to block and prevent premature
release, or by modifying the inner pores surface to control drug binding
affinity. While drug release in non-porous SNPs is controlled by chem­
ical binders or by silica matrix degradation (Souris et al., 2014; Tang and
Cheng, 2013). As reported below, silica versatility allows different SNP
structures construction with wide possibilities of shape, size, function­
alization, and encapsulated active principles.
2.1. Methods for silica nanoparticles synthesis
Chemical synthesis is the main route used to obtain different SNPs
types. It includes microemulsion method, Stöber’s method, and sol–gel
method (Jeelani et al., 2020; Souris et al., 2014).
R.P. Morais et al.
SNPs synthesis by the microemulsion method has been used since the
90′ s (Arriagada and Osseo-Asare, 1994). In this method, the alkyl sili­
cate molecules solubilized in the oil phase diffuse in a surfactant layer,
forming micelles in the presence of water (Jeelani et al., 2020; Mebert
et al., 2017). The micelles stabilized by surfactants (tweens or pluronics)
act as nanoreactors for SNPs synthesis. It is inside these nanoreactors
that silica precursors undergo hydrolysis and condensation reactions to
form SNPs (Fig. 1). This method involves oil-in-water (O/W) micelles or
water-in-oil (W/O) reverse micelles formation (Jeelani et al., 2020;
Selvarajan et al., 2020; Yoo and Pak, 2013). Microemulsion is a ther­
modynamically stable, isotropic, highly tunable system, in which the
micelles size and consequently SNPs can be adjusted by changing water
to surfactant proportion. Porous and non-porous SNPs can be prepared
by this method (Souris et al., 2014). The ease of reaction control is an
advantage of this method. However, the use of organic solvents and
surfactants is a disadvantage due to the high cost, the need for purifi­
cation, and recovery of nanoparticles for large-scale synthesis (Mebert
et al., 2017).
The sol–gel method was first used in 1845 by M. Ebelman (Dimitriev
et al., 2008) to obtain glass. Since then, due to its ability to form pure
and homogeneous products in mild conditions, the method still con­
tinues to be used in glass production, which has been perfected to pro­
duce other ceramic materials, such as silica (Jeelani et al., 2020;
Rahman and Padavettan, 2012). The sol–gel method involves hydrolysis
and condensation of metallic alkoxides such as tetraethylorthosilicate
(TEOS, Si(OC2H5)4) or inorganic salts such as sodium silicate (Na2SiO3)
in the presence of mineral acid (for example, HCl) or base (for example,
NH3) acting as catalysts (Jeelani et al., 2020). Hydrolysis of silica pre­
cursor molecules forms silanol groups. The condensation/polymeriza­
tion between the silanol groups creates siloxane bridges (Si – O – Si)
forming a three-dimensional structure of silica covered with –OH
groups (Arriagada et al., 2019; Rahman and Padavettan, 2012). Some of
this method advantages are direct, scalable, and controllable synthesis.
In addition, the particles size, distribution, and morphology can be
controlled by changing the reaction parameters, such as temperature,
pH, surfactant concentration, silica source, and catalyst (Mebert et al.,
2017).
The Stöber’s method developed in 1968 by Stöber et al. (Stöber et al.,
1968) from a silica alkoxide alcohol aqueous solution in the presence of
ammonia as catalyst, is a sol–gel process that generates spherical and
monodisperse silica particles with uniform size (50–2000 nm in diam­
eter). This technique is based on controlled hydrolysis and silica pre­
cursor condensation, in most cases TEOS, occurring in the presence of
excess water and a low molar alcohol such as ethanol. The particle size
and morphology (to a lesser extent) can be adjusted during synthesis
Fig. 1. Schematic illustration of the microemulsion method to produce silica nanoparticles. Adapted from ref. (Selvarajan et al., 2020).
3
International Journal of Pharmaceutics 614 (2022) 121439
through changes in water/silane ratio, type of catalyst or solvent, and
temperature (Jeelani et al., 2020; Mebert et al., 2017; Souris et al.,
2014). Many contemporary researches describe SNPs synthesis using the
Stöber method or its optimizations (Barrera et al., 2016; Gholami et al.,
2013; Y.C. Lin et al., 2018; Z. Lin et al., 2018; Ren et al., 2020). Fig. 2
shows the experimental conditions most used to synthesize SNPs with
different structures and morphologies through the sol–gel process using
TEOS as silica precursor.
Novel methods to synthesize SNPs were described. One such method
is the microwave-assisted method, where mesoporous SNPs synthesis
occurs in an electromagnetic field along with a fast heating speed
(Farjadian et al., 2019). Microwaves can provide high localized heating
that may be higher than the reaction vessel recorded temperature
(Kumar et al., 2017). As compared to hydrothermal process that utilizes
high pressure and temperatures using autoclave heating, there are many
advantages of this technique such as rapid heating to crystallization
temperature, faster super saturation by the rapid dissolution of precip­
itated gels, and a shorter crystallization time, besides being a low-cost
approach (Kumar et al., 2017; Narayan et al., 2018). Various reports
found that the result by microwave heating can produce high ordered
mesoporous SNPs within a very short time and with high purity
(Abdelaal and Shaikjee, 2020; Peres et al., 2018).
Another method that is rapid, cost effective, and capable of being
operated under ambient conditions for SNPs production is sonochemical
synthesis. Ultrasonic irradiation causes cavitation in a liquid medium
where the formation, growth, and implosive collapse of bubbles occurs,
resulting the generation of high-speed microjets, which can generate
SNPs (Masjedi-Arani et al., 2014). The use of ultrasound during the
synthesis can generate uniformly shaped, monodisperse, and size-
controlled spherical SNPs with relatively short reaction times (Kim
et al., 2016). A recent trend is biogenic synthesis that uses bacteria,
fungi, algae (biomass), and plant compounds (extract and metabolites)
in the production of SNPs (Jeelani et al., 2020). SNPs can be synthesized
using agro-industrial by-products considered as waste material such as
sugarcane bagasse (Falk et al., 2019), rice husk (Athinarayanan et al.,
2015), rice straw (Nandiyanto et al., 2016), and olive residue (Rezaeian
et al., 2021). The biogenic synthesis is an economically viable, energy
saving, and green approach.
2.2. Strategies for silica nanoparticles surface modification
SNPs surface can be modified through chemical (by covalent
bonding) or physical (by physical adsorption) functionalization. Phys­
ical modification is generally reversible and is not as common as
chemical modification due to non-covalent bond instability (F. Chen
R.P. Morais et al.
Fig. 2. The experimental conditions commonly used in silica nanoparticles synthesis by the sol–gel process from TEOS. Adapted from ref. (Liberman et al., 2014).
et al., 2018; L. Chen et al., 2018).
SNPs chemical modification is made possible by the presence of high
density of silanol and siloxane groups on SNPs surface. The number of
available silanol groups and the SNPśshape are dependent on the syn­
thetic route. For example, these groups can react with a silane (abundant
and commercially available) by introducing other functional groups on
SNPs surface. The most frequently used silanes have amine or sulfur
groups at the end of an alkylsilane (for example, 3-aminopropyl trie­
thoxysilane (APTS) and 3-mercaptopropyl trimethoxysilane (MPTS)),
along with several PEG-silanes. APTS and MPTS can act as coupling
agents between SNPs and other chemical moieties (F. Chen et al., 2018;
L. Chen et al., 2018; Liberman et al., 2014). As an example, APTS was
used to graft amino group (NH2) into hollow mesoporous SNPs to load
the anti-inflammatory drug sulfasalazine (Ghasemi et al., 2017). In
addition, through PEG-silane, PEG molecules are grafted onto SNPs
surface (Cauda et al., 2010; He et al., 2011).
SNPs surface modification for subsequent molecules of interest fix­
ation is generally carried out by two main strategies: co-condensation
(direct incorporation) during synthesis and post-synthesis graft
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International Journal of Pharmaceutics 614 (2022) 121439
(Fig. 3) (Jeelani et al., 2020; Souris et al., 2014; Vallet-Regí, 2014). In
co-condensation, the organofunctional silane is added during the syn­
thesis together with a source of silica. The functionalization occurs when
surface silanol groups react with organofunctional silane. This strategie
resultes in uniform incorporation of functional groups (Idris et al., 2020;
Jeelani et al., 2020; Souris et al., 2014; Vallet-Regí, 2014). These
organofunctional silane agents have the structure R’-Si-X3, where X
represents alkoxy (OR), and R’ is an organofunctional group. In the
presence of water, hydrolysis occurs to produce alkoxysilanols and,
occasionally, silane triols, as well as the condensation of silanols into
siloxanes (Idris et al., 2020). The hydrolysis and condensation reactions
of co-condensation method are as follows:
Hydrolysis: R Si(OR)3 + 3H2 O⇄R Si(OH)3 + 3R OH
′ ′ ′
Condensation: 2R Si(OH)3 ⇄R Si(OH)2 OSi(OH)2 R + H2 O
′ ′ ′
Organoalkoxysilanes can be co-condensed into growing nano­
particles to produce an inorganic–organic hybrid for further additional
R.P. Morais et al. International Journal of Pharmaceutics 614 (2022) 121439

Fig. 3. Schematic representation of surface modification strategies: co-condensation (1) and post-synthesis grafting (2). CTAB is the cetyltrimethylammonium
bromide surfactant, F127 is the triblock copolymer targeting agent, and NH4OH is ammonium hydroxide catalyst. Adapted from ref. (Selvarajan et al., 2020).

functionalization (Idris et al., 2020; Souris et al., 2014). The organo­
alkoxysilanes commonly used to functionalize SNPs are APTS, methyl­
triethoxysilane (MTES), vinyltriethoxysilane (VTES), 3-
aminopropyltrimethoxysilane (APTMS), 3-glycidoxypropyl-trimethoxy­
silane (GPTMS), and 3-acryloxypropyltrimethoxysilane (AOPTMS). The
co-condensation of two organoalkoxysilanes can insert basic and acidic
functional groups into SNPs structure, resulting in new properties and
chemical applications (Souris et al., 2014). In addition, certain orga­
nosilanes play a dual role, they can functionalize SNPs surface and
transform their shape. SNPs morphological variants can be synthesized
by the co-condensation method by incorporating organosilanes, and
nanoparticles morphology will depend on type and quantity of intro­
duced organoalkoxysilane precursor (Narayan et al., 2018). Huh et al.
(2003) found that organoalkoxysilane precursors presence during
condensation influenced particle final shape, and changing the precur­
sor or its concentration, SNPs morphology were adjusted to various
shapes, including spheres, tubes, and rods of various dimensions. In
addition, it is through this method that functional groups can be
incorporated without significantly affecting SNPs pore topology (Souris
et al., 2014).
The post-synthesis graft in SNPs explores the presence of surface
silanol groups (Si–OH) that act as convenient anchor points for organic
functionalization. The graft is commonly performed by silylation on the
free (– – Si–OH)) and geminal silinal (Si(OH) ) groups, although
– 2
hydrogen-linked silanol groups are less accessible to modification, as
they quickly form hydrophilic networks among themselves. The original
nanoparticles morphology and pore structure remain intact with the
graft, although the technique often results in non-uniform distributions
of organic functional groups (Souris et al., 2014). Zaharudin et al.
(2020) observed morphology preservation, after functionalizing meso­
porous SNPs with amine, carboxyl, and thiol groups using the post-
synthesis graft technique. The authors observed in TEM images that
the original nanoparticles morphology was preserved. In addition, the
post-synthesis graft method provides numerous opportunities to cova­
lently attach diverse labile functional groups, such as ester group, for
example, that is prone to hydrolyze (Mirzaei et al., 2020; Vallet-Regí,
2014) on SNPs surface. A problematic issue with post-synthesis graft
technique is the possible blocking of pores opening by the functional
groups, which can inevitably limit the access of drug molecules to sites
deep inside the pores (Vallet-Regí, 2014).
administered in a biological environment, since surface modification
plays a fundamental role in altering the surface reactivity improving
SNPs biocompatibility. In addition, without surface modification, the
silanol (Si–OH) groups present on SNPs surface can interact with bio­
logical molecules, such as lipids and cell membrane proteins, altering
these molecules’ structure (Tang et al., 2012).
Functionalization allows modifying specific SNP locations (wall and
pore entry and the outer/inner surface) with functional groups and
molecules (F. Chen et al., 2018; L. Chen et al., 2018; Jeelani et al., 2020).
These groups and functional molecules include spacers for colloidal
stability (Loiola et al., 2019), therapeutic agents (Xie et al., 2014),
agents for active targeting (Ricci et al., 2018), blocking molecules to
stimulate drug release (Moorthy et al., 2019) among others (Fig. 4).
2.3.1. Lipid coating
The presence of an outermost lipid layer around SNPs allows for a
better interaction with the stratum corneum and other skin layers, in
addition to providing increased biocompatibility and ability to prevent
nanoparticles aggregation (Iannuccelli et al., 2014; Tada et al., 2014). In
an in vivo skin permeation study, lipid-coated SNPs have already been
shown to permeate the skin to a greater extent (about 42%) than un­
coated SNPs (about 10%) (Iannuccelli et al., 2014). The lipophilic nature
of lipid-coated SNPs was able to increase their permeation in the stratum
corneum, although they had a larger size (363 ± 74 nm in size) than the
uncoated SNPs (162 ± 51 nm in size). Furthermore, lipid-coated SNPs
exhibited a more marked tendency to reach deeper layers stratum

2.3. Surface modification of silica nanoparticles for topical and

transdermal administration

It is recommended to functionalize SNPs that are intended to be Fig. 4. Multifunctionality of porous silica nanoparticles.

5
R.P. Morais et al.
corneum when applied on the volar forearm (region having low hair
follicles density) compared with the dorsal (region having high hair
follicles density) forearm application, suggesting a preferential pathway
through the lipid domain among corneocytes rather than along the
follicle orifices.
2.3.2. Positively charged functional groups
It is assumed that the first permeation stage is the attachment of
nanoparticles to skin cells membrane. It is well known that the epithelial
cell membranes on skin surface are negatively charged. In this way,
functionalizing SNPs surface with positively charged functional groups
(for example, NH2 group) is a strategy to improve their permeation
through the skin (Baspinar and Borchert, 2012; Nafisi et al., 2018; Yil­
maz and Borchert, 2006). The positively charged nanoformulations are
absorbed intensely by the negatively charged corneocytes, which in­
crease encapsulated drug retention time and bioavailability, especially
those of poorly soluble drugs (Baspinar and Borchert, 2012; Yilmaz and
Borchert, 2006). Examples of research that used this type of function­
alization strategy to increase drugs permeability are described in the last
sessions.
2.3.3. Targeting agents
The drugs targeted delivery to a specific location on skin has been
receiving attention in dermatology (Chen et al., 2021; Schneider-Rauber
et al., 2020). However, high precision and accuracy drug delivery to skin
target sites (for example, hair follicle, pilosebaceous gland, and dermis
layers) is challenging, due to the protective skin structure. Therefore, the
superficial nanosystems modification is an essential factor to achieve
this goal (Chen et al., 2021). Recently, they investigated the role of
PEGylation in targeted SNPs delivery to hair follicles (Al Mahrooqi et al.,
2021). It was observed that SNPs functionalized with polyethylene
glycols (PEGs) penetrated the cutaneous appendages, and nanoparticles
functionalized with PEG 5000 Da penetrated more deeply into hair
follicles compared to those functionalized with PEG 750 Da. Because the
longer PEG chains are more flexible than the shorter PEG chains, they
allowed greater protection for the remaining thiol groups on nano­
particle surface, providing deeper penetration by reducing the particle-
Fig. 5. Schematic illustration of representative stimuli-responsive drug delivery silica nanoparticles (SNPs). SNPs incorporating capping agents (1 and 2) and
sensitive linkers (3).
6
International Journal of Pharmaceutics 614 (2022) 121439
tissue bond. In addition to acting as a targeting agent, PEGs form a
hydrophilic layer around SNPs, which increases the dispersion and half-
life of these nanoparticles by delaying opsonization, that is, proteins
adsorption to nanoparticles, thus allowing immune response escape
(Rosenholm et al., 2010; Tang et al., 2012).
2.3.4. Stimulus-responsive agents
Surface functionalization offers numerous possibilities to develop
stimuli responsive systems in order to delivery therapeutic molecules on
demand (Möller and Bein, 2017). Smart nanocarriers are being designed
owning characteristics that respond to stimuli and can trigger the asset
release only when and where needed. These responsive elements are
added to nanoparticles by means of surface modification strategies
(Karimi et al., 2016). In general, these intelligent nanocarriers incor­
porate one or two elements, namely, a sensitive linker and/or a capping
agent (Fig. 5). The responsive linker is capable of breaking, degrading or
undergoing a conformational change in the provided stimulus presence.
Capping agents, such as inorganic nanoparticles (INPs), polymers or
macromolecules, block the pores entry and hinder premature drug exit
(Vallet-Regí et al., 2018).
SNPs can be modified to respond to a variety of different stimuli.
These can be endogenous factors such as enzyme (Liu et al., 2015), pH
(Yan et al., 2020) and reactive oxygen species (ROS) (Xu et al., 2019) or
exogenous factors such as light (Li et al., 2020), ultrasound (Paris et al.,
2015), magnetic field (Chen et al., 2016), and temperature (J.T. Sun
et al., 2012; M. Sun et al., 2012).
In the development of topical and transdermal stimuli-responsive
systems, it is necessary to take into account during the design of these
systems the layer in the skin where the stimulus manifests (in the case of
endogenous stimuli) or which skin layer it reaches (in the case of
exogenous stimuli). Depending on which skin layer it is intended to
release, on demand, the encapsulated drug, one must think about which
synthesis materials and surface modification strategies to use in order to
the system be able to penetrate and permeate or to stay on the skin
surface, in order to achieve the target location for release. For example,
polymers such as chitosan, which in addition to being a pH-responsive
material, has been shown to be a permeation enhancing agent (He
R.P. Morais et al.
et al., 2009). In this way, chitosan can be used in the development of pH-
responsive systems that intend on permeation (Alruwaili et al., 2020). In
addition, stimulus-responsive systems can be modified, for example,
with positively charged functional groups or lipids that are strategies
used to increase skin permeation, which were discussed previously.
Besides, these systems can be incorporated into formulations containing
permeation enhancers, in order to increase their skin permeation ca­
pacity (Dhal et al., 2020).
To the best of our knowledge, the stimuli that have been investigated
for delivering skin medications on demand based on SNPs include the
following parameters.
2.3.4.1. Enzymes. The deregulation of certain enzymes, being down or
overexpressed in certain pathological states, can be used to trigger drug
release from SNPs (Karimi et al., 2016; Manzano and Vallet-Regí, 2020).
The skin has a metabolic capacity, where numerous enzymes facilitate a
wide range of biotransformations, but intrinsic enzymes are generally
scarce in skin metabolism, and their exploration in the development of
stimulus-responsive systems for drug release is rarely reported. How­
ever, a regulated or specific production of certain enzymes can occur
under pathological conditions. In this context, bacterial enzymes
resulting from infectious processes in skin wounds are the most inves­
tigated as a triggering stimulus (Chen et al., 2021). Wu et al. (2015)
developed mesoporous SNPs biohybrids capable of releasing antimi­
crobial agents in the presence of hyaluronidase, an enzyme produced by
the pathogenic bacteria Staphylococcus aureus. Mesoporous SNPs were
loaded with the antibiotic amoxicillin and later coated with lysozyme,
hyaluronic acid, and 1,2-ethanediamine (EDA) -modified polyglycerol
methacrylate (PGMA) using the layer-by-layer (LBL) method. In vitro
tests showed that hyaluronidase triggered the specific nanosystem
cleavage. In addition, the nanosystem antimicrobial activity was eval­
uated in vivo in a mouse model of S. aureus-infected mice, resulting in an
almost complete inhibition of bacterial growth, with a bacteriostatic rate
of 99.9%, after epidermal administration.
2.3.4.2. pH. The skin has pH variations. Between its compartments, the
pH gradient varies from 4.5 to 7.5, with normal skin surface being more
acidic due to acidic constituents and exocrine secretions from the skin
glands and less acidic in deep areas. Changes in skin pH can also be
related to pathological conditions, such as atopic dermatitis, acne,
wounds, and psoriasis (Chen et al., 2021). In this way, the inequalities of
pH conditions in the skin can be used as a trigger to promote bioactive
agents release in target locations. Mesoporous SNPs loaded with antigen
(ovalbumin) and covered with lipid bilayer were used to coat micro­
needle arrays in order to build a pH sensitive system for delivering in­
tradermal antigen (Tu et al., 2017). Hence, silicon microneedle arrays
were chemically modified to obtain a pH sensitive surface (positively
charged at pH 5.8) using pyridine groups. Ex vivo system application to
human skin resulted in successful nanoparticles release due to a change
in pH from 5.8 to 7.4. The authors pointed out that the method is not
restricted to antigens delivery for intradermal vaccination but can also
be used to deliver any compound that can be encapsulated in meso­
porous SNPs such as drugs, RNA, DNA, and proteins.
2.3.4.3. Reactive oxigen species. Reactive oxygen species (ROS) play a
vital role in several biological processes. Generally, endogenous ROS are
maintained at a moderate level, but pathological conditions trigger
oxidative stress causing its overproduction. Many dermatological dis­
orders, such as photosensitivity diseases, certain types of skin malig­
nancy, and some inflammatory conditions have been shown to be
associated with ROS overproduction (Chen et al., 2021). This biological
change aroused researchers’ interest in ROS exploration as a trigger for
stimulus-responsive delivery systems. Hydrogen peroxide (H2O2) is one
of typical ROS.H2O2-Responsive mesoporous SNPs were integrated with
microneedle patches for glucose-monitored transdermal insulin delivery
7
International Journal of Pharmaceutics 614 (2022) 121439
(Xu et al., 2017). The authors developed a mesoporous SNPs modified
with 4-(imidazoyl carbamate) phenylboronic acid pinacol ester (ICBE)
that contained glucose oxidase and insulin by a host–guest complexation
between ICBE and α-cyclodextrin. Glucose oxidase was encapsulated to
convert glucose into gluconic acid and generate H2O2. The phenyl­
boronic ester on nanoparticle surface can be oxidized in H2O2 presence,
which resulted in host–guest complexation destruction, drug-loaded
mesoporous SNPs disassembly and, consequently, preloaded insulin
release. After transdermal microneedle administration in diabetic rats,
insulin exhibited glucose-mediated and H2O2-responsive release
behaviors.
2.3.4.4. Temperature. Changes in skin temperature are related to local
diseases involving inflammatory conditions. The thermal difference
between healthy and diseased skin can be used as a trigger to initiate the
drugs release only at intended locations. Among the materials, thermo-
responsive polymers have attracted the most interest to build
temperature-responsive systems, as are capable of responding to local
temperature variation, changing naturally their hydration profile (Chen
et al., 2021). Thermosensitive mesoporous SNPs have been designed for
topical delivery of the antioxidant quercetin (Ugazio et al., 2016). SNPs
mesopores were functionalized by copolymerizing the thermo-
responsive polymer N-isopropylacrylamide (NIPAM) with 3- (meth­
acryloxypropyl) trimethoxysilane (MPS). To verify the thermo-
responsive behavior, quercetin profiles release from mesoporous SNPs
with larger mesoporous size (5.0 nm) and smaller pore size (3.5 nm)
were monitored at 20 and 40 ◦ C, in other words, below and above the
lower critical solution temperature (LCST). At temperatures above LCST,
the copolymer chains collapse, allowing the release of immobilized drug
molecules within mesopores. The results showed that the thermo-
responsive behavior was more evident in mesoporous SNPs with larger
mesoporous size (20.0% difference in quercetin release between the two
temperatures) compared to mesoporous SNPs with smaller pore size
(11.8% difference between the two temperatures). Regarding the ex vivo
permeation capacity of mesoporous SNPs with larger pore sizes, they
showed no transepidermal penetration of quercetin and only 2.17 μg/
cm2 of quercetin accumulated in the skin, which was desired because it
is a formulation for photoprotection.
2.3.4.5. Light. Light is a particularly attractive tool for activating drugs
release from stimulus-responsive systems. The wavelengths of ultravi­
olet (UV, 200–400 nm), visible light (400–750 nm) or near infrared
(NIR, 750–2000 nm) can be used to activate responsiveness to light (Tao
et al., 2020). When using an external light source, the chemical structure
can be disturbed by inducing the delivery system photocleavage or
photoisomerization and adjusting the drug release profile to obtain
better control over treatment dose and duration. Different light pene­
tration depths can be reached in skin tissues. The greater the wavelength
the greater the depth reached, as skin components spread light more
efficiently with shorter wavelengths, which reduces penetration depth
(Chen et al., 2021; Costa et al., 2019). NIR and visible lights have a
better safety profile for humans than UV. The absorption of UV light,
especially in the UVB range (280–320 nm), causes progressive damage
to human skin, generating free radicals, destroying vitamins A and C,
damaging collagen and DNA (Costa et al., 2019; Martínez-Carmona
et al., 2017). Recently, biodegradable mesoporous SNPs responsive to
visible light have been developed for topical drugs administration in
osteoarthritis treatment (Zhao et al., 2021). The nanosystem was built
by supramolecular interaction between mesoporous SNPs modified with
azobenzene and β-cyclodextrin-modified poly (2-methacryloyloxyethyl
phosphorylcholine). The authors observed that visible light was able to
trigger azobenzene isomerization and, thus, to induce the drug release
after passing through the dermal tissue (nude mouse skin).
R.P. Morais et al.
2.3.5. Loading of active ingredientes
The efficiency of loading and releasing drugs from SNPs depends
strongly on the chemical characteristics of surface functionalization. The
Si-OH groups present on SNPs surface are important to control the drugs
loading through physical adsorption (Karimi et al., 2016). In addition,
thanks to the high surface area and large pore volume (porous and
mesoporous SNPs), surface functionalization (both external and inter­
nal) provides a high loading capacity for a variety of bioactive com­
pounds, whether hydrophobic or hydrophilic drugs. Hydrophobic drugs,
for example, can be loaded onto SNPs through functional groups con­
taining aromatic rings, which induce hydrophobicity SNPs surface, thus
preventing polar substances loading (Karimi et al., 2016; Narayan et al.,
2018). On the other hand, functional groups molecular dimensions on
pore surface can directly influence its diameter, which can affect drug
loading and quantity within the pore. Another important point to note is
drug release prevention before SNPs reach the target site. For this pur­
pose, drugs can be linked to SNPs structure through a cleavable covalent
bond, or pore entrances can be sealed by adding removable caps
responsive to stimuli after drug loading (Karimi et al., 2016).
3. Skin & silica nanoparticles interaction
Skin is considered the largest human organ. It is one of our first
defenses against the outside body environment (Khavkin and Ellis,
2011), preventing chemical and microbiological agents to enter, the
excessive water loss, and controling the body thermoregulation (Kolar­
sick et al., 2011). For any dermatological application, whether cosmetic
or medicinal, the skin physiological functions cannot be neglected and
in-depth studies on skin-product interface complexity, permeation,
distribution, and elimination are required. In this section, a brief
description about the structures able to serve as therapeutic targets is
presented and permeation routes are presented.
Anatomically, the skin is a heterogeneous organ that can be divided
into two layers, epidermis and dermis, attached to an underlying layer
called hypodermis (Fig. 6). The epidermis is constituted by approxi­
mately 95% of keratinocytes – keratin-producing cells - which are
Fig. 6. The layers of human skin (epidermis and dermis) and subcutaneous tissue (hypodermis). Extended: epidermis and its strata (1) and dermis (2), hypodermis
(3) and their structures and components.
8
International Journal of Pharmaceutics 614 (2022) 121439
differentiated in a cyclic and dynamic process starting from the ‘stratum
basale’ cells. This differentiation gives rise to different layers within the
epidermis, leading to different cells maturation degree. The last differ­
entiation stage occurs when cells undergo cornification and become
flattened, lose their nucleus and intracellular content, turning into cor­
neocytes (Angelova-Fischer et al., 2018; Jepps et al., 2013; Khavkin and
Ellis, 2011; Kolarsick et al., 2011; Koppes et al., 2017; Rawlings and
Harding, 2004; Wong et al., 2016; Yosipovitch et al., 1998; Zsikó et al.,
2019). Corneocytes are surrounded by an organized hydrolipidic mantle
formed by hydrophilic molecules - mostly amino acids from filaggrin
protein degradation (Koppes et al., 2017) - and lipids such as ceramides,
cholesterol, and fatty acids resulting from cells maturation (Jepps et al.,
2013; Wong et al., 2016). This layer defines the permeation kinetics
limiting step of dermatological products (Ghasemiyeh and Mohammadi-
Samani, 2020; Jepps et al., 2013; Rawlings and Harding, 2004; Zsikó
et al., 2019). Products such as moisturizers, repellents, and sunscreens
are designed to stay on that stratum corneum with no need of deep
permeation.
In the innermost epidermis layers, cells present a three-dimensional
voluminous shape, are abundantly joined by structures called desmo­
somes, which give it adhesion and mechanical strength to remain united
(Rawlings and Harding, 2004; Simpson et al., 2011). In contrast to the
stratum corneum, which has lipophilic characteristics, viable epidermis
contains a large amount of water, which determines its hydrophilicity
(Lemos et al., 2018). Closer to the epidermis basal layer, other cell types
are also found such as melanocytes, Langerhans cells and Merkel cells
(mechanoreceptors) (Khavkin and Ellis, 2011; Kolarsick et al., 2011).
Melanocytes are located on the basal epidermis layer, being
responsible for melanin production and deliver to keratinocytes through
their membrane projections (Videira et al., 2013). Factors such as UV
radiation, inflammation, hormonal dysregulation, and stress (Eves et al.,
2006; Lotti et al., 2002; Videira et al., 2013) can stimulate melanocytes,
which end up producing more melanin causing pigmentation and
eventually, spots on the skin. Melanocytes are usually targets for der­
mocosmetics with a lightening purpose, which means that to reach
them, it is necessary to cross an efficient keratinocyte barrier (D’Mello
R.P. Morais et al.
et al., 2016; Kolarsick et al., 2011).
Langerhans cells compose the skin immune system and are respon­
sible for antigens uptake and presentation to T lymphocytes (Khavkin
and Ellis, 2011; Kolarsick et al., 2011). Allergies development by
dermatological products are directly related to the ability to activate
those cells (Callard and Harper, 2007; Malachin et al., 2017; Rancan
et al., 2012) which constitutes another challenge in dermatological
products, therefore, an ideal product must be inert to Langerhans cells.
Just below the epidermis, the basal lamina is a porous membrane
formed type IV collagen, laminin, and proteoglycans that acts as a bar­
rier and control the exchange of fluids and cells between dermis and
epidermis (Kolarsick et al., 2011). Fibroblasts are the main cells found in
the dermis, being responsible to collagen (mainly type I and III) and
elastin synthesis which provide mechanical strength to this tissue
(Khavkin and Ellis, 2011; Kolarsick et al., 2011; Wong et al., 2016).
During aging there is a progressive decrease in collagen, elastin, and
proteoglycan fibers production, causing the skin to lose its elasticity and
vitality (Chaudhary et al., 2020). That is the reason of an increasing
number of dermocosmetic products that aim to delay aging by stimu­
lating collagen and elastin production, or by preventing its degradation
(Chaudhary et al., 2020; Kwatra, 2020).
The cutaneous appendages, like pilous and sweat glands, sebaceous
glands and hair follicules originate in the dermis, and connect to the
epidermis (Jepps et al., 2013). Such skin-associated structures are
specialized in maintaining the body homeostasis in different ways
(Kolarsick et al., 2011). Local treatments that aimed do treat or beau­
tifying these structures are possible as well, through cosmetics or cos­
meceuticals use. It means that each of these parts constitutes a specific
target for problems like hyperhidrosis, acne and hair loss or hirsutism.
At a deeper skin level, below the dermis is the hypodermis (subcu­
taneous adipose tissue). The main cells of hypodermis are adipocytes,
which are arranged in lobes (Jepps et al., 2013; Khavkin and Ellis, 2011;
Kolarsick et al., 2011). This is the skin layer that cosmetics for cellulitis
and lipodystrophy treatment are destined for. It can be noted that a
cosmetic that aims to reduce fat concentration within the adipocytes
needs to permeate many layers until reaching its target and may be a
reason for great failure on the part of these products.
When describing the skin, it is important to consider its pH, which on
epidermis surface is generally acidic, between 4 and 6, with small var­
iations throughout the body and internally is neutral, close to 7.4
(Prakash et al., 2017; Proksch, 2018). Maintaining the acid mantle is
essential to keep the skin functional barrier (Prakash et al., 2017) and
altering this balance can induce diseases such as acne, bacterial in­
fections, dermatitis, and delayed wound healing (Bullock et al., 2020;
Fig. 7. Potential penetration pathways through the skin. 1. Transepidermal pathway: intercellular (transport between corneocytes through the lipid matrix) and
transcellular (transport crossing corneocytes and intercellular lipids). 2. Transappendageal pathway: transfollicular (transport through hair follicles) and tran­
sudoriparous (transport through sweat glands).
9
International Journal of Pharmaceutics 614 (2022) 121439
Proksch, 2018). In this way, the compatibility between product and skin
must be respected, in order not to cause skin changes and irritations
(Prakash et al., 2017; Proksch, 2018). If the skin pH reaches values close
to 7, lipid ionization is certain, and a repulsion between the hydrophilic
heads will cause irritation and flaking of the skin (Lieckfeldt et al.,
1995).
To better plan products skin permeation, it is necessary to keep in
mind the targeted layer desired. Cosmetic products, by definition,
should not reach systemic circulation (CosmeticsInfo, 2021). On the
other hand, therapeutic drugs are especially added to formulations
containing chemical enhancers to facilitate their entry into the systemic
circulation (Herman and Herman, 2015).
As already mentioned, stratum corneum penetration is challenging
for products applied on skin. To achieve this, molecules should pass to
adjacent layers through intercellular pathway (between cells), trans­
cellular pathway (crossing cell membranes) or via cutaneous append­
ages (Fig. 7). In general, due to hydrolipidic mantle nature, most of
hydrophobic molecules reach their destinations by passing through the
intercellular pathway, while small compounds of neutral hydrophilic
nature preferentially pass through the transcellular pathway (Ghase­
miyeh and Mohammadi-Samani, 2020; Herman and Herman, 2015;
Sheshala et al., 2019).
Many authors dispute that only a small range of molecules can
effectively permeate to the layers below epidermis, in contrast, others
claim that substances applied to skin can be detected in the blood at
defined times after application (Herman and Herman, 2015; Malachin
et al., 2017; Matsuo et al., 2016; Ostrowski et al., 2014a; Wani et al.,
2020), and therefore it is an illusion to think that a cosmetic product will
not reach the bloodstream. The easy access to dermatological products
along with the lack of clear information about their permeation and
accumulation effects, make the consumer blinded about the possible
undesirable effects. In face of the exposed, detailed studies on these
molecules’ distribution, accumulation, and excretion are necessary
(Rancan et al., 2012, Desprez et al., 2018; López-Sánchez et al., 2021;
Steinmetz et al., 2021), otherwise, unexpected reactions can happen.
Plenty of cosmetics and cosmeceuticals containing INPs are now
available to consumers. They are mainly cosmetics containing gold (Au),
silver (Ag), zinc oxide (ZiO), and titanium dioxide (TiO2) nanoparticles
that serve as antioxidants, antibacterial, and UV light reflectors,
respectively (Ferraris et al., 2021). In fact, nanoparticles penetration can
be a desired goal, or not, depending on the effects wanted to achieve. For
example, in the case of photoprotection, if nanoparticles (NPs) used in a
formulation penetrate the deeper layers of skin, it no longer exerts the
intended effect, failing to achieve its objective (Y.C. Lin et al., 2018; Z.
R.P. Morais et al.
Lin et al., 2018; Ugazio et al., 2016). On the other hand, transdermal
nanosystems for systemic drug delivery must be able to permeate the
skin layers and reach blood vessels, only in this way they can meet the
objective of their construction.
Some studies comparing INPs with other types of organic and
deformable NPs, such as liposomes or transferosomes (Ascenso et al.,
2015; Cosco et al., 2015) confirm that the last one is able to translocate
through the stratum corneum, present greater skin permeation than
INPs, such as silica, TiO2 and iron (Fe) NPs (Knorr et al., 2019). SNPs are
claimed to stay on the skin surface, without a deep permeation (Salvioni
et al., 2021), but that is a very controversial topic. In turn, studies have
shown that Langerhans cells were able to internalize the SNPs that
ended up in the bloodstream and caused systemic effects (Matsuo et al.,
2016; Rancan et al., 2012). Matsuo et al. (2016) observed that SNPs not
only do penetrate skin, but also described their presence in tissues such
as lymph nodes, liver, and brain under normal conditions. Also, some
authors have shown that despite their size, submicron inorganic parti­
cles, including for example, iron oxide (FeO) and AuNPs can permeate
the skin depending on the vehicle in which they are found (Cao et al.,
2021; Musazzi et al., 2017). Still others claim that permeation to deeper
layers only occurs via cutaneous appendage (Bolzinger et al., 2011).
Although it occurs through a smaller area (0.1% of total skin surface),
recent investigations demonstrate their relevance in topically applied
nanoparticles penetration. Hair follicles tend to form agglomeration
sites and allow a deeper penetration for a variety of particle types. Since
they extend towards the lower parts of the dermis, they act as an effi­
cient reservoir for drugs and nanoparticles, where they can diffuse
continuously to surrounding spaces, cross the capillary walls, and reach
the blood system (Busch et al., 2021; Knorr et al., 2019; Lemos et al.,
2018).
To better understand and take conclusions about permeation, dis­
tribution, interaction with skin structures, content release, as well as the
elimination of such nanoparticles, it is necessary to know their physi­
cochemical characteristics, size, shape, surface and charge (Iannuccelli
et al., 2014; Lemos et al., 2018; Rancan et al., 2012). Pathways under­
taken and nanoparticles distribution can be monitored by analytical
techniques and image analysis (e.g. inductively coupled plasma optical
emission spectroscopy/mass spectroscopy (ICP-OES/MS), transmission
electron microscopy/energy-dispersive X-ray spectroscopy (TEM/EDX),
scanning electron microscopy/EDX (SEM/EDX) and confocal laser
scanning microscopy (CLSM)) that allow to obtain detailed information
of the skin layers after product application (Cao et al., 2021; Matsuo
et al., 2016; Nigro et al., 2018; Rancan et al., 2012; Xu et al., 2020).
Regarding particles charged surfaces and the way they affect
permeation, much remains to be clarified. Ostrowski et al. (2014a,b) and
reported that functionalized SNPs with approximately 55 nm and posi­
tively charged are not able to penetrate murine skin, even if the skin
barrier is compromised (Ostrowski et al., 2014a). In a more recent study,
Jung et al. (2019) observed that negative-charged 33 nm and 78 nm
SNPs (functionalized with carboxylate groups) did not permeate the
stratum corneum of human cadaver skin. In contrast, Nafisi et al. (2018)
demonstrated that SNPs functionalized with positively charged groups,
were more efficient to deliver lidocaine to human skin ex vivo (drug
detection at the receptor fluid). Iannuccelli et al. (2014) proved that
SNPs polarity has an even more pronounced role than size itself, by
demonstrating that 360 nm particles coated with lipids were detected,
by tape stripping method, at the stratum corneum in in vivo tests with
humans. In addition, Sapino et al. (2017) added SNPs loaded with
methotrexate in various vehicles, aqueous and oily, and concluded that
vegetable oils significantly increase the drug release to the receptor
fluid.
In view of the above, it is observed that cutaneous SNPs application
will remain in the emerging field until all the mechanisms by which it is
governed are fully understood.
10
International Journal of Pharmaceutics 614 (2022) 121439
4. Biocompatibility of silica nanoparticles – Toxicity
Nanotechnology is a very suitable tool to solve problems regarding
the apparent solubility and delivery of drugs. However, for some types of
nanoparticles, especially for INPs, what is known so far about the
toxicity and accumulation of such products in the human body is often
controversial (Chen et al., 2020; Mohammadpour et al., 2019). Two
main questions about nanoparticles biocompatibility need to be raised
concerning the possible material toxicity. The first one is about the raw
material itself, which must be non-toxic and biocompatible, in this
context biopolymers have an advantage over inorganic materials, since
we do not have enzymes to degrade the latter one. The second concerns
about the nanomaterial size, as it is known that smaller particles can
permeate the body more deeply, bypassing the immune system, reticu­
loendothelial system, and reaching more organs (Busch et al., 2021; L.
Chen et al., 2018; Guo et al., 2021; Matsuo et al., 2016; Wills et al.,
2016).
Silica toxicity to the lungs, when inhaled, is already well established
(Cao et al., 2017; Murugadoss et al., 2017; Shin et al., 2017), and the
same pulmonary effects were linked due the inhalation of others INPs
like ZnO and TiO2 (Garcés et al., 2021) or even, AuNPs and AgNPs
(Talarska et al., 2021). However, the effects caused by other adminis­
tration routes needs to be better explored. With the increasing passively
consumption of INPs in food and medicine, an improved understanding
of its effects is necessary (F. Chen et al., 2018; L. Chen et al., 2018; Guo
et al., 2021; Murugadoss et al., 2017; Shin et al., 2017). In a study by
Deng et al. (2021), it was demonstrated that after 2 weeks of oral SNPs
administration to rats, the particles concentration in several organs was
significantly higher than in the control group, showing the effect of
biodistribution and bioaccumulation. In addition, a study carried out by
Cao et al. (2017), have proved that after SiO2 administration to rats via
inhalation, the particles were able to cause significant damage to the
rodent’s liver, showing potential particles distribution throughout the
organism. An extensive review by Murugadoss et al. (2017), performed
from 2010 to 2016, revealed that the main mechanisms of silica in vitro
toxicity are associated with oxidative stress due to the generation of free
radicals, directly reflecting in genotoxicity, stimulating the innate im­
mune system with increased pro-inflammatory cytokine production,
autophagy, and apoptosis (Deng et al., 2021; Guo et al., 2021; Mur­
ugadoss et al., 2017; D.P. Wang et al., 2020, W.H. Wang et al., 2020).
These results are not very different when compared to other INPs
toxicity. Shrivastava et al. (2016) did a 2-week study of AuNPs oral
administration that caused significant increase in free radicals and in­
flammatory interleukins in rats treated compared to the control group.
Confirming, once again, the need for detailed studies and dose adjust­
ments. In vivo tests demonstrate that the main affected organs after oral,
intravenous or inhalation silica administration are lungs, liver, spleen,
kidneys, heart, and brain (Hozayen et al., 2019; Liang et al., 2018;
Murugadoss et al., 2017; Rawat et al., 2017). SNPs distribution route is
extremely dependent on the administration route (Guo et al., 2021),
however there are few studies regarding to transdermal application
route.
Most authors seem to agree that SNPs toxicity depends on their
physicochemical properties, in addition to other factors such as the dose,
the time of exposure and the formulation applied (F. Chen et al., 2018; L.
Chen et al., 2018; Chen et al., 2020; Giovannini et al., 2018; Hadipour
Moghaddam et al., 2019; Mohammadpour et al., 2020, 2019). Some
authors, for example, associate SNPs porosity, with greater toxicity
when the pores are large. A larger surface area increases the likelihood
of adherence to biological structures, causing greater unwanted effects
(Chen et al., 2020; Mohammadpour et al., 2019). Therefore, modifica­
tions to SNPs design, including size, composition, and surface chemistry
are being thought and designed to adjust the toxicity profile, with a
focus on increasing biocompatibility and decreasing toxicity (F. Chen
et al., 2018; L. Chen et al., 2018; Li et al., 2019; Nafisi et al., 2017).
In the context of the necessary tests, it is known that in vitro assays
R.P. Morais et al. International Journal of Pharmaceutics 614 (2022) 121439

are important ways of conducting a great screening for new synthesized
materials, for this, nanoparticulate materials toxicity is commonly
investigated using different cell lines. However, due to the huge number
of protocols and the great variability among nanoparticles many dis­
parities are found between in vitro and in vivo tests and, therefore,
generalizations cannot be made (L. Chen et al., 2018; Guo et al., 2021;
Hozayen et al., 2019; Mohammadpour et al., 2020; Shin et al., 2017; Xu
et al., 2020). Surprisingly, rare studies on in vivo systemic toxicity
generated by topically applied SNPs are available. Many studies are
limited to in vitro particle-cell interaction and most focus only on skin
permeation, not going beyond that.
Ryu et al. (2018) carried out an extensive study of subchronic
toxicity with the continuous application, for 90 days, of 20 nm colloidal
silica NPs in an area corresponding to 10% of Sprague Dawley rats body
area. Lu et al. (2018) used Ag-funcionalized mesoporous nanoparticles
to treat infected wounds in rats for 5 days. In both studies, no significant
clinical, hematological, biochemical, and histological changes were
found. Although small changes were found in the analyzed parameters,
none of them can be directly correlated with skin silica exposure. Due to
the widespread use of silica in dermatological products, some studies try
to predict whether the use of SNPs in people affected by atopic derma­
titis or contact dermatitis could have their inflammatory conditions
aggravated by using such products. Hirai et al. (2012, 2015) proved that
in these individuals IgE production may be exacerbated, due to an in­
crease in Th2 defense response mechanism, which may even lead to
anaphylaxis. Apparently, it is only when SNPs permeation is done in a
more aggressive way (e.g., subcutaneous injections) that it is possible to
detect NPs in some organs such as regional lymph nodes, although
without any evidence of toxicity (Ostrowski et al., 2014a).
Most studies focus their attention on the effects of in vitro toxicity and
skin permeation on 3D models of skin, but it is evident the lack of studies
on distribution and elimination of SNPs in the body. In the case of
(copper oxide) CuO and ZnO nanoparticles, some of the toxicity is
related to ion dissociation and deep permeation of Cu+ and Zn+ ions that
can cause skin irritation (Holmes et al., 2020, 2016). The same, is not
valid to SNPs, thus, the synthesis of new silica frameworks requires
intense investigation of their toxic properties, since the various struc­
tural and surface changes that silica can suffer from, may reflect on
unknown impacts on biological organisms generating adverse effects not
previously observed. Some examples of systemic in vivo studies are listed
in Table 1.
5. Silica nanoparticles in cutaneous and transdermal therapy
With the advent of nanotechnology applied to cancer therapies, the
use of drug nanocarriers to target the drug to tumor without damaging
normal body cells was a major achievement for medical science. Among
the nanotechnological advances for skin cancer treatment, the use of
silica-based nanosystems has proved to be an attractive and promising
therapeutic strategy due to the several superior characteristics already
reported, in comparison with other nanocarriers. In this context, Sapino
et al. (2015) proposed a nanoformulation based on mesoporous SNPs
(particle size of 250 ± 50 nm) for topical delivery of the phytocomposite
quercetin for melanoma therapy. Quercetin is a flavonoid with strong

Table 1
Studies concerning local or systemic SNPs toxicity in the last decade.
SNPs Type Purpose Permeation type Tecidual/Systemic toxicity References

N-(6-aminohexyl)-
aminopropyltrimethoxysilane (AHAPS)
functionalized SiO2-NP 55 nm, positively
charged
MSNs functionalized with 3 -
aminopropyltriethoxysilane alkoxide
(APTES) and incorporated with
Indomethacin by sol–gel method
MSN decorated with PTHPMA-co-AEMA
(tetrahydropyranyl Methacrylate and amino
ethyl methacrylate
Amorphous silica from 30 to 1000 nm,
negatively charged, combined or not with
Dermatophagoides pteronyssinus (Dp)
antigens
Amorphous silica of 30 nm combined or not
with Dermatophagoides pteronyssinus (Dp)
antigens
MSNs-NH2 Ag-decorated, 61.8 nm, and
negatively charged produced by Sol-gel
method
MSNs negatively charged, 300–500 nm by
sol–gel method
Spherical SiO2-NP with a diameter of 55 ± 6
nm Surface functionalization with AHAPS
Colloidal SiO2, 20 nm in size treated with L-
arginine and negatively charged
Analyze the AHAPS-SiO2-NP
penetration on skin with normal
and altered barrier function
Anti-melanoma activity of
Indomethacin
Develop a novel stimuli-responsive
anticancer device
To investigate the relationship
between the SNPs size and
adjuvant activity using a model for
atopic dermatitis (AD)
Investigate the effects of topical
application of mite extract and
amorphous silica nanoparticles, on
allergic sensitization and Atopic
Dermatites
Wound healing
salicylic acid and ketoconazole for
antifungal treatment and wound
healing
To modulate allergic contact
dermatitis when SNPs were
applied with axazolone
Toxicological effects only
Only when injected into Not detected in the analyzed organs. No (Ostrowski
subcutaneous tissues NPs distribution beyond the regional lymph et al., 2014a)
were detected in regional node was observed.
lymph node
Subcutaneous injections No organ toxicity; biochemical analyzes did (Ferreira
not show kidney damage; absence of et al., 2020)
genotoxicity prevented by NPs use
Crossed the skin when the No harmful effects on skin surface. (Anirudhan
patch containing NPs was and Nair,
stimulated with 2018)
Ultrasound
Intradermal injections nSP70 can penetrate the skin barrier and (Hirai et al.,
enter keratinocytes and Langerhans cells. 2012)
Enhanced IL-18 and thymic stromal
lymphopoietin production, leading to
systemic Th2 response and aggravation of
AD-like skin lesions as induced by Dp-
antigen treatment.
Applied to the skin for 13 Low-level IgG production with little change (Hirai et al.,
weeks in IgE production (IgE-biased immune 2015)
response) and increased sensitivity to
anaphylaxis.
Applied over incisions for No toxicity was found: no change in weight; (Lu et al.,
5 days no hematological changes; no biochemical 2018)
changes in AST, ALT, alkaline phosphatase,
albumin, blood urea nitrogen, creatinine,
cholesterol and triglyceride. No histological
alterations heart, liver, spleen, lung and
kidney of the rats
Formulations containing Histopathological tests around the wound (Masood
SNPs were applied on skin showed zero erythema score as compared to et al., 2021)
for 14 days drug suspension which showed an erythema
score of four
The formula was applied No effects were observed in all clinical, (Ostrowski
during 5 consecutive days histologic, morphometric, and molecular et al., 2014b)
on lesional skin parameters investigated (IgE and skin)
90 days of exposure to A complete clinical, hematological, (Ryu et al.,
rats’ skin biochemical, and histopathological analysis 2014)
showed no toxicity

11
R.P. Morais et al. International Journal of Pharmaceutics 614 (2022) 121439

antioxidant activity that can reverse UV-induced oxidative skin damage,
in addition, it has anti-inflammatory and anticancer properties, however
low water solubility, low stability and short half-life may restrict its use
in skin products and therapies (Sapino et al., 2015). In order to over­
come these difficulties, the authors encapsulated quercetin in SNPs
functionalized with aminopropyl and then evaluated this nanosystem
potential to act as a topical transporter for quercetin release through
photodegradation, ex vivo permeation in swine skin, and cell prolifera­
tion tests in vitro. For carrying out photodegradation and ex vivo
permeation tests in porcine skin, SNPs were incorporated into an O/W
emulsion. The results showed that functionalized SNPs improved quer­
cetin photostability, among 0.0084% w/w of encapsulated quercetin
contained in the O/W emulsion, 98.9 ± 1.8 of its was not
photodegraded. SNPs also increased skin quercetin penetration, the
nanoformulation, containing 0.27% w/w of flavonoid, showed higher
amounts of quercetin retained in the skin (10.89 μg/cm2) compared to
formulation containing free quercetin. Besides, quercetin-encapsulated
SNPs inhibited JR8 melanoma cells proliferation to a greater extent
than quercetin alone. At a concentration of 60 μM, the nanosystem
caused about 50% inhibition of cell proliferation and in lower concen­
trations (1, 10, 30 μM), the nanosystem did not influence cell
proliferation.
SNPs are also being integrated into photodynamic therapy (PDT) to
treat skin cancer. It is a minimally invasive therapy, which has shown
promising results in several malignancies treatment, including mela­
noma and non-melanoma skin cancer (Calixto et al., 2016; Zielińska

Fig. 8. A) Effect of Verteporfin-mesoporous silica nanoparticles (Ver-MSNs) on B16F10 cells in dark conditions and under red light exposure. MTT assay of B16F10
cells was carried out after 4 h incubations with Ver-MSNs. Results are expressed as mean values ± standard deviation. *** p < 0.001 referred to non-irradiated (0 s)
plain mesoporous silica nanoparticles MSNs. ◦◦◦ p < 0.001 referred to irradiated mesoporous silica nanoparticles MSNs. B) Ver-MSNs nanoparticles inhibit mouse
melanoma tumor growth. Results are expressed as mean values ± standard deviation. *** p < 0.001 referred to the control. p < 0.05 referred to MSNs. C)
Representative photos of tumor masses obtained after sacrifice of animals treated with glycerol (Vehicle), MSNs and Ver-MSNs. D) Immunofluorescent images of
CD31 staining (green) as an indication of tumor angiogenesis and nuclear DAPI counterstain (blue). Magnification = 20 × . Reprinted with permission from ref.
(Clemente et al., 2019), Copyright 2019 Elsevier. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of
this article.)

12
R.P. Morais et al.
et al., 2018). PDT combines a light with a specific wavelength and a
photosensitizer. When these two elements interact, in the presence of
oxygen, ROS are generated leading to selective destruction of tumor
cells (Arriagada et al., 2019; Calixto et al., 2016; Zielińska et al., 2018).
Therefore, Clemente et al. (2019) investigated in vitro and in vivo PDT
efficacy with mesoporous SNPs functionalized with aminopropyl loaded
with verteporfin, an FDA approved hydrophobic photosensitizer (Zie­
lińska et al., 2018), as a potential treatment for skin melanoma. The
results of mouse melanoma cell line (B16-F10) proliferation assay
showed that the combination of mesoporous SNPs functionalized with
aminopropyl/verteporfin and red-light irradiation (693 nm) was able to
significantly reduce cells proliferation in a concentration ranging from
0.1 to 10 μg/ml. Besides, the effect was already detectable at 0.1 μg/ml,
with 68.26% (0.157 ± 0.008 SD, p < 0.001) cell viability compared to
simple SNPs irradiated with red light (Fig. 8A). When the prepared
nanoparticles (5 μg/ml in glycerol) were administered topically to
melanoma-bearing mice and stimulated by red light (applied four times
in 16 days), tumor mass was reduced by 50.2 ± 6.6% compared to un­
treated mice (glycerol only) (Fig. 8B and 8C). In addition, the authors
also observed a decrease in tumor vascularization (Fig. 8D), suggesting
that the in vivo nanosystem antitumor effect can be mediated not only by
direct cytotoxicity to tumor cells, but also by inhibition of tumor neo­
angiogenesis, a fact that was not detected in the treatment only with
mesoporous SNPs.
The chronic nature and complications associated with wounds that
do not heal have led to the emergence of nanotechnology-based thera­
pies that aim to accelerate the healing process and, consequently, repair
damaged skin. Nanodevices can not only act in regeneration and repair,
but also allow the delivery on demand of specific therapeutic molecules
to the injured area. Quignard et al. (2017) reported that ultra-thin SNPs
with positive surface charge (~10 nm) as sources of silicic acid favored
wound healing in vitro. Suspensions of SNPs with different degrees of
surface charge (positive and negative) and under sub-saturated condi­
tions (below 2 mM Si) were evaluated. In a wound healing model with
human skin fibroblast cells (CCD-25SK) amine-functionalized SNPs
(positively charged) were able to release silicic acid (the bioactive silica
form) in the culture media, and to promote wound closure more effec­
tively than negatively charged SNPs at a dose of 50 μM. According to the
authors, this effect may be related to these nanoparticles easy cell
internalization, followed by their intracellular dissolution, releasing si­
licic acid at a faster rate (50–70% after 76 h of incubation) than its direct
uptake from the media (20–25% after 6 h of incubation).
Another study demonstrated dendritic mesoporous SNPs (with hy­
drodynamic particle size of ~150 nm and pore size of ~13.78 nm) ad­
hesive ability to promote and accelerate wound healing (Pan et al.,
2020). The authors proposed an innovative adhesive strategy based on
SNPs for closing skin wounds. After application, SNPs formed nano­
composites with body fluid from the wounds, and subsequently elicited
an acute inflammatory response that initiated skin wound repair pro­
cess. Meanwhile, rapid SNPs biodegradation and elimination prevented
persistent inflammation, ensuring accelerated healing and skin tissue
restoration. The results of in vivo wound closure and wound healing tests
showed that the SNPs accelerated the healing process (approximately 3
days) and increased wound rupture resistance on day 10 by 143%
compared to the control group.
On the other hand, skin lesions are often accompanied by bacterial
infections that hinder the repair process. Mebert et al. (2018) reported a
new wound healing dressing incorporating core–shell SNPs (with
diameter of 336 ± 43 nm) loaded with two topical antibiotics (genta­
micin sulfate and sodium rifamycin) in type I collagen hydrogels. Sul­
fonate groups surface modified SNPs allowed significant gentamicin
(5950 μg/g) adsorption while silica shell layer grafted with mercapto­
propyl groups, allowed rifamycin (670 μg/g) adsorption. Antibiotics
release from collagen-silica nanocomposite, containing 30 mg/mL SNPs,
allowed a sustained in vitro antibacterial effect against Staphylococcus
aureus over 10 days. In addition, in a skin infection in vivo model (Wistar
13
International Journal of Pharmaceutics 614 (2022) 121439
rats), the nanocomposite considerably reduced bacteria number (2 log
steps) on the infected skin.
Still based on this subject, among plants extracted compounds that
have antibacterial and wound healing properties, curcumin, a yellow
polyphenol extracted from Curcuma longa roots, has been highlighted in
many scientific research (Hamam and Nasr, 2020; Mirzahosseinipour
et al., 2020). Despite its excellent properties, its use in therapeutic for­
mulations is limited due to its low water solubility, physicochemical
instability, rapid metabolism, and reduced bioavailability (J.T. Sun
et al., 2012; M. Sun et al., 2012). In order to overcome these limitations
and increase therapeutic efficacy, nanosystems have been designed to
protect, deliver and target curcumin to specific sites of interest. Faced
with these challenges, Hamam and Nasr (2020) proposed a topical
formulation (1% curcumin) based on curcumin-loaded mesoporous
SNPs (SNPs with size of 363.0 ± 11.30 nm loading 98.72% of curcumin)
as a wound-healing agent. The in vivo wound healing study carried out in
Wistar rats for 21 days showed that the percentage of wound contraction
in curcumin-nanoformulation treated rats was higher compared to that
of rats treated with sulfadiazine (control formulation), however this
difference was not statistically significant (P > 0.05). On the last day of
measurement (day 21), both formulations stimulated complete wound
closure. In addition, excision lesion cross-sections of skin specimens
were obtained for histological evaluation of inflammation, angiogenesis,
fibroblast proliferation, presence of collagen, and reepithelization. For
both formulations, inflammatory reactions reduced considerably on day
21 of treatment, the angiogenesis process was almost complete on day 7,
fibroblast proliferation increased visibly on day 14, and a high degree of
wound reepithelization was achieved on day 21, without significant
differences between the test and control formulation. However, on day
21, the collagen level increased significantly in rats treated with cur­
cumin nanoformulation compared to those treated with sulfadiazine.
In another study, SNPs loaded with curcumin were used in antimi­
crobial photodynamic therapy (aPDT) for wound healing (Mirza­
hosseinipour et al., 2020). Antimicrobial and antibiofilm efficacy of
curcumin-loaded SNPs (particle sizes ranging from 36 to 40 nm) against
Pseudomonas aeruginosa and Staphylococcus aureus bacteria and aPDT
effect on wound healing were investigated through in vitro tests. In
aPDT, curcumin and curcumin-loaded SNPs were used as photosensi­
tizers and the light source employed was blue (465 nm), corresponding
to the maximum absorption of curcumin. In the photodynamic inacti­
vation test of planktonic cells, 10 min irradiated curcumin-loaded SNPs
(1 mg/mL) showed superior antimicrobial activity, showing a signifi­
cant reduction in S. aureus planktonic cells growth (>6. log10 CFU, p <
0.05) and P. aeruginosa planktonic cells (>6.log10 CFU, p < 0.05)
compared to the control group (Fig. 9A). Similar behavior was observed
using biofilms, illustrating the efficacy of irradiated curcumin-loaded
SNPs (1 mg/mL), exhibiting significant photoinactivation against
S. aureus biofilms (P < 0.01,> 3 log10 CFU reduction) and P. aeruginosa
(P < 0.01,> 5 log10 CFU reduction) (Fig. 9B). In addition, curcumin-
loaded SNPs have been shown to have wound healing properties, as
confirmed by in vitro scratch assay using HDF fibroblast cell (Fig. 9C and
D).
Silica-based nanosystems have also been designed to treat skin
fungal infections. Econazole (ECO) is an imidazole antifungal widely
used in fungal skin infections treatment (Verma and Pathak, 2012),
however the efficacy and bioavailability of ECO have been limited by
their poor aqueous solubility and dissolution rate (Al-Marzouqi et al.,
2008). In order to overcome this limitation, Montazeri et al. (2019)
loaded ECO into amine-functionalized mesoporous SNPs to improve
topical antifungal delivery. The nanosystem was tested in vitro for
antifungal activity against Candida albicans, as well as in vivo through
skin irritation test to assess the possibility of skin irritation. The cream
(with 1% w/w of ECO) containing amine functionalized SNPs loaded
with ECO (in 1/1 proportion of ECO and SNPs) showed greater anti­
fungal activity against Candida albicans in relation to the other pro­
portions (1/2 and 1/3) and the control, a cream with free ECO. The
R.P. Morais et al. International Journal of Pharmaceutics 614 (2022) 121439

Fig. 9. A) Bacterial survival of S. aureus and P. aeruginosa planktonic following aPDT with curcumin (50 μg/mL) and (50 μg/mL and 1 mg/mL). B) Effect curcumin
(50 μg/mL) and curcumin-SiNp (50 μg/mL and 1 mg/mL) exposure - aPDT on killing of biofilm -grown strain of S. aureus and P. aeruginosa. C) In vitro scratch wound
healing assay of HDF fibroblast cells in presence of curcumin and curcumin-SiNP monitored by light microscopy. D) Bar graph illustrating percentage wound closure
at indicated time points (0, 2, 6, and 24 h after scratching when the cells were treated with the 50 μg/mL concentration of curcumin and curcumin-SiNP) during the
scratch wound assay. * P < 0.05 represents significant difference versus the control. Reprinted with permission from ref. (Mirzahosseinipour et al., 2020), Copyright
2020 Elsevier.

authors attributed the nanosystem superior antifungal activity to posi­
tive surface charge (functionalization with NH2 groups), a superficial
modification that helped improve fungi penetration. In addition, no
irritation was observed after application of the nanosystem-containing
cream on rabbit skin after 72 h.
Another dermatological disorder is psoriasis, characterized by
hyperproliferation and aberrant keratinocytes differentiation. Prolifer­
ation inhibition is one of the effective options for psoriasis treatment
(Mo et al., 2020). Mo et al. (2019) observed that erianin, a natural
compound extracted from the plant Dendrobium chrysotoxum Lindl, has a

14
R.P. Morais et al.
potent inhibitory effect on keratinocyte proliferation. In order to
improve the low water compound solubility, increase the anti­
proliferation activity and improve its skin distribution, Mo et al. (2020)
developed dendritic mesoporous silica nanospheres loaded with erianin
as a promising proposal for psoriasis treatment. Therefore, the nano­
system (erianin concentration of 30 nM) cells viability and anti­
proliferative effect on human keratinocyte (HaCaT) cells were accessed.
The results showed that erianine-loaded dendritic mesoporous silica
nanospheres (particle mean size 161 nm/pore size 4.6 nm) presented an
antiproliferative and pro-apoptotic effect superior to the erianine-loaded
dendritic mesoporous silica nanospheres (particle mean size 164 nm/
pore size 3.5 nm) and to free erianin. Cell viabilities were 61.8% (eria­
nin), 49.3% (nanospheres loaded with erianin showing smaller pore
size) and 48.3% (nanospheres loaded with erianin showing larger pore
size). Besides, initial or late apoptosis percentages were respectively
8.5% and 3.0% (erianin), 9.5% and 5.5% (nanospheres loaded with
erianin with smaller pore size) and 11.7% and 4.0% (nanospheres
loaded with erianin having a larger pore size). In the ex vivo skin
permeation test with pigskin, gel formulation (Carbopol gel) containing
erianin-loaded 4.6 nm pore size nanospheres showed greater drug
accumulation than the gel containing 3.5 nm pore size nanospheres and
the gel loaded with free erianin. The authors attributed this result to
greater surface area of nanospheres with a larger pore size, which would
facilitate drug retention and release on the skin.
Fibrosis is another disease that can affect skin. It is commonly
characterized by excessive skin collagen deposition. In response to tissue
damage, collagen fibers act by preventing the rest of the tissue from
being harmed, creating a thick border that causes fibrosis. An example of
such a disease is scleroderma (Sng et al., 2018). In this context, Morry
et al. (2015) proposed a new platform for skin fibrosis treatment based
on mesoporous SNPs coated with polyethyleneimine (PEI) and poly­
ethylene glycol (PEG) (hydrodynamic size of 104 ± 1.7 nm), loaded
HSP47-targeted small interfering RNA (siRNA). HSP47 is a protein that
plays an important role in collagen homeostasis, by inducing excessive
collagen synthesis, leading to fibrotic diseases. The authors strategy to
combat fibrogenesis was to take advantage of intrinsic antioxidant
properties of mesoporous SNPs and the promising capacity of siRNAs in
gene silencing (gene neutralization through interfering RNA) in order to
reduce HSP47 levels, particularly superexpressed in fibrotic tissues. An
effective treatment to skin fibrosis was obtained using the described
nanocarrier. Treatment of primary murine dermal fibroblast cells with
nanocarrier (17.5 μg/mL of nanoparticles) under conditions of
menadione-induced oxidative stress reduced ROS. After 1 h menadione
exposure cellular ROS increased 7.6 times, and cells nanocarrier pre-
treatment decreased ROS production to non-menadione level and
similar to that obtained by an established antioxidant, N-acetylcysteine.
In addition, intradermal nanomaterial injection (dose of 220 μg nano­
particles as 0.65 nmol siRNA) in mice with bleomycin-induced sclero­
derma (in vivo skin fibrosis model) effectively decreased skin HSP47
protein expression to normal level, which resulted in a reduction in pro-
fibrotic gene expressions and skin thickness (19%, p ≤ 0.01 vs. bleo­
mycin alone).
In order to improve chronic itching treatment, research (Heck et al.,
2017) has proposed a film-forming formulation containing porous silica
particles (Syloid® XDP 3050) loaded with the antipruritic drug non­
ivamide (capsaicin synthetic analogue) for skin sustained delivery of this
active ingredient. The authors tested the formulations on the following
criteria: skin permeation (ex vivo test through post-auricular porcine
skin), skin penetration (ex vivo test by skin surface biopsy followed by
cyanoacrylate cryosection) and skin irritation (in vivo test with healthy
volunteers). Although nonivamide concentration in the test formulation
(0.9% nonivamide) was approximately twenty times greater than in
conventional clinically proven therapy (hydrophilic nonivamide cream
at 0.025% and 0.05%), nonivamide amount and fluxpermeated by skin
area were similar. This proved that the formulation permeation profile is
at a therapeutically safe and efficient rate. As viable epidermis is the
15
International Journal of Pharmaceutics 614 (2022) 121439
capsaicinoids action site, the authors examined nonivamide concentra­
tion that penetrated in this skin region. Since substantially higher stra­
tum corneum drug levels might have a negative impact on the
formulation safety, the amount of oil-loaded powder was tenfold
reduced consequently decreasing nonivamide content (0.09% non­
ivamide). In the ex vivo penetration assay, test formulation containing
0.09% nonivamide and standard formulation (0.05% nonivamide hy­
drophilic cream), resulted in the same order of nonivamide concentra­
tions magnitude present in the stratum corneum. The tested formulation
had a sustained penetration profile, showing within 1 to 12 h incubation
time a continuous increase in penetrated nonivamide, which was still
present at the action site after 24 h incubation. In addition, the in vivo
skin irritation test showed that the formulation (0.09% nonivamide) was
not irritating to skin after an incubation period of 1 h.
The drug lidocaine is commonly used as a topical anesthetic, how­
ever its low water solubility and negligible tissue absorption limit its
bioavailability when applied to the skin (Nafisi et al., 2018). To over­
come these limitations Nafisi et al. (2018) incorporated this anesthetic
into amine functionalized mesoporous SNPs (particle size 95 nm). In
vitro release using cellulose dialysis membrane (conditions: 37 ◦ C and
pH 7.4) and ex vivo drug permeation in human skin by using vertical
diffusion Franz cells were investigated. The authors observed a greater
lidocaine release for amine-functionalized mesoporous SNPs (61%) than
non-functionalized SNPs (20%) in the first 3 h. Also, the amine-
functionalized mesoporous SNPs allowed for better skin lidocaine
permeation compared to non-functionalized SNPs. Ex vivo permeation
data of nanosystems were compared to the same control concentration
(lidocaine hydroalcoholic solution, 0.4 mg/mL). After 24 h, almost 64%
of the amine-functionalized mesoporous SNPs drug content was
permeated, while the control solution showed 36%, and the non-
functionalized mesoporous SNPs exhibited 13%. The results found
regarding high permeation of nanosystem lidocaine released was
attributed to electrostatic interaction between positive surface charges
of amine functionalized SNPs and negative charge of the skin cells
membrane.
An attractive alternative to minimize the challenges associated with
other routes of drug administration, such as oral and parenteral, is the
transdermal route. Advanced devices based on SNPs are being designed
for transdermal drug delivery. For example, a recent study developed
cotton patches based on chitosan-pullulan hydrogel and mesoporous
SNPs loaded with the alkaloid colchicine (particle size 167,1 ± 51,36
nm) to treat osteoarthritis (Mohamed et al., 2020). First, colchicine was
encapsulated in mesoporous SNPs (drug-entrapment efficiency 67.4 ±
3%), which were incorporated into a chitosan-pullulan hydrogel, and
loaded in cotton gauze forming an easy-to-apply transdermal patch. The
final colchicine amount in the prepared patch was 0.5 mg/cm2. The
developed system combined the virtues of nanometer size and huge
SNPs surface area to chitosan/pullulan hydrogel matrix sustained
release effect. The nanodevice permeation performance was investi­
gated using isolated rat skin (ex vivo), laser confocal microscopy using
fluorescein using excised rat skin and its efficacy as osteoarthritis
treatment in rat model (in vivo). The ex vivo permeation test demon­
strated that colchicine-containing transdermal patches (free and
entrapped in mesoporous SNPs) permeated five and seven times,
respectively, deeper in skin than aqueous colchicine solution. Increased
penetration promoted by the hydrogel patch incorporating fluorescein
encapsulated in mesoporous SNPs was demonstrated by a broader and
more intense distribution of fluorescein in all skin layers. In addition, in
a therapeutic investigation using in vivo model of monoiodine-induced
osteoarthritis (MIA) the mesoporous SNPs treated animals displayed
improved locomotor activity (by 74%), blood glutathione level (23%)
and notable decline in malondialdehyde (34%), nitric oxide (28%), TNF-
α (61%), and COX-2 (74%) levels, which are stress biomarkers oxidative.
R.P. Morais et al. International Journal of Pharmaceutics 614 (2022) 121439

6. Silica nanoparticles in cosmetology
Silica is a component of many cosmetic products. SNPs can be found
in leave-in cosmetic products for hair, skin, lips, face and nails. SNPs are
used to enhance the effectiveness, texture, and shelf-life of cosmetic
products. It adds absorbency and acts as an anti-caking agent (Fytianos
et al., 2020).
It is known that sunscreens are considered a valuable tool in
providing photoprotection against ultraviolet radiation (UVR) harmful
effects (Burnett and Wang, 2011). Thus, to reduce inherent sunscreens
deficiencies, many studies have sought to find new and better forms of
photoprotection, focusing on methods related to encapsulation and
incorporation to form more stable, aesthetically acceptable (more
pleasant to the skin) formulations, with high UVR protection capacity
and low health risks. SNPs have been reported to have high photo­
stability and UVR protection effects (Knežević et al., 2018; D.P. Wang
et al., 2020, W.H. Wang et al., 2020). In this context, Y.C. Lin et al.
(2018) and Z. Lin et al. (2018) produced two versions of hydrogel

Fig. 10. A) (a) Ex vivo two-photon microscopic images of porcine skins obtained after 4 h of rhodamine 6G-labeled bp-SNPs (yellow) topical application. The blue
signal represents collagen second harmonic generation in the dermal layer. (b) Fluorescence images of porcine skin tissue histological section described in (a).
Control image of skin without treatment. The red signal represents rhodamine-6G and the blue signal represents DAPI. (c) Behavior of different sunscreens types
when applied to skin. B) (a) Schematic of in vivo anti-UV assessment and (b) photoimages of murine dorsal skin obtained after 3 days of topical application of various
samples and treatment with high-dose UVB. (c) H & E-stained histological sections of murine dorsal skin tissues described in (b) and (d) normalized epidermal
thicknesses of the histological sections described in (c) (n = 3, * P < 0.05 and ** P < 0.01). Reprinted with permission from ref. (Yoo et al., 2020), Copyright 2020
American Chemical Society. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

16
R.P. Morais et al.
Carbopol 940-based sunscreen, one containing avobenzone-loaded
mesoporous silica microparticles (single MS), that were synthesized
with a structure-directing agent (Pluronic P123) and the other con­
taining avobenzone-loaded mesoporous silica microparticles (hybrid
MS), that were developed with the combination of two structure-guiding
agents (Pluronic P123 and Pluronic F68). The hybrid MS exhibited a
greater specific surface area (853 m2/g) than the single MS (764 m2/g)
and particle sizes of about 1.5 and 1 μm, respectively. These nano­
formulations effectiveness (0.67% avobenzone) has been evaluated in ex
vivo and in vivo tests. The ex vivo skin permeation assay on pigskin
revealed that the absorption of avobenzone contained in the nano­
formulations was one-third to one-half of the free control, thus trapping
avobenzone in microparticles reduced its skin absorption, where its
action would be undesirable. Specifically, the hydrogel containing
hybrid MS demonstrated lower avobenzone deposition compared to
single MS (p < 0.05). In addition, nanoformulations UVA protection was
investigated in vivo in nude mouse. Topical application of hydrogel
containing hybrid MS on mice skin before UVA irradiation prevented the
increase of transepidermal water loss (TEWL), formation of furrows in
the skin, keratinocyte apoptosis, and neutrophils infiltration that are
indications of skin photodegradation.
Recently, Yoo et al. (2020) proposed sunscreens based on biocom­
patible and biodegradable organosilica nanoparticles with self-
encapsulated phenyl motifs using phenylsilane precursors (bp-SNPs)
for simultaneous UVR absorption/reflection. The bp-SNPs size (75–95
nm) was designed to be large enough to reflect the UVA, but small
enough to be imperceptible when applied, thus preventing the formu­
lation from leaving a white layer on the skin. This study objective was
achieved, and the bp-SNPs were clearly transparent with low opacity
when compared with inorganic filters. The bp-SNPs ex vivo penetration
was evaluated by applying to pig skin a fluorophore rhodamine-6G-
labeled nanoparticles suspension and analyzed by means of two-
photon and fluorescence microscopy. Microscopy images obtained
from swine skins after 4 h of rhodamine-6G-labeled bp-SNPs topical
application revealed that the nanoparticles tended to adhere to skin
outer without penetrating the dermis (Fig. 10Aa). In addition, the
fluorescence images of cryo-sectioned skin tissues showed that most of
the bp-SNPs were accumulated on the skin tissues surface (Fig. 10Ab).
The bp-SNPs in vivo protective effect was evaluated against sunburn on
the skin of nude mice. After applying the bp-SNPs (0.5 mg/mL) and the
positive and negative controls to the mice dorsal skin and exposing them
to a UVB lamp for three days, it was demonstrated that the non-treated
skin tissue was significantly damaged, and erythema (redness of the
skin) was observed. However, the skin tissue that was treated with bp-
SNPs and the positive control (0.1 mg/mL of TiO2 nanoparticles and
0.3 mg/mL of ZnO nanoparticles) exhibited the stratum corneum
outermost layer flaking of but without visible erythema or edema
(Fig. 10Bb). Histological skin tissues sections were prepared to assess the
epidermal and dermal layers damage caused by sunburn (Fig. 10Bc). In
unprotected skin, significant epidermal thickening and epidermal hy­
pertrophy were observed. As shown in Fig. 10Bd, the epidermal layer
thicknesses of UV exposed unprotected skin was twice thicker than
normal skin. However, bp-SNPs treated skin did not present severely
epidermal thickness under UR exposure and its anti-UV effect was
comparable to that of commercially available positive control
nanoparticles.
Silica particles also acted as a stabilizing agent in a lip gloss formu­
lation (Drakontis and Amin, 2020). In this study, a combination of
biosurfactants (rhamnolipids and sophorolipids) with silica particles
(Aerosil R 202, R 812 and R 812S) were used to formulate a sustainable
lip gloss emulsion. The formulations viscosity profile was evaluated
using the following parameters: silica particles diameter size, formula­
tion particles concentration, together with the different types of bio­
surfactant and used oils. In addition, pigments were added to samples to
form the final lip gloss formulation so its performance after application
could be investigated. It was found that the silica particle diameter size
17
International Journal of Pharmaceutics 614 (2022) 121439
had a significant impact on formulation viscosity profile. Of the three
diameters examined (Aerosil R 202/14 nm, Aerosil R 812/6.5 nm and
Aerosil R 812S/7 nm), the largest presented the highest viscosity, at the
same time that it generated yield stress due to an effective network
formation. The silica particles concentration also influenced formulation
viscosity, with an increasing concentration showing an increase in vis­
cosity. In terms of biosurfactants, rhamnolipids and sophorolipids
showed very similar behavior, which meaned that they act as an
emulsifier and does not affect the system rheological behavior. Silicone
oil replacement with other natural oils was only possible with canola
and castor oil, since jojoba, squalene, and mineral oil did not stabilize it.
The formulation rheology provided a stable emulsion, the shear-
thinning effect ensured lip gloss easy applicability, while viscosity and
elasticity provided a good product fixation to lips. After applying the
final formulation to the lips, pigments and the oil shine effect were
visible. In addition, the application proved to be easy and not too sticky,
due to the silica particles present.
7. Conclusions
Knowing skin anatomy and physiology is of fundamental importance
to understand SNPs behavior, interaction, and mechanisms of bio­
distribution, metabolization, and elimination when they are adminis­
tered on the skin. Despite efforts to evaluate these points, there is still no
clear understanding of skin SNPs permeability and toxicity, and the
research so far does not allow reaching a consensus on the subject.
Therefore, more investigative studies are needed, especially studies
involving long-exposure tests. However, the use of functionalization
strategies to modify SNPs surface, in addition to making them more
biocompatible, can be useful tools in silica nanosystems intelligent
construction with high skin penetration and permeation capacity.
Among the functionalization strategies, the insertion of positive groups
on SNPs surface, such as amine groups, sets up the most frequently used
strategy by the selected studies to promote SNPs skin permeation. In
addition, these studies demonstrate high SNPs potential to improve
drugs cutaneous penetration and consequently the therapeutic perfor­
mance. Therapeutic SNPs cited were able to deliver the bioactive com­
pounds to the skin (local delivery) and act as transdermal formulations,
releasing the encapsulated actives in a controlled manner or even on
demand. The nanoencapsulation allowed increasing the physicochem­
ical stability and apparent solubility of drugs with low stability and low
aqueous solubility. Such limitations imply an insignificant cutaneous
absorption of the drug and a reduction in its bioavailability. SNPs are
already employed in cosmetic industry, thanks to their excellent prop­
erties and their low production cost. New uses for SNPs in cosmetics and
cosmeceuticals products has also been proposed being mostly studies
that exploit photoprotection, show promising results.
8. Future perspectives
Although it is a research field still little explored, silica nanosystems
development for topical use is moving in the right direction, that is, in
search of more studies. However, there is still much to be explored, so
we can highlight some gaps that need to be filled: i) lack of standardi­
zation methods for toxicological and in vitro, ex vivo, and in vivo efficacy
experiments on skin, allowing a proper comparison of results between
different research groups; ii) insufficient data on SNPs safety/toxicity
profile; iii) lack of evidence-based randomized clinical studies exploring
SNPs therapeutic efficacy and safety for topical use and iv) lack of
knowledge about SNPs industrial scale production. Therefore, the use of
SNPs in clinical practice and in consumer cosmetic/dermocosmetic
products will largely depend on the progress and success of future
research.
The pharmaceutical and cosmetic markets are in fact attentive to
new technological discoveries stemming from scientific research that
prove efficacy and safety. A new class of products that was born from the
R.P. Morais et al.
cosmetic industry desire to go beyond simply adorning and beautifying
the skin, cosmeceuticals, are considered functional cosmetic products, as
their bioactive formulations exert a beneficial therapeutic effect on skin
appearance. Finally, the future challenge of topical silica nano­
formulations will probably be to improve skin well-being, through
cosmeceutical formulations development, which address important
functional issues to meet consumer demands, especially biodegradable
nanoformulations based on organic silicon. Organic silicon is essential
for skin, as it acts as an antioxidant, fighting free radicals and stimu­
lating collagen synthesis.
CRediT authorship contribution statement
Renata Pinho Morais: Investigation, Conceptualization, Method­
ology, Writing – original draft. Sabrina Hochheim: Investigation,
Conceptualization, Writing – original draft. Carolina C. de Oliveira:
Supervision, Writing – review & editing, Methodology, Conceptualiza­
tion. Izabel C. Riegel-Vidotti: Supervision, Writing – review & editing,
Funding acquisition, Methodology, Conceptualization. Cláudia E.B.
Marino: Supervision, Writing – review & editing, Funding acquisition,
Methodology, Conceptualization.
Declaration of Competing Interest
The authors declare the following financial interests/personal re­
lationships which may be considered as potential competing interests:
Renata Pinho Morais reports financial support was provided by Coor­
dination of Higher Education Personnel Improvement. Sabrina Hoch­
heim reports financial support was provided by Coordination of Higher
Education Personnel Improvement. Claudia Eliana Bruno Marino re­
ports financial support was provided by National Council for Scientific
and Technological Development.
Acknowledgements
The authors acknowledge National Council for Scientific and Tech­
nological Development (CNPq), Brazil (grant C.E.B. Marino - 303126/
2019-1 and grant I.C. Riegel-Vidotti - 306038/2017-0) and Coordina­
tion for the Improvement of Higher Education Personnel (CAPES), Brazil
(Finance code 001) for financial support.
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