 "($.5+ &,(0&((05(3 "($.5+ &,(0&((05(3
 "($.5+,*,5$. &+1.$3 "($.5+,*,5$. &+1.$3
&+11.1)(',&,0($&6.596%.,&$5,104 &+11.1)(',&,0(

$012$35,&.($4('!3($5/(052231$&+(4)13 -,0$0&(3$012$35,&.($4('!3($5/(052231$&+(4)13 -,0$0&(3
945(/$5,&(7,(8 945(/$5,&(7,(8
,&+$(.14(2+,$:
"0,7(34,591).13,'$
,&1.($5$3(..,
"0,7(34,591) 165+.13,'$
+$.,:;$5110,
"0,7(34,591) 165+.13,'$
$3$+.(/$0
 "($.5+ &,(0&(4(05(3(83.($04
4$.(/$.46+4&('6
1..185+,4$0'$'',5,10$.813-4$5+5524',*,5$.4&+1.$3.46+4&('641/#)$&26%4
$351)5+($015(&+01.1*91//104(12.$4/41//104$0'5+(0&1.1*91//104
(&1//(0'(',5$5,10(&1//(0'(',5$5,10
,$:,&+$(.14(2+$5$3(..,,&1.(;$5110, +$.,:$0'.(/$0 $3$+$012$35,&.($4('
!3($5/(052231$&+(4)13 -,0$0&(3 945(/$5,&(7,(8
&+11.1)(',&,0($&6.59
6%.,&$5,104

+5524',*,5$.4&+1.$3.46+4&('641/#)$&26%4
!+,435,&.(,4%316*+551916)13)3(($0'12(0$&&(44%95+( &+11.1)(',&,0($5 "($.5+,*,5$. &+1.$35
+$4%((0$&&(25(')13,0&.64,10,0 &+11.1)(',&,0($&6.596%.,&$5,104%9$0$65+13,:('$'/,0,453$5131) "
($.5+,*,5$. &+1.$313/13(,0)13/$5,102.($4(&105$&5,*,5$. &+1.$3.46+4&('6
2.62.6
Nanoparticle-BasedTreatment
ApproachesforSkinCancer:A
SystematicReview
MichaelJosephDiaz,NicoleNatarelli,ShalizAflatooni,SarahJ.Aleman,
SphurtiNeelam,JasmineThuyTran,KamilTaneja,BrandonLucke-Woldand
MahtabForouzandeh
SpecialIssue
UpdatesonSkinCancerPrevention,EarlyDiagnosisandTreatment
Editedby
Dr.SimoneHarrisonandDr.KarlijnThoonen
SystematicReview
https://doi.org/10.3390/curroncol30080516
Citation: Diaz, M.J.; Natarelli, N.;
Aflatooni, S.; Aleman, S.J.; Neelam, S.;
Tran, J.T.; Taneja, K.; Lucke-Wold, B.;
Forouzandeh, M. Nanoparticle-Based
Treatment Approaches for Skin
Cancer: A Systematic Review. Curr.
Oncol. 2023, 30, 7112–7131. https://
doi.org/10.3390/curroncol30080516
Received: 13 June 2023
Revised: 1 July 2023
Accepted: 17 July 2023
Published: 25 July 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Systematic Review
Nanoparticle-Based Treatment Approaches for Skin Cancer:
A Systematic Review
Michael Joseph Diaz
1,
*, Nicole Natarelli
2
, Shaliz Aflatooni
2
, Sarah J. Aleman
3
, Sphurti Neelam
1
,
Jasmine Thuy Tran
4
, Kamil Taneja
5
, Brandon Lucke-Wold
6
and Mahtab Forouzandeh
7
1
College of Medicine, University of Florida, Gainesville, FL 32610, USA
2
Morsani College of Medicine, University of South Florida, Tampa, FL 33602, USA
3
School of Medicine, Louisiana State University, New Orleans, LA 70112, USA
4
School of Medicine, Indiana University, Indianapolis, IN 46202, USA
5
Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
6
Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA
7
Department of Dermatology, University of Florida, Gainesville, FL 32606, USA
* Correspondence: michaeldiaz@ufl.edu
Abstract:
Nanoparticles have shown marked promise as both antineoplastic agents and drug carriers.
Despite strides made in immunomodulation, low success rates and toxicity remain limitations within
the clinical oncology setting. In the present review, we assess advances in drug delivery nanoparticles,
for systemic and topical use, in skin cancer treatment. A systematic review of controlled trials, meta-
analyses, and Cochrane review articles was conducted. Eligibility criteria included: (1) a primary
focus on nanoparticle utility for skin cancer; (2) available metrics on prevention and treatment
outcomes; (3) detailed subject population; (4) English language; (5) archived as full-text journal articles.
A total of 43 articles were selected for review. Qualitative analysis revealed that nanoscale systems
demonstrate significant antineoplastic and anti-metastasis properties: increased drug bioavailability,
reduced toxicity, enhanced permeability and retention effect, as well as tumor growth inhibition,
among others. Nanoformulations for skin cancers have largely lagged behind those tested in other
cancers–several of which have commercialized formulae. However, emerging evidence has indicated
a powerful role for these carriers in targeting primary and metastatic skin cancers.
Keywords: nanoparticle; skin cancer; drug carriers; systematic review; organic; inorganic
1. Introduction
The American Cancer Society estimates that north of 95 thousand new melanomas
will be diagnosed in 2023, with an expected death toll of nearly 8 thousand [
1
]. Risk factors
for skin cancer development include positive family history, sun and ultraviolet radiation
exposure, genodermatoses, and light complexion, among others. Beyond complications
and outcomes, skin cancer also imposes significant financial strains: the annual cost of
treating skin cancer has been estimated at over USD 8 billion since 2007, compared to total
treatment costs of USD 3.6 billion from 2002 to 2006 [
2
,
3
]. Per-case treatment costs for basal
cell carcinoma and squamous cell carcinomas diagnosed in 2011, secondary to occupational
solar radiation exposure, were greater than CAD 5.5 thousand and 10.5 thousand, respec-
tively [
4
]. Worse yet, accumulating evidence indicates that primary melanoma survivors
are at an elevated risk of developing keratinocyte carcinoma, thereby disproportioning
these outcomes across the population [5,6].
Although most skin cancers are comfortably excised as localized diseases, therapeutic
approaches for locally advanced and metastatic skin cancers are frequently complicated
by dysimmune toxicities and limited efficacies [
7
]. Nanoparticles (NPs)—defined as par-
ticles with one dimension < 100 nm—have recently emerged as promising drug delivery
systems for such antineoplastic drugs, owing to their enhanced targeting, permeability, and
Curr. Oncol. 2023, 30, 7112–7131. https://doi.org/10.3390/curroncol30080516 https://www.mdpi.com/journal/curroncol
Curr. Oncol. 2023, 30 7113
retention [
8
,
9
]. NPs have further shown great promise in overcoming multidrug resistance
and cytotoxicity barriers intrinsic to current targeted treatment modalities [
10
,
11
], with
considerable variance attributed to their classification (Figure 1).

‐
‐
‐
‐
‐ ‐
‐
‐
‐
‐
‐
‐
‐

Figure 1.
Nanoparticle types. There are two (2) major classes of nanoparticles: organic (polymeric
and lipid-based) and inorganic. Each class has specific advantages and mechanisms. Polymeric
nanoparticles proffer enhanced bioavailability and a controlled release profile, but they are limited by
complex manufacturing and potential toxicity. Inorganic nanoparticles proffer uniquely tunable sizes,
shapes, and conjugations, but they are limited by biodegradability concerns and long-term toxicity.
Lipid nanoparticles proffer high biocompatibility and biodegradability, but they are limited by
reduced payload capacities and stability challenges. PTT: photothermal therapy; PDT: photodynamic
therapy. Figure created with Biorender.com.
However, despite their well-recognized utility in the treatment of aggressive cancers,
a comprehensive review of their role and critical potential in the treatment of advanced
cutaneous carcinomas remains needed. Here, we appraise and critique the current body of
relevant research, with an emphasis on key NP types and their associated benefits, for the
development of cutaneous carcinoma therapeutics.
2. Methods
2.1. Study Design
A systematic review of controlled trials, randomized controlled trials (RCTs), meta-
analyses, and Cochrane Review articles was conducted in accordance with the latest
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) guide-
lines [
12
]. This review was registered in the international prospective register of systematic
review (PROSPERO) (CRD42023442468).
2.2. Search Strategy
The Cochrane Library, PubMed, EMBASE, and Scopus databases were broadly queried
on 10 March 2023 to retrieve all relevant articles since 1 January 2000. The main keyword
search terms were “nanoparticle” and “skin cancer”. Query requirements were restricted
to the Title and Abstract fields (“[tiab]”). Search records were managed with Covidence, a
web-based collaboration software platform [13].
Curr. Oncol. 2023, 30 7114
2.3. Eligibility Criteria
All initial search results were subjected to the following inclusion criteria: (1) has a pri-
mary focus on nanoparticle usage for primary skin cancer; (2) includes evidence-supported
metrics that report prevention and treatment data; (3) details the subject population (i.e.,
number of human subjects or cell line type). Criteria for exclusion were (1) non-English
articles, (2) Abstract-only text (or otherwise unavailable full-text), and (3) yet-published
clinical trials. Authors NN, SA, and SJA conducted the eligible article selection process.
Disputes were resolved by MJD or JTT.
3. Results
3.1. Literature Search Results
Our initial sensitivity search yielded 329 records, which were preliminarily screened
on the Title and Abstract fields. Of these, 211 records were excluded either because of
duplication (n = 8) or because they failed to meet the stated eligibility criteria (n = 203).
A total of 118 articles were retrieved for full-text evaluation; 43 articles were selected for
review. Figure 2 provides a detailed overview of the search and filtration process.

‐
‐
‐
‐
‐
‐ ‐
‐
‐
‐ ‐ ‐ ‐
‐
‐
Figure 2. PRISMA flow diagram.
3.2. Primer on Nanoparticle Utility for Skin Cancer Treatment
The use of NPs in anti-skin cancer therapy has gained popularity due to their unique
physicochemical properties that increase the efficacy of cancer treatments. NPs have shown
promising results in skin cancer therapy through various mechanisms of action, such as en-
capsulating therapeutic moieties in photodynamic therapy (PDT), conducting heat-induced
damage in photothermal therapy (PTT), inducing activation and phenotype alteration in im-
munomodulation, and enhancing drug delivery and penetration in chemotherapy [
14
–
17
].
Various treatment types are illustrated in Figure 3.
Curr. Oncol. 2023, 30 7115
Figure 3.
Anti-cancer applications of nanoparticles. Nanoparticles have been tested in skin cancer
treatment via four (4) primary treatment methods: photodynamic therapy, photothermal therapy,
activating the immune system to attack cancer cells, and improving the delivery of chemotherapy
to cancer cells. CD8+ T: CD8+ T cell. M: macrophage. NK: natural killer cell. ROS: reactive oxygen
species. Figure created with Biorender.com.
Several studies have demonstrated the efficacy of NPs in improving photodynamic
therapy. PDT is a non-invasive technique that is used in dermatology, predominantly, for
the treatment of actinic keratoses and non-melanoma skin cancers. More recently, their
use in cutaneous melanomas has been described. PDT requires three components—the
photosensitizer, which must penetrate the skin, excitation light, and oxygen [
17
]. The
photosensitizer is placed inside the targeted cancer cell or in the tumor tissue. When the
light is administered, it excites and activates the photosensitizer and generates reactive
oxygen species (ROS), which can lead to the apoptosis of the cancer cells and the destruc-
tion of tumor tissues [
17
]. At the same time, however, PDT lacks selectivity, and the ROS
can damage surrounding healthy tissues as well [
17
]. Another issue with PDT is the low
bioavailability and delivery of naturally occurring photosensitizers, such as protoporphyrin
IX (PphIX). A nanoparticle-based delivery system can encapsulate PphIX into NPs that pen-
etrate the epidermal barrier and allow for targeted delivery to tumor cells [
18
]. To increase
the specificity of nanoparticle delivery, the properties of NPs can be altered to increase
interactions with cancer cells. Cancer cells often overexpress integrin receptors (
α
v
β
3)
on their cell surface [
18
]. Targeted delivery of TiO
2
NPs, which have shown cytotoxicity
against melanoma cells, conjugated to a Arg-Gly-Asp (RGD) motif, would thus make PDT
more selective, promoting binding with integrin
α
v
β
3 [
18
,
19
]. TiO
2
NPs, conjugated to
RGD, exhibit a cytotoxic effect in
α
v
β
3 integrin-expressing mice melanoma cells but not in
the normal cells lacking this integrin [
18
]. In addition to TiO
2
-based PDT, ultra-small hollow
silica nanocarriers (HSdots) (~10 nm) can serve as nanocarriers for the targeted topical
delivery of photosensitizer zinc phthalocyanine (ZnPc) [
20
]. ZnPC is a porphyrin that is
excited by near-infrared light. When ZnPC-loaded HSdots are conjugated to folic acid,
they selectively target squamous cell carcinoma (SCC) regions due to the high number of
folic acid receptors in SCC tissues [
20
]. Photosensitizers can also be loaded into solid lipid
nanocarriers for more effective drug delivery and increased selectivity in tumor cells [
17
].
Phthalocyanine aluminum chloride (AlPc), another example of a photosensitizer, absorbs
light between 660 and 770 nm. Mello et al. reported that AlPc, alone, did not permeate the
Curr. Oncol. 2023, 30 7116
skin, but when it was encapsulated by butter-based solid lipid NPs (SLN-AlPc), there was
a permeation of approximately 100% with 8 h of contact [
17
]. The increase in penetration of
the photosensitizer, using the nano-based delivery system, can be attributed to the small
size (~17 nm) of SLN-AlPc and the interactions of the solid lipid NPs with the stratum
corneum [
17
]. Once delivered to the tumor site, PDT with SLN-AlPc treatment yielded
ROS generation, increased the expression of caspase-3, and decreased the expression of
Bcl-2 [
17
]. Thus, the small size of NPs allows for effective penetration of the epidermal
barrier and targeted delivery to tumor cells, leading to selective tumor cell toxicity [
17
,
18
].
Photothermal therapy is similar to PDT but without the need for ROS to interact with
target cells or tissues. PTT requires the conversion of near-infrared light into heat that
can damage cancer cells. PTT can lead to the risk of recurrence or metastasis, however,
due to the incomplete elimination of tumor cells [
21
]. The introduction of NPs into the
tumor sites can allow for more efficient destruction of cancer cells through the excitation of
NPs, inducing a moderate temperature increase and inducing irreversible cell damage to
cancerous cells while minimizing harm to non-target tissues [
21
]. Magnetite (Fe
3
O
4
) NPs
are one such type of NP that demonstrates high absorptivity at near-infrared wavelengths.
When Fe
3
O
4
NPs are activated with near-infrared irradiation, they efficiently convert light
into heat and induce apoptosis [
21
]. NPs can also be utilized in combination therapy
involving PTT and immunotherapy. When both types of skin cancer therapies are used
together, it can stimulate further tumor shrinkage and reduce the risk of recurrence and
metastasis [
22
]. This was demonstrated in a study that synthesized polydopamine-coated
Al
2
O
3
NPs and injected the NPs directly into B16F10 melanoma allografts in mice for
PTT. Then, CpG, a potent stimulator of Th1-type cells, was injected into the mice, so
tumor volumes and the number of living mice were recorded. The Al
2
O
3
within the NP
worked with the CpG to trigger a robust cell-mediated immune response that allowed for
increased elimination of residual tumor cells. After the combined treatment, 50% of the
mice successfully achieved the goal of tumor eradication and survived for 120 days [
22
].
Gold and silver nanoparticle-assisted PTT, or plasmonic photothermal therapy (PPTT)
represents another route. When gold and silver NPs are irradiated, electrons are excited;
then, they relax and emit strong localized heat that can destroy nearby surrounding cancer
cells [
23
]. Gold and silver NPs can be combined with carbon nanotubes, which have high
thermal conductivity after laser excitation, as effective agents for PPTT [23].
NPs can suppress tumor growth through targeted immunomodulation. Studies have
demonstrated NPs altering macrophage polarization towards an M1-like phenotype and
increasing CH8+ T cell density [
24
,
25
]. Among them, one study utilized nanosized mem-
brane vesicles, known as extracellular vesicles (EVs), which were isolated and purified
from the ginseng root, known for their anticancer properties [
26
]. Mice with B16F10
melanoma were treated with ginseng-derived NPs (GDNPs) therapy [
26
]. GDNP treat-
ment significantly suppressed melanoma growth in tumor-bearing mice by increasing the
presence of M1 macrophages detected in tumor tissue [
26
]. A separate study found that
chitosan-poly(acrylic acid) NPs (CS-PAA), loaded with R848 and MnCl
2
(R-M@CS-PAA
NPs), can also exert an anti-tumor effect by promoting the M1 phenotype [
24
]. R848 is a
toll-like receptor (TLR)7/8 agonist that is known to effectively drive the M1 polarization
of tumor-associated macrophages [
24
]. Administration of R848 alone, however, can cause
adverse side effects. Mn
2+
can also enhance the activation of CD8+ T cells and natural
killer cells [
24
]. R-M@CS-PAA NPs enhanced the polarization of macrophages into the
M1 phenotype, and they inhibited the proliferation of B16F10 cells [
24
]. Another study
utilized the immunogenic NPs formulated in micron-sized crystals [
25
]. Cucumber mosaic
virus-like particles, containing tetanus toxin peptide (CuMVTT) NPs covered in a micro-
crystalline tyrosine (MCT) adjuvant, were injected into tumor sites. CD8+ T cell density
was increased in the B16F10 melanoma tumors treated with CuMVTT + MCT [
25
]. Further,
a study sought to enhance immune checkpoint inhibition therapy through antigen delivery
by using an E2 protein nanoparticle conjugated to a CpG adjuvant and an MHC-I restricted
glycoprotein 100 epitope (gp100). It was found that immunization with CpG-gp-E2 NPs
Curr. Oncol. 2023, 30 7117
significantly increased CD8+ T cell percentage at the tumor site. The group that received
the combination treatment showed a striking increase in survival compared to groups
receiving CpG-gp-E2 alone (p < 0.001) or anti-PD1 alone (p < 0.001) [
27
]. The surface
characteristics of the nanoparticle can also be adjusted to significantly affect the cell entry
and intracellular behaviors of NPs to enhance immunomodulation. A new, highly specific
inhibitor JQ-1 was shown to be effective in the internalization and reduction in expression
of PD-L1 in cancer cells, dendritic cells, and tumor-associated macrophages. A silica core,
with etched polydopamine NPs loaded with JQ-1, allows for a sustained release pattern of
the drug, reducing the expression of PD-L1 on cancer cells and, simultaneously, activating
the immune system, as well as reducing the risk of tumor recurrence and metastasis [
16
].
The increased roughness of NPs exhibited elevated cellular uptake, allowing the effective
entry of JQ-1 into the residual tumor cells. Further, the use of NPs coated with sucrose
can prevent aggregation and promote favorable interaction with the tumor microenviron-
ment [
28
]. When silver NPs were coated with sucrose (S-AgNPs), stability was increased in
an aqueous solution, making them suitable intravenous agents. S-AgNPs also enhanced
the antitumor activity of anti-PD-1 treatment and significantly increased tumor-infiltrating
CD8+ T cells [28].
Moreover, organic NPs have been evidenced to deliver chemotherapy drugs, in a
targeted way, to prevent toxicity to healthy cells, enhance drug penetration depth, and
provide targeted drug delivery [
14
,
15
]. Fe
2
O
3
NPs can be conjugated to L-cysteine (L-
cys) to increase stability, and then, they can be bound to doxorubicin (Dox). Binding
Dox to L-cys-coated Fe
2
O
3
NPs allowed for efficient Dox delivery after internalization
into melanoma cells. After the rapid uptake of Fe
3
O
4
-L-Cys-Dox NPs in melanoma cells,
within 3 h of treatment, there were noticeable apoptotic effects detectable at 48 h post-
exposure [
14
]. Another study demonstrated the preparation of chitosan NPs to enhance
the tumor penetration capability of 10-hydroxycamptothecin (HCPT) [
15
]. Chitosan is a
cationic polysaccharide that can interact with negatively charged biological membranes by
electrostatic interaction [
15
]. Thus, when HCPT is encapsulated into the core of chitosan-
coated NPs, the charge interaction with biomembranes allows for penetration deep into the
tumor and promotes internalization by tumor cells [
15
]. Further,
in vitro
analysis displayed
sustained release patterns, whereas HCPT, alone, exhibited a very rapid release rate [15].
Table 1 provides a comprehensive summary of 15 full-text articles selected for describ-
ing the general utility of NPs for the treatment of skin cancers.
Table 1.
Summary of studies retrieved to develop a scoping primer on the utility of nanoparticles to
target and treat skin cancer (n = 15).
Author, Year Study Design Key Findings
Toderascu, 2023 [14]
Controlled trial,
mouse (B16F10) and human
(A375) metastatic melanoma
cells
−L-Cysteine (L-Cys)-coated
magnetic iron oxide
nanoparticles (NPs) loaded with
doxorubicin (Dox) induce a
95–98% apoptosis in B16F10 and
A375 melanoma cells
Guo, 2020 [15]
Controlled trial,
Mice melanoma B16F10 and
B16F1 cells
−10-Hydroxycamptothecin
encapsulated in chitosan
nanoparticles significantly
enhance tumor penetration and
significantly inhibited the
progression of tumor (p < 0.05)
Xue, 2022 [16]
Controlled trial,
Mice with B16F10 melanoma
−Silica-based core–shell
nanoparticles (JQ-1@PSNs-R)
improved the therapeutic effect
of photothermal
immunotherapy
Curr. Oncol. 2023, 30 7118
Table 1. Cont.
Author, Year Study Design Key Findings
Mello, 2022 [17]
Controlled trial,
Mice with B16F10 melanoma
−Lipid based nanoparticles
associated with
aluminum-pthlaocyanin
(SLN-AlPC) allowed for the
distribution of hydrophobic
drugs and thus a potential
system to transport
photosensitizers
−Compared to control, B16F10
cells treated with SLN-AlPC
produced a higher amount of
reactive oxygen species
(p < 0.0001)
Dayan, 2018 [18]
Controlled trial,
Mice melanoma B16F10
cancer cells
−The TiO
2
–DLDH
RGD
nanobiocomplex improves
TiO
2
—based photodynamic
therapy through an integrin
targeted delivery approach and
controlled-release of ROS
−In the presence of
TiO
2
–DLDH
RGD
there was a
cytotoxic effect observed in
αvβ3 integrin-expressing mice
melanoma cells (B16F10)
following UVA illumination
Bilkan, 2023 [19]
Controlled trial,
Human melanoma cell line
−Titanium oxide nanoparticles
combined with UV-A radiation
significantly increased the
percentage of apoptotic cells
(p < 0.05)
Dam, 2019 [20]
Controlled trial,
Human cutaneous SCC lines
−ZnPC-loaded HS dots led to
greater than 90% SCC death
after one laser exposure with
photodynamic therapy with a 2-
to 3-fold increase in caspase 2
expression, indicating apoptosis
Wang, 2022 [21]
Controlled trial,
BALB/c mice
−Iron oxide nanoparticle clusters
in combination with
photothermal therapy
significantly inhibited the
growth of implanted tumor
xenografts in BALB/c mice by
reducing tumor volumes by
77.8%
Chen, 2018 [22]
Controlled trial,
Mice melanoma B16F10
cancer cells
−
After photothermal therapy and
immunotherapy treatment with
polydopamine-coated Al
2
O
3
nanoparticle and injection with
CpG adjuvant, 50% of mice
achieved the goal of tumor
eradication and survived for
120 days
Curr. Oncol. 2023, 30 7119
Table 1. Cont.
Author, Year Study Design Key Findings
Behnam, 2018 [23]
Controlled trial,
Mice with B16F10 melanoma
−Ag NPs decorated on carbon
nanotubes significantly reduced
melanoma tumor size after
plasmonic photothermal
therapy
Liu, 2021 [24]
Controlled trial,
Mice with B16F10 melanoma
−Chitosan-poly(acrylic acid)
nanoparticles (CS-PAA NPs)
loaded with R848 and MnCl
2
(R-M@CS-PAA NPs) modulates
the immune cells in the tumor
microenvironment by
promoting the maturation of
APCs and significantly
increasing the proportion of
CD8+ T cells and significantly
increased the polarization of M2
macrophages to M1
macrophages
Mohsen, 2022 [25]
Controlled trial,
Mice with B16F10 melanoma
−Cucumber mosaic virus-like
particles containing a tetanus
toxin peptide (CuMVTT)
conjugated to a microcrystalline
tyrosine adjuvant injected into
B16F10 melanoma tumors
significantly inhibited tumor
growth and significantly
increased CD8+ T cell
infiltration (p < 0.0001)
Cao, 2019 [26]
Controlled trial,
Mice with B16F10 melanoma
−Ginseng-derived nanoparticles
promoted the polarization of
M2 to M1 phenotype and
significantly decreased tumor
growth
Neek, 2020 [27]
Controlled trial,
Mice with B16F10 melanoma
−More than 50% of the mice
treated with protein E2
nanoparticles contain CpG
oligonucleotide and
glycoprotein 100 melanoma
antigen epitopes (CpG-gp-E2)
in combination with anti-PD-1
treatment were tumor-free
Kuang, 2022 [28]
Controlled trial,
mouse (B16F10) and human
(A375) metastatic melanoma
cells
−Ag nanoparticles coated with
sucrose (S-AgNPs) in
combination with treatment
with PD-1 mAbs showed potent
antitumor effects with mild
systemic immunotoxicity
3.3. Inorganic Nanoparticles
Inorganic nanoparticles, such as titanium dioxide [
18
], zinc oxide [
21
], carbon nan-
otubes, gold nanoparticles, silver nanoparticles, and silica nanoparticles have been exten-
sively tested as therapeutic drug delivery systems for skin cancer prevention (i.e., sun
protection) and treatment.
Curr. Oncol. 2023, 30 7120
3.3.1. Gold Nanoparticles (AuNPs)
AuNPs have been shown to penetrate and accumulate effectively in tumoral tissue
due to their high biocompatibility, customizable surface properties, and their ability to be
conjugated to other molecules [
29
,
30
]. AuNPs effectively absorb photon energy following
laser exposure and convert it to heat, which can dissipate and evoke damage to nearby
cancer cells, making them effective to utilize in photothermal therapy (PTT) [
30
]. PTT
experiments using AuNPs have consistently shown prolonged survival in melanoma tumor
models, as well as effective tumor regression due to the cell death of skin cancer cells, with
limited damage to surrounding healthy tissue [
30
–
33
]. AuNPs have also proven efficacious
in stabilizing photosensitizers in photodynamic therapy (PDT) and providing enhanced
cellular uptake, leading to increased amounts of skin cancer cell apoptosis and singlet
oxygen generation [
34
]. The function of AuNPs has been enhanced by coating them with
other materials or conjugating them to other molecules [
29
,
32
,
33
,
35
,
36
]. Coating AuNPs
with materials, such as red blood cell membranes, has allowed for a significant reduction
in the rapid physiological clearance of NPs by the monocyte–macrophage system [
35
].
The conjugation to cell-penetrating peptides, such as tumor-targeting adaptor folic acid,
has allowed for enhanced cellular uptake and elevated PTT effects [
32
]; conjugation to
cell-targeting molecules, such as anti-HER2 and melanoma-associated antigen antibodies,
allows for selective killing and uptake via melanoma cells [
33
,
36
]; conjugation to other
antitumor therapies, such as betulin, has resulted in increased growth inhibition and the
proliferation of melanoma cells
in vitro
[
29
]. Utilizing AuNPs with other anti-skin cancer
therapies has proven efficacious due to the properties that allow them to selectively enter
into tumor cells and inhibit the growth of cancer cells. Further exploration of the use of
AuNPs with varying therapies may continue to prove beneficial.
3.3.2. Silver Nanoparticles (AgNPs)
AgNPs exhibit high biocompatibility, resistance to oxidation, and a wide array of
antimicrobial and anti-inflammatory activities [
37
,
38
]. AgNPs, when compared to AuNPs,
have been found to have a greater photodynamic effect in PDT and generate more cytotoxic
reactive oxygen species following irradiation, resulting in higher extinction coefficients in
tumor cells, higher ratios of scattering to extinction, and higher field enhancement [
37
].
AgNPs, similarly to AuNPs, exhibit good optical absorbance and low toxicity towards
normal cells, so they are a viable material for use in PTT as well [
23
,
39
]. AgNPs used
alone in PTT, against a murine model of melanoma, have been shown to invoke up to 45%
necrosis of tumor cells, and when conjugated to carbon nanotubes, they can invoke up
to 70% necrosis [
23
]. AgNPs coated with bovine serum albumin have also been utilized
in PTT, and they are able to invoke nearly complete tumor cell death at temperatures
above 45
◦
C while also proving to have inhibitory effects on the angiogenesis of tumor
cells [
39
]. AgNPs have also shown greater anti-tumor effects upon optimization with
other materials or when synthesized in different manners. A study has shown that AgNPs
synthesized from Fusarium incarnatum fungal extracts have an ability to inhibit tyrosinase
activity (the main enzyme in the biosynthesis of melanin), in melanoma cells, in a dose-
dependent manner [
38
]. In addition to maximizing their cytotoxic effects, it is equally
as important to maximize the ability of AgNPs to reach cancer cells. This has been done
by coating AgNPs with materials that make them more likely to be taken up into cancer
cells, such as polyvinylpyrrolidone (PVP). PVP-AgNPs have been shown to decrease the
genotoxic effects of AgNP therapy, as well as allow for an enhancement in the rates of
cancer cell apoptosis [
40
]. New and improved methods of enhancing the use of AgNPs with
other cancer therapies, new methods of synthesis, or ways to coat the molecules are being
reported in the literature, and they may lead to the development of new and improved
methods of treating human skin cancer.
Curr. Oncol. 2023, 30 7121
3.3.3. Silica Nanoparticles (SiNPs)
SiNPs are silica core polyethylene glycol shell NPs with the ability to function as drug
delivery molecules and circumvent the dose-limiting toxicities posed by many anti-skin
cancer therapies. They are cleared by the kidneys and have low tissue uptake in most
organs, making them an efficacious adjunct therapy in the treatment of skin cancer [
41
].
SiNPs exhibit favorable pharmacokinetics and low tissue accumulation, so they have been
optimized with cell-targeting molecules to directly target cancer cells [
41
,
42
]. There is
a method that has been shown to be efficacious is conjugating SiNPs to melanocortin-1
receptor, targeting alpha melanocyte-stimulating hormones. This method was found to
exhibit effective tumor penetration and distribution
in vivo
, as well as accumulation and
retention of SiNPs in melanoma tumors
in vivo
[
42
]. Another method, utilizing the same
alpha melanocyte-stimulating hormone functionalization, has shown enhanced efficacy
of targeted radiotherapy in melanoma models via efficient internalization of the NPs, as
well as favorable tumor uptake and retention. Melanoma-bearing mice treated with this
therapy were found to exhibit higher lengths of survival compared to control groups [
41
].
SiNPs have also been utilized as a system of drug delivery via loading the NPs with
anti-cancer drugs, such as verteporfin, cisplatin, or resveratrol [
43
–
45
]. SiNPs loaded with
verteporfin were found to nearly abolish the appearance of lung micrometastases, and
they showed reduced lymphangiogenesis of a murine model of melanoma [
43
]. SiNPs
loaded with cisplatin led to reduced toxicity in healthy cells when compared to cisplatin
therapy alone, and they are effective at successfully inhibiting tumor growth in
in vitro
and
in vivo
studies [
45
]. SiNPs loaded with resveratrol led to the increased bioavailability
and solubility of resveratrol, leading to efficiency cytotoxicity in the cells of two melanoma
cancer lines [
44
]. The potential drawback of loading SiNPs with other anti-cancer therapies
is that resveratrol, in the previous study, was found to crystallize in the pores of the NPs,
potentially preventing total release of the drug [
44
]. Overall, SiNPs provide favorable
pharmacological characteristics that may be utilized alongside other therapies to enhance
their efficacy and improve outcomes. Further evaluation may provide better insight into
how to best exploit their advantageous characteristics.
Table 2 provides a comprehensive summary of 18 full-text articles selected for the
review of inorganic NPs in the context of skin cancer treatment.
Table 2.
Summary of articles reporting on the utility of inorganic nanoparticles for skin cancer
treatment (n = 18).
Author, Year Study Design Key Findings
Mioc, 2018 [29]
Case-control,
Human melanoma cell line
A375
−Betulin coated gold
nanoparticles presented a
dose-dependent cytotoxic effect
and induced apoptosis in all
tested cell lines
Suarasan, 2022 [30]
Case-control,
Agarose-based skin biological
phantoms and B16:F10
melanoma cells
−AuNPs in the form of
nanotriangles were found to
produce the greatest PTT effects
Bonamy, 2023 [31]
Case-control,
Human melanoma cell line
SK-MEL-28
−AuNPs synthesized by green
chemistry are less cytotoxic than
gold nanoparticles alone
Zhang, 2018 [32]
Case-control,
Murine melanoma cell line
B16-BL6
−Necroptosis of melanoma cells
using PTT is temperature
dependent and is observed in
gold nanorod (GNR)-mediated
PTT
Curr. Oncol. 2023, 30 7122
Table 2. Cont.
Author, Year Study Design Key Findings
Li, 2020 [33]
Case-control,
B16 mouse melanoma cells
−Gold nanoparticles conjugated
to a monoclonal antibody to
melanoma-associated antigens
targeting melanoma achieved
complete eradication of tumors
in a murine model of
melanoma.
Chi, 2020 [34]
Case-control,
A431 cells and HaCat cells
−PDT with gold nanoparticles
conjugated to 5-ALA
significantly suppressed cell
viability, increased cell
apoptosis and singlet oxygen
generation in both HaCat and
A431 cells.
Zhao, 2022 [35]
Case-control,
B16-F10 melanoma cells
−Red blood cell
membrane-camouflaged gold
nanoparticles had an
antiproliferation and
apoptosis-inducing effect on
B16-F10 cells which might be
mediated by oxidative stress of
reactive oxygen species.
Jeon, 2019 [36]
Case-control,
B16-F10 melanoma cells
−Gold nanoparticles conjugated
to anti-HER2 antibodies were
found to show condensation of
nuclei and translocation of
apoptosis-inducing factor and
cytochrome c from
mitochondria into the nucleus
and cytoplasm, respectively.
Malindi, 2022 [37] Systematic review
−Silver nanoparticles have the
potential to enhance
photodynamic therapy for
melanoma treatment.
Himalini, 2022 [38]
Case-control,
Human skin melanoma
SK-MEL-3 cells
−
Mycosynthesized AgNPs can be
considered as effective
anti-melanogenic agents.
Kim, 2021 [39]
Case-control,
B16F10 murine melanoma
cells
−Bovine serum albumin (BSA)
coated silver nanoparticles
showed a considerable
light-to-heat conversion ability,
suggesting their utility as
photothermal agents.
−BSA-silver nanoparticles
showed marked cytocidal
effects on melanoma cells
Behnam, 2018 [23]
Case-control,
B16/F10 melanoma cell lines
injected into mice
−
Integration of carbon nanotubes
with silver nanoparticles could
enhance the optical absorption
of carbon nanotubes and
improve tumor destruction in
plasmonic photothermal
therapy.
Curr. Oncol. 2023, 30 7123
Table 2. Cont.
Author, Year Study Design Key Findings
Valenzuela-Salas, 2019 [
40
]
Case-control,
B16-F10 murine skin
melanoma cells from
C57BL/6J mice
−Nanoparticles coated with
polyvinylpyrrolidone (PVP)
were shown to have antitumor
activity with a survival rate
almost 4 times higher than
treatment with cisplatin alone.
Zhang, 2020 [
41]
Case-control,
B16F10 murine melanoma
cells
−Silica nanoparticles conjugated
to alpha-melanocyte stimulating
hormone were found to have
enhanced treatment efficacy and
a clear survival benefit in
melanoma models.
Chen, 2018 [42]
Case-control,
B16F10 melanoma bearing
mice
−Melanocortin-1 receptor
targeting silica nanoparticles
were found to have favorable
in vivo renal clearance kinetics
and receptor-mediated tumor
cell internalization allowing for
therapeutic applications
Clemente, 2021 [43]
Case-control,
B16-F10 melanoma bearing
mice
−
Mesoporous silica nanoparticles
were found to half
lymphangiogenesis when
compared to control, and
mesoporous silica nanoparticles
loaded with verteporfin were
found to nearly abolish
lymphangiogenesis.
Marinheiro, 2021 [44]
Case-control,
Human A375 and MNT-1
melanoma cell cultures
−
Mesoporous silica nanoparticles
loaded with resveratrol were
found to have a decreased
melanoma cell viability in vitro.
Draˇca, 2021 [45]
Case-control,
B16F1 melanoma cell lines and
B16F1 melanoma bearing mice
−
Mesoporous silica nanoparticles
loaded with cisplatin were
found to significantly diminish
tumor volume in syngeneic
model of mouse melanoma
induced in C57BL/6 mice.
3.4. Organic Nanoparticles
The use of organic nanoparticles, such as liposomes, solid lipid nanoparticles, poly-
meric nanoparticles, dendrimers, mAb nanoparticles, and extracellular vesicles have also
shown unique promise in skin cancer research. Compared to inorganic NPs, the organic
NPs report greater functionalization with cancer-targeting ligands and increased drug
loading versality. Noteworthy findings from studies on lipid and polymeric NP-based
treatment in the context of skin cancer have been summarized below.
3.4.1. Lipid Nanoparticles (LNPs)
LNPs are a drug delivery system composed of ionizable lipids, allowing enhanced sol-
ubility and bioavailability while reducing toxicity. The search strategy yielded nine studies
evaluating LNP use in the treatment of melanoma. LNPs loaded with temozolomide (TMZ),
anti-parasitic benzimidazole, plumbagin, Zataria multiflora essential oil, and Mentha longi-
flora and Mentha pulegium essential oils have demonstrated cytotoxicity against melanoma
cells
in vitro
. Mentha longiflora/Mentha pulegium-LNPs and Zataria multiflora-LNPs reduced
cell viabilities to under 10% and 13%, respectively [
46
,
47
]. Benzimidazole-LNPs induced
Curr. Oncol. 2023, 30 7124
cancer cell apoptosis, generated reactive oxygen species, and inhibited Bcl-2 expression
in cancer cells while sparing toxicity among healthy HEK293T cells [
48
].
In vivo
murine
studies were additionally conducted with plumbagin-loaded lipid–polymer hybrid NPs
(LPNP) and TMZ-LNPs. Intravenous administration of plumbagin-LPNPs resulted in the
disappearance of 40% and regression of 10% of B16-F10 melanoma tumors [
49
]. Similarly,
TMZ-LNPs inhibited B16-F10 melanoma growth and vascularization without apparent
toxicity [
50
]. Selective targeting capability of aptamer-associated LNPs has also been evalu-
ated. Compared to free SA and SA-LPNPs lacking CD20 aptamers, CD20+ melanoma cells
demonstrated significantly greater uptake of CD20-SA-LPNPs, resulting in enhanced cyto-
toxicity
in vitro
and
in vivo
with murine models [
51
]. Aluminum-phthalocyanine-LNPs
also demonstrated strong intro photodynamic activity among melanoma cells, suggesting
utility in photodynamic therapy [17].
In addition to primary cytotoxicity, LNPs have been evaluated as a therapeutic strategy
to combat drug resistance, specifically, among BRAF-mutant melanoma cell lines [
52
,
53
].
Authors have discovered microRNAs, namely miR-204-5p and miR-199b-5p, involved in
drug resistance development [
53
]. The overexpression of miR-204-5p and miR-199b-5p
inhibit melanoma cell growth
in vitro
, both alone and in combination with BRAF/MEK
inhibitors (MAPKi), suggesting their antagonism of resistance. LNPs loaded with microR-
NAs effectively inhibited their target oncogenes, Bcl-2 and VEGF-A, impaired melanoma
cell proliferation and viability, and potentiated the efficacy of MAPKi. In addition, Fattore
et al. evaluated the microRNA-LNPs among mouse models injected with A375 (n = 7) or
M14 (n = 10) melanoma cell lines [
52
]. While the NPs strongly potentiated the effects of
target therapies, greater tumor inhibition was observed in A375 mice compared to M14
mice. Authors subsequently assessed miR-204-5p and miR-199b-5p expression and found
greater uptake in A375-derived tumors [52]. The results of these two studies demonstrate
both the
in vitro
and
in vivo
potentiation of targeted melanoma therapy, demonstrating
the potential utility of microRNA-LNPs in resistant melanoma. However, LNP uptake and
efficacy may be dependent on the tumor-derived cell line.
3.4.2. Polymeric Nanoparticles
Polymeric NPs are composed of biocompatible polymers, which may be synthetic
or natural in origin. In addition to the previously described studies conducted by Zeng
et al. [
51
] and Sakpakdeejaroen et al. [
49
], employing lipid–polymer hybrid NPs, three
studies evaluated the therapeutic potential of polymeric nanoparticle (PNP) in the manage-
ment of melanoma. A 2021 study developed and evaluated an
α
-mangostin-loaded PNP
topical gel formulation [
54
]. Measurable outcomes included drug release, skin permeation,
cytotoxic effects against B16-F10 melanoma cells, and
in vitro
radical scavenging activ-
ity [
54
]. The PNPs demonstrated biphasic drug release, which is characterized by immedi-
ate release followed by sustained release. Confocal microscopy on rat skin demonstrated
α
-mangostin-PNP penetration up to 230.02
µ
m compared to dye solution penetration of
only 15.21
µ
m [
54
]. Compared to free
α
-mangostin gel, the
α
-mangostin-PNPs depicted a
significantly greater cytotoxic and antioxidant effect (p < 0.05) [
54
]. After 48 h, melanoma
cell viability was 18.50% for
α
-mangostin-PNPs compared to 80.87% for free
α
-mangostin
gel [
54
]. These findings suggest that
α
-mangostin-PNPs may be a promising approach for
the treatment of skin cancer due to their biphasic drug release, enhanced skin permeation,
direct cytotoxicity, and radical scavenging activity.
Similarly, Ferraz and colleagues observed concentration-dependent cell death against
B16-F10 melanoma cells with S-nitromercaptosuccinic acid-PNPs [
55
]. S-nitrosothiols depict
therapeutic potential as
•
NO donors. S-nitromercaptosuccinic acid-PNPs also demonstrated
selective toxicity, as melanoma cells were reportedly more sensitive to cell death compared
to healthy melanocytes. Cytotoxicity was characterized by caspase-dependent apoptotic
features, oxidative stress, mitochondrial superoxide production, and protein thiol group
oxidation. In contrast, free S-nitromercaptosuccinic acid and empty chitosan NPs failed
to exhibit cytotoxicity [
55
]. In addition to
in vitro
analysis, Xiong et al. assessed
in vivo
Curr. Oncol. 2023, 30 7125
efficacy of dacarbazine-PNPs with a murine model [
56
]. Dacarbazine-PNPs were further
modified with nucleic acid aptamer AS1411 for the active targeting of malignant melanoma
(dacarbazine-PNPs-Apt).
In vivo
analysis found the greatest tumor growth inhibition with
dacarbazine-PNPs-Apt compared to free dacarbazine and dacarbazine-PNPs, although all
three active treatments significantly reduced tumor growth compared with the saline and
blank nanoparticle control groups. Specifically, the aptamer allowed for the targeting of
melanoma cells, while tumor acidity released dacarbazine [
56
]. Collectively, these studies
demonstrated the ability of PNPs to enhance skin penetration and drug release, as well
as exhibit direct cytotoxicity against malignant melanoma cells, both
in vitro
and
in vivo
.
Furthermore, aptamer modification may be useful to enhance drug localization, thereby
increasing drug delivery and efficacy while reducing cytotoxicity to healthy cells. Den-
drimers are spherical polymeric macromolecules with highly branched characterizations.
Their unique branches allow for the targeting of nucleic acids.
Table 3 provides a comprehensive summary of 12 full-text articles selected for review
of organic NPs in the context of skin cancer treatment.
Table 3.
Summary of articles reporting on the utility of organic nanoparticles for skin cancer treatment
(n = 12).
Author, Year Study Design Key Findings
Mello, 2022 [17]
In vitro
study with murine
B16-F10 melanoma cells
−Aluminum-phthalocyanine-LNPs
demonstrated strong intro
photodynamic activity among
B16-F10 melanoma cells
−Photoactivated
aluminum-phthalocyanine-LNPs
exhibited a 50% cytotoxicity
concentration of 19.62 nM;
treatment induced apoptosis
Kelidari, 2022 [46] In vitro study
−Mentha longiflora/Mentha
pulegium-LNPs reduced cell
viability
Valizadeh, 2021 [47] In vitro study
−Zataria multiflora-LNPs
demonstrated a dose-dependent
antiproliferative effect
Movahedi, 2021 [
48] In vitro study
−Benzimidazole-LNPs induced
cancer cell apoptosis, generated
reactive oxygen species, inhibited
Bcl-2 cancer cell expression, created
morphological change of cancer
cells, and significantly reduced
migration
Sakpakdeejaroen,
2021 [49]
In vivo murine study
(n = 25 total, n = 5 each
group)
−Intravenous administration of
plumbagin-LPNPs resulted in the
disappearance of 40%, regression of
10%, and stability of 20% B16-F10
melanoma tumors (n = 5)
Clemente, 2018 [50]
In vivo study with
B16-F10 melanoma in
C57/BL6 mice
−TMZ-LNPs inhibited B16-F10
melanoma growth and
vascularization, without observed
toxicity
Zeng, 2018 [51]
In vivo study and murine
in vivo study
−
–salinomycin-loaded lipid-polymer
nanoparticles with anti-CD20
aptamers displayed effective
delivery of salinomycin to CD20+
melanoma cells
Curr. Oncol. 2023, 30 7126
Table 3. Cont.
Author, Year Study Design Key Findings
Fattore, 2020 [52]
In vivo murine study
(n = 7 A375; n = 10 M14)
−microRNA-loaded LNPs
potentiated the effects of target
therapies
−
Greater tumor inhibition with A375
mice compared to M14 mice
Fattore, 2020 [
53] In vitro study
−microRNA-loaded LNPs inhibited
Bcl-2 and VEGF-A, impaired
melanoma cell proliferation and
viability, and potentiated the
efficacy of MAPKi
Md, 2021 [54]
In vitro and in vivo rat
study
−α-mangostin-loaded polymeric
nanoparticle gel enhanced
α-mangostin delivery observed by
a significant cytotoxic effect and
antioxidant effect compared to
α-mangostin gel (p < 0.05)
Ferraz, 2018 [55] In vivo murine study
−S-nitromercaptosuccinic acid-PNPs
induced cell death against B-16-F10
melanoma cells in a
dose-dependent manner
−Free S-nitromercaptosuccinic acid
and empty chitosan nanoparticles
did not exhibit cytotoxicity
Xiong, 2022 [56] In vitro study
−Dacarbazine-loaded targeted
polymeric nanoparticles
demonstrated greater A875
melanoma growth inhibition
compared to free dacarbazine and
dacarbazine-PNPs
4. Discussion
This systematic review aimed to evaluate developments made in NP therapy, specifi-
cally, for cutaneous carcinomas. Nanotechnology may improve current skin cancer thera-
pies due to its unique properties as a primer. NP size is advantageous for epidermal barrier
penetration, resulting in the selective toxicity of tumor cells [
17
,
18
]. NPs can be used to
deliver photosensitizers and drugs to targeted tumor cells. Moreover, NP-based delivery
systems have the advantage of customization with conjugation and coating, allowing for
increased specificity and decreased off-targeting. These alterations improve the outcomes
of PDT, PTT, immunotherapy, chemotherapy, and combination therapy, as evident through
multiple studies discussed throughout this review. When conjugated with certain motifs,
NPs can increase the specificity of PDT by promoting NP-photosensitizer binding with
integrins that are overexpressed on cancer cells [
18
]. Conjugation with other molecules can
increase stability of the NP delivery system and prolong the release of chemotherapeutic
drugs [
14
,
15
]. The coating of certain inorganic NPs, such as AuNPs with red blood cell
membranes or AgNPs with bovine serum albumin, can optimize the effects of NP-based
delivery [
35
,
57
]. These studies showcase the versatility of NPs when modified using conju-
gation and coating. Such results suggest that NP-based delivery systems can improve the
efficacy of skin cancer treatment due to the tailored properties of the NPs.
Inorganic NPs. AuNPs, AgNPs, and SiNPs are among some of the inorganic NPs that
may prove favorable for drug delivery systems. AuNPs and AgNPs are viable options
for PDT and PTT since they emit localized heat to destroy cancer cells and exhibit low
toxicity to normal cells [
23
]. Conjugation and coating only serve to enhance these NP-based
delivery systems. With PTT, AgNPs conjugated with carbon nanotubules showed improved
Curr. Oncol. 2023, 30 7127
tumor destruction when compared to AgNPs only [
23
]. Unlike AuNPs and AgNPs, SiNPs
can be used for drug delivery. Loading SiNPs with anti-cancer drugs, such as cisplatin, led
to reduction in normal cell toxicity due to the targeting nature of the NPs [
45
]. However,
SiNPs may also prevent the total release of anti-cancer drugs, such as resveratrol, due to
the drug crystalizing within the pores of the NPs [
44
]. These basic results suggest that
SiNPs may be a feasible option for drug-based skin cancer therapy, but further studies are
warranted to improve delivery. AuNPs and AgNPs also exhibit promising results, both
individually and in conjunction with other therapies. New methods for the conjugation
and coating of AuNPs and AgNPs may prove beneficial for skin cancer treatment, and
further exploration of may lead to the development of improved PDT and PTT.
Organic NPs. LNPs and polymeric NPs are organic NPs that show potential for
skin cancer treatment. LNPs have demonstrated cancer cell apoptosis, tumor growth
inhibition and regression, and significant cell-reuptake when conjugated with anti-CD20+
aptamer [
17
,
49
–
51
]. LNPs may also be used in PDT as aluminum-phthalocyanine-LNPs that
efficiently delivered the photosensitizers, resulting in apoptosis of the cancer cells. Based
on the successful results of previous studies, continued research in this topic may yield
beneficial results for multiple types of therapies. PNPs have demonstrated effective skin
penetration and drug release, resulting in the cytotoxicity of skin cancer cells [
54
–
56
]. PNP–
aptamer conjugation may also improve drug delivery to cancer cells and decrease normal
cell toxicity. Studies suggest that the effects of
α
-mangostin-PNPs, such as biphasic drug
release, enhanced skin permeation, and direct cytotoxicity, make it a potential approach for
PNP-based therapy [
54
]. Considering the versatility and efficacy of NPs, nanotechnology is
highly promising for the future development of skin cancer therapies.
Delivery. Nanoparticle drug delivery for skin conditions can be administered via
several routes, including subcutaneous, intravenous, and intra-arterial injection (Figure 4);
however, the means of drug administration may alter its biodistribution and efficacy [58].

‐
‐
‐
‐
‐
‐
‐
‐
‐
‐ ‐
‐
‐ ‐
‐
‐
‐
Figure 4.
Routes of administration. There are four primary routes of administration for NP-based
skin cancer therapy: subcutaneous, transdermal, intravenous, and intra-arterial. Figure created with
Biorender.com.
Curr. Oncol. 2023, 30 7128
Nanocarriers consisting of lipids, metals, or polymers represent a promising feature of
transdermal drug delivery for skin disease therapeutics, as they have been employed to
successfully increase drug penetration, prolong drug release, and facilitate targeted drug
delivery to specific locations of the skin
in vivo
[
59
]. Nanoparticle-based technology offers
the potential to expand the use of transdermal routes of administration that minimize the
pain and invasiveness associated with the other routes, and it allows for deeper skin pene-
tration [
60
]. Due to the novelty of this paradigm, few clinical trials have been conducted
on skin cancer patients. A recent phase 1/2 clinical trial investigated the safety, efficacy,
and tolerability of a topical nanoparticle paclitaxel ointment on breast cancer patients with
cutaneous metastases, and it found the treatment to be safe and well tolerated. There
is a shortage of approved clinical trials for NP-based drug delivery systems due to the
toxicity issues that warrant further research to ensure high safety for the implementation of
nanomedicine in the clinical setting. Although NP-based treatments overcome many of the
barriers associated with conventional therapy, the systemic side effects, such as nausea and
argyria, should be assessed prior to further clinical authorization. With the advancements in
nanoparticle-based treatments, new routes of drug administration should continue further
exploration to enhance precision therapeutics and optimize drug delivery [61].
5. Conclusions
Herein, we conducted a systematic review regarding advancements in nanoparticle
utility for advanced cutaneous carcinomas. The introduction of NP-based delivery systems
has ushered in a wealth of new insights into the active and passive targeting of cancer
cell populations. While their self-therapeutic properties have yet to be fully established,
the potential benefits of NP-based therapies are clear. It is likely that we will soon see
significant strides made in the development of multifunctional, stimuli-responsive, and
mutation-selective NPs. Future investigation should aim to elucidate the mechanism
and the predisposing factors of toxic NP aggregation and degradation, as well as the
protective
in vivo
countermeasures. The strengths of this review were its adherence to
the PRISMA and Cochrane Handbook for Systematic Reviews of Interventions guidelines,
where applicable, and the integration of multiple study designs in the eligibility criteria.
Potential limitations include the lack of quality assessment and language restriction.
Author Contributions:
Conceptualization, M.J.D. and J.T.T.; methodology, M.J.D.; validation, B.L.-W.
and M.F.; formal analysis, M.J.D., N.N., S.A., S.J.A. and S.N.; writing—original draft preparation,
M.J.D., N.N., S.A., S.J.A., S.N. and J.T.T.; writing—review and editing, M.J.D., N.N., S.A., S.J.A. and
S.N.; visualization, K.T.; supervision, B.L.-W. and M.F. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Melanoma Skin Cancer Statistics. Available online: https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.
html (accessed on 14 April 2023).
2. Guy, G.P.; Machlin, S.R.; Ekwueme, D.U.; Yabroff, K.R. Prevalence and costs of skin cancer treatment in the U.S., 2002–2006 and
2007–2011. Am. J. Prev. Med. 2015, 48, 183–187. [CrossRef]
3.
Kao, S.Y.Z.; Ekwueme, D.U.; Holman, D.M.; Rim, S.H.; Thomas, C.C.; Saraiya, M. Economic burden of skin cancer treatment in the
USA: An analysis of the Medical Expenditure Panel Survey Data, 2012–2018. Cancer Causes Control
2023
, 34, 205–212. [CrossRef]
4.
Mofidi, A.; Tompa, E.; Spencer, J.; Kalcevich, C.; Peters, C.E.; Kim, J.; Song, C.; Mortazavi, S.B.; Demers, P.A. The economic burden
of occupational non-melanoma skin cancer due to solar radiation. J. Occup. Environ. Hyg. 2018, 15, 481–491. [CrossRef]
5.
Sun, H.; Li, Y.; Zeng, F.; Meng, Y.; Du, S.; Deng, G. Melanoma survivors are at increased risk for second primary keratinocyte
carcinoma. Int. J. Dermatol. 2022, 61, 1397–1404. [CrossRef]
6.
Espinosa, P.; Pfeiffer, R.M.; García-Casado, Z.; Requena, C.; Landi, M.T.; Kumar, R.; Nagore, E. Risk factors for keratinocyte skin
cancer in patients diagnosed with melanoma, a large retrospective study. Eur. J. Cancer 2016, 53, 115–124. [CrossRef]
Curr. Oncol. 2023, 30 7129
7.
Diaz, M.J.; Mark, I.; Rodriguez, D.; Gelman, B.; Tran, J.T.; Kleinberg, G.; Levin, A.; Beneke, A.; Root, K.T.; Tran, A.X.V.; et al.
Melanoma Brain Metastases: A Systematic Review of Opportunities for Earlier Detection, Diagnosis, and Treatment. Life
2023
, 13,
828. [CrossRef]
8.
Wu, J. The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its
Application. J. Pers. Med. 2021, 11, 771. [CrossRef]
9.
Gavas, S.; Quazi, S.; Karpi´nski, T.M. Nanoparticles for Cancer Therapy: Current Progress and Challenges. Nanoscale Res. Lett.
2021, 16, 173. [CrossRef]
10.
Liu, J.P.; Wang, T.T.; Wang, D.G.; Dong, A.J.; Li, Y.P.; Yu, H.J. Smart nanoparticles improve therapy for drug-resistant tumors by
overcoming pathophysiological barriers. Acta Pharmacol. Sin. 2017, 38, 1–8. [CrossRef] [PubMed]
11.
Haider, M.; Elsherbeny, A.; Pittalà, V.; Consoli, V.; Alghamdi, M.A.; Hussain, Z.; Khoder, G.; Greish, K. Nanomedicine Strategies
for Management of Drug Resistance in Lung Cancer. Int. J. Mol. Sci. 2022, 23, 1853. [CrossRef]
12.
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G.; PRISMA Group. Preferred reporting items for systematic reviews and
meta-analyses: The PRISMA statement. PLoS Med. 2009, 6, e1000097. [CrossRef]
13.
Covidence Systematic Review Software, Veritas Health Innovation, Melbourne, Australia. Available online: https://www.
covidence.org (accessed on 10 March 2023).
14.
Toderascu, L.I.; Sima, L.E.; Orobeti, S.; Florian, P.E.; Icriverzi, M.; Maraloiu, V.A.; Comanescu, C.; Iacob, N.; Kuncser, V.; Antohe,
I.; et al. Synthesis and Anti-Melanoma Activity of L-Cysteine-Coated Iron Oxide Nanoparticles Loaded with Doxorubicin.
Nanomaterials 2023, 13, 621. [CrossRef]
15.
Guo, H.; Li, F.; Qiu, H.; Liu, J.; Qin, S.; Hou, Y.; Wang, C. Preparation and Characterization of Chitosan Nanoparticles for
Chemotherapy of Melanoma Through Enhancing Tumor Penetration. Front. Pharmacol. 2020, 11, 317. [CrossRef]
16.
Xue, J.; Zhu, Y.; Bai, S.; He, C.; Du, G.; Zhang, Y.; Zhong, Y.; Chen, W.; Wang, H.; Sun, X. Nanoparticles with rough surface
improve the therapeutic effect of photothermal immunotherapy against melanoma. Acta Pharm. Sin. B
2022
, 12, 2934–2949.
[CrossRef]
17.
Mello, V.C.; Araújo, V.H.S.; de Paiva, K.L.R.; Simões, M.M.; Marques, D.C.; da Silva Costa, N.R.; de Souza, I.F.; da Silva, P.B.;
Santos, I.; Almeida, R.; et al. Development of New Natural Lipid-Based Nanoparticles Loaded with Aluminum-Phthalocyanine
for Photodynamic Therapy against Melanoma. Nanomaterials 2022, 12, 3547. [CrossRef]
18.
Dayan, A.; Fleminger, G.; Ashur-Fabian, O. RGD-modified dihydrolipoamide dehydrogenase conjugated to titanium dioxide
nanoparticles—Switchable integrin-targeted photodynamic treatment of melanoma cells. RSC Adv.
2018
, 8, 9112–9119. [CrossRef]
19.
Bilkan, M.T.; Çiçek, Z.; Kur¸sun, A.G.C.; Özler, M.; E¸smekaya, M.A. Investigations on effects of titanium dioxide (TiO
2
) nanoparticle
in combination with UV radiation on breast and skin cancer cells. Med. Oncol. 2022, 40, 60. [CrossRef]
20.
Dam, D.H.M.; Zhao, L.; Jelsma, S.A.; Zhao, Y.; Paller, A.S. Folic acid functionalized hollow nanoparticles for selective photody-
namic therapy of cutaneous squamous cell carcinoma. Mater. Chem. Front. 2019, 3, 1113–1122. [CrossRef]
21.
Wang, X.; Xuan, L.; Pan, Y. Photothermal ablation of murine melanomas by Fe
3
O
4
nanoparticle clusters. Beilstein J. Nanotechnol.
2022, 13, 255–264. [CrossRef] [PubMed]
22.
Chen, W.; Qin, M.; Chen, X.; Wang, Q.; Zhang, Z.; Sun, X. Combining photothermal therapy and immunotherapy against
melanoma by polydopamine-coated Al
2
O
3
nanoparticles. Theranostics 2018, 8, 2229–2241. [CrossRef] [PubMed]
23.
Behnam, M.A.; Emami, F.; Sobhani, Z.; Koohi-Hosseinabadi, O.; Dehghanian, A.R.; Zebarjad, S.M.; Moghim, M.H.; Oryan, A.
Novel Combination of Silver Nanoparticles and Carbon Nanotubes for Plasmonic Photo Thermal Therapy in Melanoma Cancer
Model. Adv. Pharm. Bull. 2018, 8, 49–55. [CrossRef]
24.
Liu, X.; Xu, Y.; Yin, L.; Hou, Y.; Zhao, S. Chitosan-Poly(Acrylic Acid) Nanoparticles Loaded with R848 and MnCl
2
Inhibit
Melanoma via Regulating Macrophage Polarization and Dendritic Cell Maturation. Int. J. Nanomed.
2021
, 16, 5675–5692.
[CrossRef] [PubMed]
25.
Mohsen, M.O.; Heath, M.; Kramer, M.F.; Velazquez, T.C.; Bullimore, A.; Skinner, M.A.; Speiser, D.E.; Bachmann, M.F. In situ
delivery of nanoparticles formulated with micron-sized crystals protects from murine melanoma. J. Immunother. Cancer
2022
, 10,
e004643. [CrossRef] [PubMed]
26.
Cao, M.; Yan, H.; Han, X.; Weng, L.; Wei, Q.; Sun, X.; Lu, W.; Wei, Q.; Ye, J.; Cai, X.; et al. Ginseng-derived nanoparticles alter
macrophage polarization to inhibit melanoma growth. J. Immunother. Cancer 2019, 7, 326. [CrossRef]
27.
Neek, M.; Tucker, J.A.; Butkovich, N.; Nelson, E.L.; Wang, S.W. An Antigen-Delivery Protein Nanoparticle Combined with
Anti-PD-1 Checkpoint Inhibitor Has Curative Efficacy in an Aggressive Melanoma Model. Adv. Ther.
2020
, 3, 2000122. [CrossRef]
28.
Kuang, X.; Wang, Z.; Luo, Z.; He, Z.; Liang, L.; Gao, Q.; Li, Y.; Xia, K.; Xie, Z.; Chang, R.; et al. Ag nanoparticles enhance immune
checkpoint blockade efficacy by promoting of immune surveillance in melanoma. J. Colloid Interface Sci.
2022
, 616, 189–200.
[CrossRef]
29.
Mioc, M.; Pavel, I.Z.; Ghiulai, R.; Coricovac, D.E.; Farca¸s, C.; Mihali, C.V.; Oprean, C.; Serafim, V.; Popovici, R.A.; Dehelean, C.A.;
et al. The Cytotoxic Effects of Betulin-Conjugated Gold Nanoparticles as Stable Formulations in Normal and Melanoma Cells.
Front. Pharmacol. 2018, 9, 429. [CrossRef]
30.
Suarasan, S.; Campu, A.; Vulpoi, A.; Banciu, M.; Astilean, S. Assessing the Efficiency of Triangular Gold Nanoparticles as NIR
Photothermal Agents In Vitro and Melanoma Tumor Model. Int. J. Mol. Sci. 2022, 23, 13724. [CrossRef] [PubMed]
Curr. Oncol. 2023, 30 7130
31.
Bonamy, C.; Pesnel, S.; Ben Haddada, M.; Gorgette, O.; Schmitt, C.; Morel, A.L.; Sauvonnet, N. Impact of Green Gold Nanoparticle
Coating on Internalization, Trafficking, and Efficiency for Photothermal Therapy of Skin Cancer. ACS Omega
2023
, 8, 4092–4105.
[CrossRef]
32.
Zhang, Y.; Zhan, X.; Xiong, J.; Peng, S.; Huang, W.; Joshi, R.; Cai, Y.; Liu, Y.; Li, R.; Yuan, K.; et al. Temperature-dependent cell
death patterns induced by functionalized gold nanoparticle photothermal therapy in melanoma cells. Sci. Rep.
2018
, 8, 8720.
[CrossRef]
33.
Li, X.; Zhong, S.; Zhang, C.; Li, P.; Ran, H.; Wang, Z. MAGE-Targeted Gold Nanoparticles for Ultrasound Imaging-Guided
Phototherapy in Melanoma. Biomed. Res. Int. 2020, 2020, 6863231. [CrossRef]
34.
Chi, Y.F.; Qin, J.J.; Li, Z.; Ge, Q.; Zeng, W.H. Enhanced anti-tumor efficacy of 5-aminolevulinic acid-gold nanoparticles-mediated
photodynamic therapy in cutaneous squamous cell carcinoma cells. Braz. J. Med. Biol. Res. Rev. Bras. Pesqui Med. E Biol.
2020
, 53,
e8457. [CrossRef]
35.
Zhao, L.; Xie, H.; Li, J. Red Blood Cell Membrane-Camouflaged Gold Nanoparticles for Treatment of Melanoma. J. Oncol.
2022
,
2022, 3514984. [CrossRef]
36.
Jeon, H.J.; Choi, B.B.R.; Park, K.H.; Hwang, D.S.; Kim, U.K.; Kim, G.C. Induction of Melanoma Cell-Selective Apoptosis Using
Anti-HER2 Antibody-Conjugated Gold Nanoparticles. Yonsei Med. J. 2019, 60, 509–516. [CrossRef]
37.
Malindi, Z.; Barth, S.; Abrahamse, H. The Potential of Antibody Technology and Silver Nanoparticles for Enhancing Photodynamic
Therapy for Melanoma. Biomedicines 2022, 10, 2158. [CrossRef]
38.
Himalini, S.; Uma Maheshwari Nallal, V.; Razia, M.; Chinnapan, S.; Chandrasekaran, M.; Ranganathan, V.; Gatasheh, M.K.;
Hatamleh, A.A.; Al-Khattaf, F.S.; Kanimozhi, S. Antimicrobial, anti-melanogenesis and anti-tyrosinase potential of myco-
synthesized silver nanoparticles on human skin melanoma SK-MEL-3 cells. J. King Saud Univ.—Sci.
2022
, 34, 101882. [CrossRef]
39.
Kim, D.; Amatya, R.; Hwang, S.; Lee, S.; Min, K.A.; Shin, M.C. BSA-Silver Nanoparticles: A Potential Multimodal Therapeutics
for Conventional and Photothermal Treatment of Skin Cancer. Pharmaceutics 2021, 13, 575. [CrossRef] [PubMed]
40.
Valenzuela-Salas, L.M.; Girón-Vázquez, N.G.; García-Ramos, J.C.; Torres-Bugarín, O.; Gómez, C.; Pestryakov, A.; Villarreal-Gómez,
L.J.; Toledano-Magaña, Y.; Bogdanchikova, N. Antiproliferative and Antitumour Effect of Nongenotoxic Silver Nanoparticles on
Melanoma Models. Oxid. Med. Cell Longev. 2019, 2019, 4528241. [CrossRef] [PubMed]
41.
Zhang, X.; Chen, F.; Turker, M.Z.; Ma, K.; Zanzonico, P.; Gallazzi, F.; Shah, M.A.; Prater, A.R.; Wiesner, U.; Bradbury, M.S.; et al.
Targeted melanoma radiotherapy using ultrasmall 177Lu-labeled
α
-melanocyte stimulating hormone-functionalized core-shell
silica nanoparticles. Biomaterials 2020, 241, 119858. [CrossRef] [PubMed]
42.
Chen, F.; Zhang, X.; Ma, K.; Madajewski, B.; Benezra, M.; Zhang, L.; Phillips, E.; Turker, M.Z.; Gallazzi, F.; Penate-Medina, O.;
et al. Melanocortin-1 Receptor-Targeting Ultrasmall Silica Nanoparticles for Dual-Modality Human Melanoma Imaging. ACS
Appl. Mater. Interfaces 2018, 10, 4379–4393. [CrossRef]
43.
Clemente, N.; Miletto, I.; Gianotti, E.; Sabbatini, M.; Invernizzi, M.; Marchese, L.; Dianzani, U.; Renò, F. Verteporfin-Loaded
Mesoporous Silica Nanoparticles’ Topical Applications Inhibit Mouse Melanoma Lymphangiogenesis and Micrometastasis In
Vivo. Int. J. Mol. Sci. 2021, 22, 13443. [CrossRef] [PubMed]
44.
Marinheiro, D.; Ferreira, B.J.M.L.; Oskoei, P.; Oliveira, H.; Daniel-da-Silva, A.L. Encapsulation and Enhanced Release of
Resveratrol from Mesoporous Silica Nanoparticles for Melanoma Therapy. Materials 2021, 14, 1382. [CrossRef] [PubMed]
45.
Draˇca, D.; Edeler, D.; Saoud, M.; Dojˇcinovi´c, B.; Dun
¯
derovi´c, D.; Ðmura, G.; Maksimovi´c-Ivani´c, D.; Mijatovi´c, S.; Kalu
¯
derovi´c,
G.N. Antitumor potential of cisplatin loaded into SBA-15 mesoporous silica nanoparticles against B16F1 melanoma cells:
In vitro
and in vivo studies. J. Inorg. Biochem. 2021, 217, 111383. [CrossRef]
46.
Kelidari, H.R.; Alipanah, H.; Roozitalab, G.; Ebrahimi, M.; Osanloo, M. Anticancer Effect of Solid-Lipid Nanoparticles Containing
Mentha longifolia and Mentha pulegium Essential Oils: In Vitro Study on Human Melanoma and Breast Cancer Cell Lines.
Biointerface Res. Appl. Chem. 2021, 12, 2128–2137. [CrossRef]
47.
Valizadeh, A.; Khaleghi, A.A.; Roozitalab, G.; Osanloo, M. High anticancer efficacy of solid lipid nanoparticles containing Zataria
multiflora essential oil against breast cancer and melanoma cell lines. BMC Pharmacol. Toxicol.
2021
, 22, 52. [CrossRef] [PubMed]
48.
Movahedi, F.; Gu, W.; Soares, C.P.; Xu, Z.P. Encapsulating Anti-Parasite Benzimidazole Drugs into Lipid-Coated Calcium
Phosphate Nanoparticles to Efficiently Induce Skin Cancer Cell Apoptosis. Front. Nanotechnol. 2021, 3, 693837. [CrossRef]
49.
Sakpakdeejaroen, I.; Somani, S.; Laskar, P.; Mullin, M.; Dufès, C. Regression of Melanoma Following Intravenous Injection of
Plumbagin Entrapped in Transferrin-Conjugated, Lipid-Polymer Hybrid Nanoparticles. Int. J. Nanomed.
2021
, 16, 2615–2631.
[CrossRef] [PubMed]
50.
Clemente, N.; Ferrara, B.; Gigliotti, C.L.; Boggio, E.; Capucchio, M.T.; Biasibetti, E.; Schiffer, D.; Mellai, M.; Annovazzi, L.;
Cangemi, L.; et al. Solid Lipid Nanoparticles Carrying Temozolomide for Melanoma Treatment. Preliminary In Vitro and In Vivo
Studies. Int. J. Mol. Sci. 2018, 19, 255. [CrossRef] [PubMed]
51.
Zeng, Y.B.; Yu, Z.C.; He, Y.N.; Zhang, T.; Du, L.B.; Dong, Y.M.; Chen, H.W.; Zhang, Y.Y.; Wang, W.Q. Salinomycin-loaded
lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells. Acta Pharmacol.
Sin. 2018, 39, 261–274. [CrossRef]
52.
Fattore, L.; Cafaro, G.; Di Martile, M.; Campani, V.; Sacconi, A.; Liguoro, D.; Marra, E.; Bruschini, S.; Stoppoloni, D.; Cirombella,
R.; et al. Oncosuppressive miRNAs loaded in lipid nanoparticles potentiate targeted therapies in BRAF-mutant melanoma by
inhibiting core escape pathways of resistance. Oncogene 2023, 42, 293–307. [CrossRef]
Curr. Oncol. 2023, 30 7131
53.
Fattore, L.; Campani, V.; Ruggiero, C.F.; Salvati, V.; Liguoro, D.; Scotti, L.; Botti, G.; Ascierto, P.A.; Mancini, R.; De Rosa, G.; et al.
In Vitro Biophysical and Biological Characterization of Lipid Nanoparticles Co-Encapsulating Oncosuppressors miR-199b-5p and
miR-204-5p as Potentiators of Target Therapy in Metastatic Melanoma. Int. J. Mol. Sci. 2020, 21, 1930. [CrossRef]
54.
Md, S.; Alhakamy, N.A.; Neamatallah, T.; Alshehri, S.; Mujtaba, M.A.; Riadi, Y.; Radhakrishnan, A.K.; Khalilullah, H.; Gupta, M.;
Akhter, M.H. Development, Characterization, and Evaluation of
α
-Mangostin-Loaded Polymeric Nanoparticle Gel for Topical
Therapy in Skin Cancer. Gels 2021, 7, 230. [CrossRef] [PubMed]
55.
Ferraz, L.S.; Watashi, C.M.; Colturato-Kido, C.; Pelegrino, M.T.; Paredes-Gamero, E.J.; Weller, R.B.; Seabra, A.B.; Rodrigues, T.
Antitumor Potential of S-Nitrosothiol-Containing Polymeric Nanoparticles against Melanoma. Mol. Pharm.
2018
, 15, 1160–1168.
[CrossRef] [PubMed]
56.
Xiong, W.; Guo, Z.; Zeng, B.; Wang, T.; Zeng, X.; Cao, W.; Lian, D. Dacarbazine-Loaded Targeted Polymeric Nanoparticles for
Enhancing Malignant Melanoma Therapy. Front. Bioeng. Biotechnol. 2022, 10, 847901. [CrossRef] [PubMed]
57.
Chepenik, K.P.; George, M. Hydrolysis of phospholipids by embryonic palate mesenchyme cells
in vitro
. Prog. Clin. Biol. Res.
1985, 163B, 369–376. [PubMed]
58.
Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for
drug delivery. Nat. Rev. Drug Discov. 2021, 20, 101–124. [CrossRef] [PubMed]
59.
Palmer, B.C.; DeLouise, L.A. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue
Targeting. Molecules 2016, 21, 1719. [CrossRef]
60.
Silva, C.O.; Rijo, P.; Molpeceres, J.; Figueiredo, I.V.; Ascensão, L.; Fernandes, A.S.; Roberto, A.; Reis, C.P. Polymeric nanoparticles
modified with fatty acids encapsulating betamethasone for anti-inflammatory treatment. Int. J. Pharm.
2015
, 493, 271–284.
[CrossRef]
61.
Patra, J.K.; Das, G.; Fraceto, L.F.; Campos, E.V.R.; Rodriguez-Torres, M.D.P.; Acosta-Torres, L.S.; Diaz-Torres, L.A.; Grillo, R.;
Swamy, M.K.; Sharma, S.; et al. Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol.
2018, 16, 71. [CrossRef]
Disclaimer/Publisher’s Note:
The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to
people or property resulting from any ideas, methods, instructions or products referred to in the content.