pharmaceutics

Review
Solid Lipid Nanoparticles: Multitasking Nano-Carriers for
Cancer Treatment
Júlia German-Cortés 1,† , Mireia Vilar-Hernández 1,† , Diana Rafael 1,2,3, * , Ibane Abasolo 1,2,3,4, *
and Fernanda Andrade 1,2,5, *

1 Drug Delivery & Targeting Group, Vall d’Hebron Institut de Recerca, Universitat Autònoma de
Barcelona (UAB), 08035 Barcelona, Spain
2 Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN),
Instituto de Salud Carlos III, 28029 Madrid, Spain
3 Functional Validation & Preclinical Research (FVPR), U20 ICTS Nanbiosis, Vall d’Hebron Institut de
Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
4 Servei de Bioquímica, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain
5 Departament de Farmàcia i Tecnologia Farmacèutica i Fisicoquímica, Facultat de Farmàcia i Ciències de
l’Alimentació, Universitat de Barcelona (UB), 08028 Barcelona, Spain
* Correspondence: diana.fernandes_de_so@[Link] (D.R.); [Link]@[Link] (I.A.);
[Link]@[Link] (F.A.)
† These authors contribute equally to this work.

Abstract: Despite all the advances seen in recent years, the severe adverse effects and low specificity
of conventional chemotherapy are still challenging problems regarding cancer treatment. Nanotech-
nology has helped to address these questions, making important contributions in the oncological
field. The use of nanoparticles has allowed the improvement of the therapeutic index of several
conventional drugs and facilitates the tumoral accumulation and intracellular delivery of complex
biomolecules, such as genetic material. Among the wide range of nanotechnology-based drug de-
livery systems (nanoDDS), solid lipid nanoparticles (SLNs) have emerged as promising systems for
delivering different types of cargo. Their solid lipid core, at room and body temperature, provides
SLNs with higher stability than other formulations. Moreover, SLNs offer other important features,
namely the possibility to perform active targeting, sustained and controlled release, and multifunc-
Citation: German-Cortés, J.;
tional therapy. Furthermore, with the possibility to use biocompatible and physiologic materials
Vilar-Hernández, M.; Rafael, D.;
Abasolo, I.; Andrade, F. Solid Lipid
and easy scale-up and low-cost production methods, SLNs meet the principal requirements of an
Nanoparticles: Multitasking ideal nanoDDS. The present work aims to summarize the main aspects related to SLNs, including
Nano-Carriers for Cancer Treatment. composition, production methods, and administration routes, as well as to show the most recent
Pharmaceutics 2023, 15, 831. studies about the use of SLNs for cancer treatment.
[Link]
pharmaceutics15030831 Keywords: solid lipid nanoparticles; nanomedicine; cancer therapy; cancer diagnostics; drug delivery;
targeted therapy
Academic Editor: Shigeru Kawakami

Received: 1 February 2023

Revised: 25 February 2023
Accepted: 28 February 2023 1. Introduction
Published: 3 March 2023
Cancer treatment, especially in advanced stages, is a high-priority unmet clinical
need since, until today, the high toxicity of chemotherapeutic treatment, their lack of
specificity to cancer cells, and the acquired drug resistance hamper a successful cancer
Copyright: © 2023 by the authors. treatment. The oncology research field has experienced great benefits from nanotechnology.
Licensee MDPI, Basel, Switzerland. Nanotechnology-based drug delivery systems (nanoDDS) brought solutions to the major
This article is an open access article drawbacks related to conventional chemotherapy, namely: (i) drug protection from degra-
distributed under the terms and dation, (ii) improving the solubility of hydrophobic drugs, (iii) increase of circulation time,
conditions of the Creative Commons (iv) reducing toxicity, (v) decreasing the required dose, and (vi) facilitating the overcoming
Attribution (CC BY) license (https:// of biological barriers. In summary, by encapsulating the chemotherapeutic drugs into
[Link]/licenses/by/ nanoDDS, it is possible to improve its therapeutic index. Moreover, nanoDDS allow the
4.0/).

Pharmaceutics 2023, 15, 831. [Link] [Link]

Pharmaceutics 2023, 15, 831 2 of 28

safe and efficient delivery of genetic material and other biomolecules that could not reach
the cells on their own [1].
A wide range of nanoDDS types have been reported in the last decades with countless
different compositions and preparation methods. Among them, solid lipid nanoparti-
cles (SLNs), constituted by a solid lipidic core at body temperature, called the attention
of multiple research groups due to their high versatility regarding different cargos and
administration routes, high stability in physiological conditions, low cost of materials,
and easy production [2]. SLNs were first developed in the early 1990s as an alternative
colloidal delivery system to overcome the limitations of the most common formulations at
the time: emulsions, liposomes, and polymeric nanoparticles [3]. The traditional colloidal
carriers deal with problems such as poor stability, polymer toxicity and degradation, high
cost, and difficulties in scaling-up the production [4]. The solid lipid core of SLNs was
a great improvement in the nanoDDS stability issues. Moreover, the possibility of using
physiologically biocompatible products in SLN composition and their scalable production
methods are highly important parameters in the development of a new nanoDDS.

2. SLN Properties
SLNs comprise a lipid core and are solid at room and body temperatures, surrounded
by a surfactant or emulsifier, stabilizing the core by lowering the interfacial tension with
the aqueous media [5]. Sometimes co-surfactants are also included in the formulation to
further reduce the interfacial tension and increase the stability. The main components of SLNs
used as lipids, surfactants, and co-surfactants and some examples and commercial names are
described in Table 1 [4–6]. When SLNs are applied to gene therapy, cationic lipids are used,
including, among others, n-[1-(2,3-dioleoyloxy)propyl]-n,n,n-trimethylammonium chloride
(DOTAP), cetrimide (CTAB), cetylpyridinium chloride (CPC), or benzalkonium chloride [7].

Table 1. Commonly used components for SLNs preparation.

Lipids
Tripalmitin (Dynasan® 116), tristearin (Dynasan® 118), tricaprylate, trimyristin
Triglycerides
(Dynasan® 114), triolein, trilaurin
Glyceril stearate (Precirol® ATO 5), glyceryl palmitostearate, glyceryl
Glycerides dibehenate (Compritol® 888 ATO), behenoyl polyoxyl-8 glycerides
(Compritol® HD5 ATO)
Fatty acids Steric acid, palmitic acid, behenic acid, lauric acid, linoleic acid, oleic acid,
Waxes Cetyl palmitate, carnauba wax, beeswax, shellac wax, otoba wax, propolis wax
Cholesterol, cocoa butter, hard fat (Gelucire® 43/01, Suppocire® bases,
Witepsol® bases), mixture of triceteareth-4 phosphate and ethylene glycol
Others palmitostearate and diethylene glycol palmitostearate (Sedefos® 75), mixture
of lauroyl polyoxyl-32 glycerides and PEG 6000 (Gelucire® 59/14), mono and
diglycerides and polyoxyl stearate (Gelot® 64)
Surfactants and Co-surfactants
Phospholipids Soy lecithin, egg lectin, phosphatidylcholine
Polysorbates Tween® and Span® derivatives
Poloxamines, poloxamers, tyloxapol, polyvinyl alcohol (PVA), vitamin E-TPGS,
Polymers polyoxyethylene-20-cetyl ether, polyoxyethylene glyceryl monostearate,
diethylene glycol monoethyl ether, propylene glycol, sodium lauryl sulfate
Taurocholic acid sodium salt, taurodeoxycholic acid sodium salt, sodium
Others dodecyl sulfate, cholesteryl oleate, ethanol, butyric acid, polyglyceryl-6
distearate

The components of the formulation must be chosen based on the desired applica-
tion (Figure 1). For example, only excipients approved for parenteral administration
023, 15, x FOR PEER REVIEW 3 of 29

Pharmaceutics 2023, 15, 831 3 of 28

Poloxamines, poloxamers, tyloxapol, polyvinyl alcohol (PVA), vitamin E-TPGS,

polyoxyethylene-20-cetyl
must be usedether,
for polyoxyethylene
intravenous [Link]
Also, themonostearate, diethylene
compatibility between the drugs and the
glycol monoethyl ether, propylene glycol, sodium lauryl sulfate
lipids/surfactants must be considered. Lipids that promote a sustained release of the drugs
Taurocholic acidforsodium salt, not
days must taurodeoxycholic acid sodium
be chosen for applications thatsalt, sodium
require dodecyl
a small permanence of SLNs in
the body, such as oral administration.
sulfate, cholesteryl oleate, ethanol, butyric acid, polyglyceryl-6 distearate

Figure 1. SchematicFigure
representation ofrepresentation
1. Schematic SLNs development
of SLNsand final applications.
development Created inCreated
and final applications. BioRen-
in BioRender.
[Link], accessed on 24 February 2023.
com, accessed on 24 February 2023.

Coating
The size of the SLNs can materials,
be adapted viscosity enhancers,
accordingly to theantioxidants,
formulationabsorption-enhancing
components and agents,
production method, preservatives,
varying from adhesives,
50–1000 and other
nm. excipientsthe
In addition, canloading
also be added to the
capacity final formulation
of hydro-
based on the drugs and the desired application [7].
phobic and hydrophilic drugs and their release profile depends on SLNs composition and
The size of the SLNs can be adapted accordingly to the formulation components
manufacturing [4,8]. The different techniques that can be applied for SLNs characteriza-
and production method, varying from 50–1000 nm. In addition, the loading capacity of
tion were previously reviewed elsewhere [7].
hydrophobic and hydrophilic drugs and their release profile depends on SLNs compo-
SLNs’ surfaces can
sition andbe manufacturing
functionalized[4,8].
withThepolyethylene glycol (PEG)
different techniques coating
that can to in- for SLNs
be applied
crease the efficiency of drug and
characterization gene
were deliveryreviewed
previously to target cells and
elsewhere [7].tissues, improve the
systemic circulation time, and decrease immunogenicity. The PEG
SLNs’ surfaces can be functionalized with polyethylene coating glycol
shields(PEG)
the sur-
coating to in-
face from aggregation, opsonization,
crease the efficiency ofand
drug phagocytosis, prolonging
and gene delivery to targetsystemic
cells andcirculation
tissues, improve the
time [9]. Moreover,systemic circulation effect
the therapeutic time, and decrease immunogenicity.
is potentially more efficient when The PEG coating
the SLNs se-shields the
lectively deliver the drug to its specific site of action with active targeting. For this, thecirculation
surface from aggregation, opsonization, and phagocytosis, prolonging systemic
time [9]. Moreover, the therapeutic effect is potentially more efficient when the SLNs selec-
SLN surface is functionalized with ligands (targeting moieties) that can selectively recog-
tively deliver the drug to its specific site of action with active targeting. For this, the SLN
nize overexpressed receptors on the surface of cancer cells and, ultimately, be translocated
surface is functionalized with ligands (targeting moieties) that can selectively recognize
inside the cells. Consequently, the selective
overexpressed receptors on thedelivery ofcancer
surface of the pharmacologically
cells and, ultimately,active com-
be translocated inside
pounds to the tumor can reduce the toxicity and harmful side effects on other healthy
the cells. Consequently, the selective delivery of the pharmacologically active compounds cells
[2]. This is being explored
to the tumoras can
a multifunctional/multitasking
reduce the toxicity and harmfulplatform
side effectsforonefficient drugcells
other healthy or [2]. This
gene delivery and as a diagnostic tool.
SLNs present some advantages, such as the capacity to load both hydrophobic and
hydrophilic drugs, biocompatibility, low susceptibility to erosion, and slow water absorp-
tion. Also, the main advantages of SLNs over liposomes rely on the higher stability and
loading capacity of hydrophobic drugs [7,10]. Importantly, some of the manufacturing
Pharmaceutics 2023, 15, 831 4 of 28

is being explored as a multifunctional/multitasking platform for efficient drug or gene

delivery and as a diagnostic tool.
SLNs present some advantages, such as the capacity to load both hydrophobic and
hydrophilic drugs, biocompatibility, low susceptibility to erosion, and slow water absorp-
tion. Also, the main advantages of SLNs over liposomes rely on the higher stability and
loading capacity of hydrophobic drugs [7,10]. Importantly, some of the manufacturing
processes used for SLNs production can be applied to large-scale production, with excellent
reproducibility being important for downstream commercial and clinical applications [11].
SLNs are the first generation of this type of lipidic particles that present some limi-
tations, including possible polymorphic transitions, particle growth and gelling, limited
cargo (although higher than liposomes), and stability of some drugs since, during storage,
lipid crystallization leads to drug expulsion and premature release [10,12]. Also, like other
nanoparticle-based drug delivery systems, SLNs also present high manufacturing costs
compared to conventional formulations. In order to overcome the limitations of SLNs, a
second-generation, nanostructured lipid carrier (NLC) was developed. NLCs differentiate
from SLNs by having a blend of solid and liquid (oils) lipids in the composition. This allows
a reduction in the melting point of the lipidic core and a higher loading capacity and storage
stability of the system [13]. Moreover, in the last years, many lipidic nanoparticles (LNPs),
some of them with mixed/hybrid properties, have been proposed, and their categorization
is not always consensual. For example, Moderna’s and BioNTech/Pfizer’s COVID-19
vaccines are referred to as LNPs or SLNs, depending on the source of information [14,15].
This makes difficult the proper identification and classification of the formulations. Despite
the similitudes among the SLNs, LNPs, and NLCs, in this review, we will focus on the use
of classic SLNs for cancer treatment.

3. SLNs Production Methods

Different methods for producing SLNs have been developed and proposed over
the years [16,17]. Each of them produces particles with specific characteristics and may
be applied to different drugs. Thus, the production method must be chosen based on
the available equipment, the properties of the drugs to be encapsulated, and the desired
application. For example, methods that comprise a step at high temperatures cannot be used
to formulate thermosensitive drugs. In the same way, drugs sensitive to organic solvents or
sonication cannot be incorporated into SLNs using methods that require the use of organic
solvents and sonication, respectively. Also, the encapsulation of hydrophilic or hydrophobic
drugs requires different methods. For example, while hydrophobic drugs can be loaded
using a single emulsion step, hydrophilic drugs require a double emulsion process. Also,
formulations intended for parenteral administration require a more controlled size and
low polydispersity of the particles and methods able to produce sterile formulations in
comparison with particles designed for oral administration. Thus, to successfully develop
an SLN formulation able to be translated from the bench to the bedside, it is of utmost
importance to choose the proper production method based on the components of the
formulations and the desired application. A brief description of the most common ones
is presented below, and an overall comparison of their advantages and disadvantages is
presented in Table 2. A more detailed and schematic representation of the different methods
is presented elsewhere [10,16,17]. Note that new methods and variations of the presented
methods are constantly being proposed.
Pharmaceutics 2023, 15, 831 5 of 28

Table 2. Advantages and disadvantages of the different SLN production techniques.

Technique Advantages Disadvantages

Effective dispersion of particles, reproducible,
HHPH Extremely high energy inputs,
simple to scale up.
high polydispersity
CHPH Suitable for thermo-sensitive drugs
Low energy inputs, flexibility of interphase,
Microemulsion Low lipid content, exposure to
simple to scale-up
high temperatures
Double microemulsion Higher particle size compared to microemulsion
No use of organic solvents, no use of high amounts of High polydispersity, poor
HSH
surfactants, low production cost encapsulation efficiency
Suitable for thermo-sensitive drugs, small particle diameter, Toxicity due to organic solvents, low
SEE
simple to scale-up lipid content, possible aggregation
Pharmaceutically accepted organic solvent, low Low lipid solvent, possible organic
SED
polydispersity, small particle diameter, simple to scale up solvent toxicity
Pharmaceutically accepted organic solvent, simple to scale Difficult to remove solvent,
SI
up, highly efficient, and versatile low lipid content
Suitable for lipophilic drugs, no organic solvent,
Coacervation Not suitable for pH-sensitive drugs
monodispersity, simple to scale-up
MAMT Controlled microwave heating, low energy inputs Problems to scale-up
Abbreviations: Hot High-Pressure Homogenization (HHPH), Cold High-Pressure Homogenization (CHPH), High
Shear Homogenization (HSH), Solvent Emulsification-Evaporation (SEE), Solvent Emulsification-Diffusion (SED),
Solvent Injection (SI), Microwave-Assisted Microemulsion Technique (MAMT).

3.1. Hot High-Pressure Homogenization

The hot, high-pressure homogenization (HHPH) technique is based on high-pressure
homogenization (HPH). Firstly, the lipid is melted 5–10 ◦ C above the melting point, and
the drug or active component is dissolved. Then, the lipid phase is dispersed into the
aqueous phase, where the surfactant was previously dissolved at the same temperature
under high-speed stirring. This pre-emulsion is then homogenized by passing the liquid
at high pressures (100–2000 bars) through a narrow gap (micron dimensions), achieving
very high velocity. Very high shear stress and cavitation forces disrupt the particles down
to the submicron range. Finally, the obtained nanoemulsion is cooled to room temperature
to allow the nanoparticles to crystalize and form the SLNs [18].

3.2. Cold High-Pressure Homogenization

Cold-high pressure homogenization (CHPH) is similar to HHPH. The lipids with
the active compound are melted 5–10 ◦ C above the melting temperature, and it is cooled
quickly with liquid nitrogen or dried ice to homogeneously distribute the drug in the solid
lipid matrix. Then, the lipid phase is milled to obtain microparticles of around 50–100 µm.
These solid microparticles are then dispersed in the aqueous phase at a cold temperature.
Finally, as in the HHPH, the pre-suspension is homogenized at high-pressure to obtain
SLNs in the range of 50–100 nm [19,20].

3.3. Microemulsion
This technique is based on the dilution of microemulsions. Microemulsions are ther-
modynamically stable, optically isotropic, and transparent. Firstly, the hydrophobic drug is
dissolved in the warm lipid (55–85 ◦ C) with the surfactant. At the same time, the water
containing the co-surfactant is heated at the same temperature and dispersed into the lipid
mixture. Then, the warm microemulsion is dispersed into cold water (2–3 ◦ C) at a ratio
varying from 1:25–1:50, under mechanical stirring. The SLNs dispersion is often purified
by tangential ultrafiltration to remove the remaining surfactant and co-surfactant [6].
Pharmaceutics 2023, 15, 831 6 of 28

3.4. Double Microemulsion

The double microemulsion is similar to the microemulsion and is widely used to
entrap hydrophilic drugs into the SLN. The hydrophilic drug is dissolved in water and
dispersed in the melted lipid (55–85 ◦ C), forming a water-in-oil dispersion. Then, the first
microemulsion is dispersed in warm water with the surfactants and co-surfactants (as
microemulsions), followed by the dispersion in cold water [5,21].

3.5. High Shear Homogenization

High shear homogenization (HSH) is a technique, like the ones referred to previously,
performed in the absence of organic solvent. Briefly, the lipid is melted 5–10 ◦ C above
the melting point, and the drug is dissolved. The aqueous phase, with the surfactant, is
heated at the same temperature and homogenized with the lipid phase by a rotor-stator
homogenizer. The nanoemulsion is let to cool down to obtain the SLNs. In HSH, the
amount of surfactant, the stirring, and the cooling time are very important to optimize the
particle size [18].
An alternative to HSH is high-speed sonication (HSS). It has the same protocol as the
HSH, but the formulation is sonicated instead of using a rotor-stator homogenizer. However,
this change also presents some disadvantages, such as the possible metal contamination
and damage to sensitive biomolecules [5,22].

3.6. Solvent Emulsification-Evaporation

The solvent emulsification-evaporation (SEE) starts with dissolving the drug and the
lipid matrix in an organic solvent. Using a high-speed homogenizer, this solution is then
emulsified with water containing the surfactant. Finally, the emulsion is passed through
the high-pressure homogenizer to obtain the nanoemulsion and kept overnight in stirring
to eliminate the organic solvent. The SLN is formed when the lipid precipitates in the
aqueous solution [23].

3.7. Solvent Emulsification-Diffusion

The solvent emulsification-diffusion method (SED) consists of saturating a partially
water-soluble solvent such as benzyl alcohol or butyl lactate with water to obtain a ther-
modynamic equilibrium between both liquids. The lipid is dissolved in the organic phase
(water-saturated solvent) and emulsified with the aqueous phase (solvent-saturated water)
containing the surfactant. Then, the emulsion is quickly diluted in water and stirred to
extract the solvent into the external water phase by diffusion, thus, precipitating the lipid
and generating the SLNs [24].

3.8. Solvent Injection

The solvent injection (SI) is a modification of the SED technique. As in SED, the lipid
and drug are dissolved in a partially water-soluble solvent or a mixture of solvents. Then,
the organic phase is rapidly injected through a needle into the aqueous phase containing
the surfactant in constant stirring. The SLNs are formed when the solvent diffuses to the
external water phase and precipitates [25].

3.9. Solvent Injection Lyophilization

The solvent injection lyophilization (SIL) is a modification of the SI. The procedure is
the same, but instead of an aqueous phase containing surfactant, it contains lyoprotectants.
Then, the system is lyophilized to obtain the dry SLNs, that, once rehydrated, forms a
dispersion [26].

3.10. Coacervation
The coacervation method is also known as fatty acid coacervation due to the use of fatty
acid alkaline salts. Firstly, a solution with a polymeric stabilizer is prepared. Then, the fatty
acid sodium salt is dispersed homogenously and heated under stirring above its Kraft point.
Pharmaceutics 2023, 15, 831 7 of 28

The drug is then dissolved in an organic solvent added to the solution and stirred until a
unique phase, and a clear solution is obtained. Finally, an acidic solution is added drop by
drop to form a suspension with a pH of around 4. The suspension is then cooled down in a
water bath under stirring at a low temperature (15 ◦ C), and the SLNs are formed [27].

3.11. Microwave-Assisted Microemulsion Technique

The microwave-assisted microemulsion technique (MAMT) is characterized by single-
pot production. The drug, lipids, and surfactants are heated in a highly temperature-
controlled microwave above the lipid melting point. The melted solution is stirred in order
to obtain a hot microemulsion that is finally dispersed in cold water (2–4 ◦ C), originating
the SLNs [28].
One of the main difficulties in developing nanomedicines relies on the production
scale-up to an industrial level. To enter the market, nanomedicines must be produced with
reproducibility from batch-to-batch the more affordable way possible at a large scale by
techniques that comply with the regulatory authorities [29]. High-pressure homogenization
(HPH) is already qualified for parenteral nutrition applications, thus having scale-up
potential for SLN production [16]. Also, some publications have published scale-up of SLNs
production using methods such as microfluidic [30] or supercritical fluid [31]. Moreover,
the SLNs that are under clinical evaluation are being produced at a large scale. Additionally,
considering that various SLN formulations are used in the cosmetic field, the step of scale-
up is already performed and only must be adapted for regulatory qualification, which may
speed-up their entrance into the pharmaceutical market.

4. Solid Lipid Nanoparticles Administration Routes

One of the major benefits of the SLNs is that by manipulating their composition and
physicochemical features, they can be adapted to numerous applications and administration
routes. Despite being highly applied for dermal applications, SLNs have the potential to
be used in other clinical applications, which is the reason why different groups have been
exploring many administration routes. In fact, the majority of the works/publications
regarding SLNs in recent years have been intended for parenteral administration [32].

4.1. Topical and Dermal Administration

SLNs are widely used for the dermal administration and treatment of skin disorders.
In fact, SLNs were first used in the cosmetic field prior to dermopharmacy/medicine. Topi-
cal administration usually presents some limitations related to the poor skin penetration of
drugs or skin irritation caused by the drug. SLN-based formulations, generally consisting
of SLNs incorporated into creams or gels, form a thin film over the skin that provides the
required hydration to the stratum corneum and enables penetration of small-size particles
through the epidermis. Moreover, the presence of SLNs increases the transport of active
compounds through the skin by improving drug solubilization in the formulation, drug
partitioning into the skin, and fluidizing skin lipids; it also protects the active compound
from light, oxidation, and hydrolysis and reduces the possible irritation caused by the direct
contact of drugs with skin [4,5,12]. Therefore, several SLN formulations have been success-
fully developed to load glucocorticoids, retinoids, anti-inflammatories, and antimycotics,
among other drugs [33,34].
Interestingly, due to their solid lipid core, SLNs present the capacity to reflect ul-
traviolet (UV) radiation. Therefore they have been widely applied in producing several
sunscreens to improve UV protection [33]. SLNs also give a smoother texture to the cream
compared to conventional cosmetics [35].

4.2. Pulmonary Administration

The pulmonary administration route allows a non-invasive local and systemic drug
administration. Contrary to the oral route, the administered drug is absorbed in the
alveolar epithelium with a large absorption area, highly permeable alveolar epithelial
Pharmaceutics 2023, 15, 831 8 of 28

membrane, and high vascularization with limited hepatic first-pass metabolism. In this
type of administration, the formulation should be nebulized through an inhaler device.
For that, all of the formulation’s physicochemical features should be controlled to obtain
nebulized particles with the perfect size [12,36,37].
There are several studies where SLNs are administered through the pulmonary route
for the treatment of diverse pulmonary pathologies, namely tuberculosis [38,39], asthma,
chronic obstructive pulmonary disease (COPD) [40], and lung cancer [41–43]. Furthermore,
there are SLN treatments administered through the pulmonary route for systemic diseases
such as diabetes [44] and hypertension [45].

4.3. Oral Administration

The oral route is non-invasive, not requiring medical assistance for drug administra-
tion. Therefore, is the preferred route of administration by patients and the most desired in
clinical practice. Several authors have studied the stability of SLNs in dried or suspension
form for oral administration [4,12]. There are some examples of SLNs orally administered in
order to improve the bioavailability of the loaded drugs; this is the case of lopinavir (for HIV
treatment) [46], risperidone (schizophrenia treatment) [47], rifampicin (tuberculosis) [48],
and hydrochlorothiazide (pediatric hypertension) [49].

4.4. Ocular Administration

Ocular delivery is a complex route of administration due to the sensitive inner struc-
ture of the eye and the poor penetration of drugs in this tissue. Therefore, the drugs are
usually locally administrated using eyedrops. In this type of administration, SLNs benefit
from their small size, meaning they do not obstruct vision, which happens with other
formulations. Additionally, SLNs can reduce the clearance by the eye’s protective mecha-
nisms due to adhesive properties related to nanometric size. Some formulations have been
tested in animal models for treating diverse ocular diseases, like retinitis pigmentosa [50],
glaucoma [51], and ocular bacterial infections [52].

4.5. Intravenous Administration

Intravenous administration is the most common administration route for chemothera-
peutic drugs. Nanomedicine has contributed to increasing the stability and bioavailability
of drugs when intravenously administrated. The formulations should be deeply character-
ized in order to be in accordance with the requirements for this administration route, mainly
the small size, serum stability, and hemocompatible components. Accordingly, to their com-
positions, SLNs are perfectly able to fulfill all the requirements for adequate intravenous
administration. The majority of the developed intravenous SLNs are intended for cancer
therapy (deeply discussed in the next sections of the present review). However, there are
also studies using intravenously administered SLNs for neurodegenerative diseases [53] as
well as for the administration of contrast agents for imaging and diagnosis [54,55].

4.6. Intranasal Administration

Managing central nervous system (CNS) disorders is challenging due to the need
for drugs to cross the blood-brain barrier (BBB) and reach the brain. The lipid nature
of lipid-based nanocarriers such as SLNs can facilitate the transition across the BBB and
translocate them into the brain through passive diffusion [56]. Few studies using SLNs have
been proposed for the nose-to-brain delivery of drugs [57]. Although the exact mechanism
of drug transport from the nose to the brain is not fully understood, and its effectiveness in
humans is unclear, intranasally administered SLNs have been shown to be more effective
in crossing the BBB than other formulations and administration routes.

5. SLNs’ Advantages for Cancer Treatment

The higher specificity of nanoDDS to the tumor site is commonly explained by the well-
known permeation and retention effect (EPR effect) (Figure 2A). Accordingly, due to their
 Pharmaceutics 2023, 15, x FOR PEER REVIEW 9 of 29

Pharmaceutics 2023, 15, 831 9 of 28

5. SLNs’ Advantages for Cancer Treatment

The higher specificity of nanoDDS to the tumor site is commonly explained by the
nanometric size, nanoDDS can profit from the weak vessel structure and the small fenestras
well-known permeation and retention effect (EPR effect) (Figure 2A). Accordingly, due to
(300–900
their nm) present
nanometric in the tumor
size, nanoDDS vasculature
can profit from the while
weaksuppressed lymphatic
vessel structure and the drainage
small causes
retention within the tissue, thus easily reaching the tumor site
fenestras (300–900 nm) present in the tumor vasculature while suppressed lymphatic by passive targeting. After
tissue accumulation, nanoDDS are more prone to suffer cell internalization.
drainage causes retention within the tissue, thus easily reaching the tumor site by passive The mechanism
for SLN internalization
targeting. into cells nanoDDS
After tissue accumulation, usually occurs
are more through
prone toclathrin- or internaliza-
suffer cell caveolin-mediated
endocytosis
tion. (Figurefor2B).
The mechanism SLNBriefly, the plasmatic
internalization into cellsmembrane surrounds
usually occurs the SLNs,
through clathrin- or forming
caveolin-mediated endocytosis (Figure 2B). Briefly, the plasmatic membrane
a vesicle. This vesicle will suffer different stages of maturation, beginning with the early surrounds
the SLNs, forming
endosome a [Link]
and finishing thevesicle will suffer
lysosome. differenton
Depending stages of maturation,
the SLN’s begin-
superficial charge and
ning with the early endosome and finishing in the lysosome.
composition, it can be degraded in the endosome or lysosome, releasing its Depending on the SLN’s
content into
superficial
the cytosolcharge
[58]. and composition,
Moreover, it can be degraded
by modulating in the endosome
the composition of theornanoDDS,
lysosome, they
re- can be
leasing its content into the cytosol [58]. Moreover, by modulating the composition of the
easily functionalized with different targeting moieties to favor active targeting against the
nanoDDS, they can be easily functionalized with different targeting moieties to favor ac-
type of cell of interest, which allows a highly specific treatment compared with the usual
tive targeting against the type of cell of interest, which allows a highly specific treatment
unspecificwith
compared conventional therapy. conventional therapy.
the usual unspecific

Figure 2. (A) Enhanced permeability and retention effect (EPR effect). Passive targeting is explained
Figure 2. (A) Enhanced permeability and retention effect (EPR effect). Passive targeting is explained
by the ability of small SLNs to pass through the gaps in the leaky tumor vasculature. (B) Passive
by the
and ability
active of small SLNs
internalization of to pass by
SLNs through the gaps
endocytosis. in the
The leaky
active tumor vasculature.
internalization implies (B)
SLNsPassive and
active internalization of SLNs by endocytosis. The active internalization implies SLNs
functionalized with an antigen and receptor-mediated internalization of the nanoparticle. Createdfunctionalized
in [Link],
with an antigen andaccessed on 24 Februaryinternalization
receptor-mediated 2023. of the nanoparticle. Created in [Link],
accessed on 24 February 2023.

Regarding SLN formulations under clinical evaluation, when searching for lipid
nanoparticles, despite the difficulties in identifying the type of formulation used, some
lipidic nanoparticles, including SLNs, appear as enrolled in clinical trials for the treatment
of different diseases. The majority are intended for topical [59,60] and oral [61] administra-
tion; however, to our knowledge, no clinical trials are ongoing to study the use of SLNs for
cancer therapy. Despite the absence of an actual clinical evaluation, based on the number of
works published and formulations under development for cancer treatment, it is expected
Pharmaceutics 2023, 15, 831 10 of 28

the translation of some of them from the bench to clinical trials in the near future. In fact,
boosted by the success of COVID-19 vaccines, the interest in lipidic nanoparticles exponen-
tially increased, and the pharmaceutical economic studies from Fortune Business Insights
predict an increase in the global market share of lipidic nanoparticles, including SLNs [62].
As referred to, SLN development began in the 1990s, with the first formulations
reaching the market in the cosmetic field. With the increasing interest in this type of system,
many patents related to the composition and techniques used have been presented. An
example is an SLN formulation to improve sorafenib bioavailability [63]. Also, another
patent relates to silymarin-loaded SLNs targeting tumor cells through folic acid surface
modification [64]. The authors claimed an active lung tumor targeting effect, with improved
bioavailability and reduced toxic effects. Oral delivery of docetaxel by means of SLNs was
also claimed in a patent for the improvement of solubility, and sustained release effect of
the drug [65]. An extended list of patents is reviewed elsewhere [66].

6. SLNs for Drug Delivery

Over the years, several researchers have developed SLN-based formulations for the
encapsulation of different anti-cancer drugs (Table 3). The ultimate goal of all these studies
was to reach an efficacious and non-toxic formulation that could be used as a clinical
alternative to improve the therapeutic index of conventional drugs. Due to the high number
of reported studies, we will focus on some of the most recent publications in this review.
For example, M.C. Leiva et al. [67] used glyceryl tripalmitate SLNs loaded with paclitaxel
(PTX) for breast and lung cancer treatment. They observed that the encapsulated PTX was
more effective in inhibiting cell proliferation than the free drug, thus improving the drug’s
therapeutic index. Another example of drug efficacy improvement was demonstrated by N.
Clemente et al. encapsulating temozolomide (TMZ) for melanoma treatment. Their SLN-TMZ
was more efficient than free TMZ in cell cultures, and in vivo, they reduced the tumor growth
and increased mouse survival by administrating a lower dose of the drug [68].
One of the major challenges regarding cancer therapy relies on the development of
drug resistance by cancer cells. Usually, after several cycles of chemotherapy, cancer cells
start to activate multi-drug resistance (MDR) mechanisms [2,69]. Most commonly, MDR
is caused by the overexpression of drug efflux pumps, such as the P-glycoprotein (P-gp),
which utilizes ATP-derived energy to pump chemotherapy drugs out of tumor cells and
protect tumor tissues from chemical toxicity [70,71]. This problem was studied by G. Guney
Eskiler et al. [72] and B. Stella et al. [73], who were able to avoid drug resistance using
SLNs. In the work of G. Guney Eskiler et al. [72], stearic acid-based SLNs encapsulating
tamoxifen (TMX) were able to reduce the cell viability of TMX-resistant breast cancer cell
line (MCF7-TamR). In the case of B. Stella et al. [73], a sodium behenate SLN encapsulating
squalenoyl doxorubicin (SQ-Dox) increased the inhibition of Dox-resistant ovarian cancer
(A2780-DoxR) cell growth and the capacity of colony formation when compared with the
cells treated with the free drugs. In another study, to overcome MDR in breast cancer,
Wenrui Wang et al. [71] studied the in vitro and in vivo efficacy of a resveratrol (Res)-
loaded SLNs formulation with and without D-α-Tocopheryl polyethylene glycol 1000
succinate (TPGS), a derivative of natural vitamin E (α-tocopherol) that inhibits the activity
of ATP-dependent P-gp. It was found that SKBR3/PR cells treated with TPGS containing
SLNs (TPGS-Res-SLNs) exhibited significant inhibition of cell migration and invasion, as
compared with free Res and SLNs without TPGS (Res-SLNs). In addition, TPGS-Res-SLNs
promoted more apoptosis of tumor cells and induced higher tumor reduction in SKBR3/PR
xenografts that the free Res or the Res-SLNs, owning a better therapeutic outcome (Figure 3).
 cells treated with TPGS containing SLNs (TPGS-Res-SLNs) exhibited significant inhibition
of cell migration and invasion, as compared with free Res and SLNs without TPGS (Res-
SLNs). In addition, TPGS-Res-SLNs promoted more apoptosis of tumor cells and induced
Pharmaceutics 2023, 15, 831
higher tumor reduction in SKBR3/PR xenografts that the free Res or the Res-SLNs, owning11 of 28
a better therapeutic outcome (Figure 3).

Figure 3. The in vivo efficacies

Figure 3. Theofin resveratrol,
vivo efficacies Res-SLNs, and
of resveratrol, TPGS-Res-SLNs
Res-SLNs, and TPGS-Res-SLNs on miceonbearing
mice bearing
SKBR3/PR xenografts.SKBR3/PR
(A) Representative images of mice on the 16th day in the different treatment
xenografts. (A) Representative images of mice on the 16th day in the different treatment
groups. (B) Digital groups.
images(B)of tumors
Digital imagesexcised
of tumorsfrom
excisedrepresentative
from representative mice mice after
after thethe indicated
indicated treatments.
treatments. (C) Body(C)
weight vs. time
Body weight curves
vs. time forfor
curves mice
micetreated withthethe
treated with indicated
indicated formulations.
formulations. (D) Tumor(D)weight
of mice in the different treatment groups. (E) Tumor volume vs. time
Tumor weight of mice in the different treatment groups. (E) Tumor volume vs. time curves for mice curves for mice treated with the
formulations. The data represented mean ± SD (n = 4). * p
treated with the indicated formulations. The data represented mean ± SD (n = 4). * p < 0.05, ** p < with
indicated < 0.05, ** p < 0.01. Reprinted
0.01. Reprinted withpermission
permissionof Frontiers Media S.A.
of Frontiers under Creative
Media Commons
S.A. under Attribution
Creative License (CC
Commons BY 4.0) from [71].
Attribution
License (CC BY 4.0) from Once
[71]. the encapsulation of a single drug in an SLN with a certain composition becomes
trivial, several authors innovate by creating stimuli-responsive formulations or systems for
Once the encapsulation
dual therapy, of a singleor drug
diagnostic, in an SLNFor
even theragnostic. with a certain
example, composition
A. Grillone et al. [74] and
T. Liu et
becomes trivial, several al. [75] produced
authors innovate SLNs
by with superparamagnetic
creating iron oxideformulations
stimuli-responsive nanoparticles (SPIONs)
or
and Nutlin-3 or Dox, respectively. A. Grillone et al. [74] successfully delivered the nanofor-
systems for dual therapy, diagnostic, or even theragnostic. For example, A. Grillone et al.
mulation through the BBB for the treatment of glioblastoma. T. Liu et al. [75] developed a
[74] and T. Liu et [Link]-sensitive
[75] produced SLNs
SLN with Doxwith
and superparamagnetic
SPIONs to reduce tumoriron growthoxide
morenanoparticles
efficiently due to the
(SPIONs) and Nutlin-3 or Dox,
combination respectively.
of magnetic A. Grillonethermal
nanoparticle-driven et al. [74] successfully
therapy delivered
and chemotherapy in vivo.
the nanoformulation through the BBB for the treatment of glioblastoma. T. Liu et al. [75] of
The use of stimuli-responsive lipids can also be a crucial strategy in the context
controlledSLN
developed a pH-sensitive and sustained
with Dox drugand
release since it allows
SPIONs an accurate
to reduce tumor manipulation
growth more of the drug
release profile. For example, through the thermal properties of the lipids, it is possible to in-
efficiently due to the combination of magnetic nanoparticle-driven thermal therapy and
crease the drug release at a specific body region, as demonstrated by M. Rehman et al. [76].
chemotherapy in vivo. They developed a thermosensitive SLN (mixture of lauric acid with oleic or linoleic acid)
The use of stimuli-responsive
loaded with 5-fluoracil lipids can
(5-FU) for also
breastbe a crucial
cancer. strategy
This SLN releasesin the context
quickly and higher ofdoses
controlled and sustained drug release since it allows an accurate manipulation of the drug drug
of 5-FU at high temperatures, such as the tumor temperature, thus increasing the
release profile. For availability
example, in the tumor and its therapeutic index.
through the thermal properties of the lipids, it is possible to
Another example is the pH-sensitive SLN developed by G. Zheng et al. [77] which
increase the drug release at a specific
added adipic body region,
acid dihryzacide to the as demonstrated
glycerin monoestereate by M.
(GMS)Rehman
[Link]. this
[76]. They developed a thermosensitive
modification, the presented SLN (mixture ofloaded
nanoformulation lauricwithacidDox
with
hadoleic or linoleic
a preferential release in
acid) loaded with the tumor acidic
5-fluoracil environment
(5-FU) (pH = cancer.
for breast 5), being possible
This SLN to observe
releasesan initial burst and
quickly release of
higher doses of 5-FU theatdrug
high (within 8 h) followed
temperatures, by a as
such more
thesustained release in time (until
tumor temperature, thus96 h). This work is
increasing
a representative example of the high versatility of SLNs since, by the simple modification
the drug availability in the tumor and its therapeutic index.
Another example is the pH-sensitive SLN developed by G. Zheng et al. [77] which
added adipic acid dihryzacide to the glycerin monoestereate (GMS) matrix. With this
modification, the presented nanoformulation loaded with Dox had a preferential release
in the tumor acidic environment (pH = 5), being possible to observe an initial burst release
Pharmaceutics 2023, 15, 831 12 of 28

of SLNs composition, it is possible to manipulate the release of chemotherapeutic drugs

and adapt such release to the desired application.
While several authors are dedicated to improving the therapeutic index of conven-
tional drugs, other researchers are more focused on substituting such drugs for more natural
compounds or at least reducing the dose of the chemotherapeutic by combination with nat-
ural substances. This is the case of the works by J.S. Baek et al. [78] and W. Wang et al. [79],
where stearic acid-based formulations were used for the encapsulation of wogonin and
curcumin, respectively. These two natural substances are very active in vitro but, due to
their unfavorable pharmacokinetics, require advanced delivery systems such as nanoDDS
for in vivo administration. Guorgui et al. [80] also loaded curcumin in stearic acid-based
SLNs and TPGS nanoparticles. They obtained higher curcumin plasma levels in mice
using the SLNs and observed tumor growth regression in Hodgkin’s Lymphoma mice
models. Moreover, when given in combination with bleomycin, Dox, and vinblastine,
curcumin showed an additive growth inhibitory effect. The authors concluded that once
adequately formulated, curcumin can be used as an adjuvant agent for the treatment of
Hodgkin’s Lymphoma.

Table 3. Examples of SLNs formulation for cancer treatment in different stages of development.

Lipid Method Drug Cancer Phase Ref

SA Hot sonication Wogonin BC In vitro [78]
Emulsification-
SA Curcumin BC In vitro [79]
solidification
Emulsification-
SA & lecithin & TPGS Resveratrol BC In vivo [71]
solidification
CP SEE Nutlin3 & SPIONS GBM In vitro (BBB model) [74]
Microemulsion cold
Trilaurin Curcumin PC In vivo [81]
dilution
Gliceryl tripalmitate HSH PTX BC and LC In vitro [67]
Resveratrol-stearated Microemulsion Omg-3 CRC In vitro [82]
SA HSH TMX BC In vitro [72]
Lauric acid & (linoleic
Hot melt encapsulation 5-FU BC In vitro [76]
acid/oleic acid)
Sodium behenate Coacervation TMZ Melanoma In vivo [68]
Behenic acid sodium salt Coacervation DOX OC In vitro [73]
SA SEE Curcumin HL In vivo [80]
Trilauriun & TPGS Microemulsion DOX and SPIONS PTC (murine) In vivo [75]
CP HPH Indirubin GBM In vitro [83]
Topotecan
CP SEE CC In vitro [84]
hydrocloride
Talazoparib
GMS HSH BC In vitro [85]
(BMN673)
Myristyl myristate Hot sonication Linalool HC and LC In vitro [86]
PTX and ascorbyl
GMS Hot sonication Melanoma (murine) In vivo [87]
palmitate
SA & lecithin SIL 5-FU Melanoma In vivo [88]
Compritol® Microemulsion AP9-cd (ligand) Leukaemia In vivo [89]
HHPH and
1-tetradecanol Temoporfin BC In vivo [90]
ultrasonication
Emulsification-
GMS, AAD, and RGD DOX BC In vivo [77]
solidification
Pharmaceutics 2023, 15, 831 13 of 28

Table 3. Cont.

Lipid Method Drug Cancer Phase Ref

SA SED PTA OC In vitro [91]
Emulsification-
Precirol® ATO5 PTX BC In vitro [92]
solidification
Imwitor® 308 and Ultrasonic
Celecoxib CRC In vitro [93]
Dynasan® 114 melt-emulsification
Lecithin &
Film dispersion method PTX, Curcumin LC In vivo [94]
DSPE-PEG2000
modified
GMS emulsion/solvent Abiraterone Acetate PC Ex vivo/In vivo [95]
evaporation method
Abbreviations: Lipid: Stearic Acid (SA), DL-α-Tocopherol methoxypolyethylene glycol succinate (TPGS), Cetyl
Palmitate (CP), Glycerol Monostearate (GMS), Adipic acid dihydrazide (AAD), Arginine-Glycine-Aspartic (RDG).
Method: Microwave-Assisted Microemulsion Technique (MAMT), Solvent Emulsification-Evaporation (SEE),
High Shear Homogenization (HSH), Solvent Injection-Lyophilization (SIL), Hot High-Pressure Homogenization
(HHPH), Solvent Emulsification-Diffusion (SED). Drug: Paclitaxel (PTX), Tamoxifen (TMX), 5-fluorouracil (5-FU),
Temozolomide (TMZ), Superparamagnetic iron oxide nanoparticles (SPIONs), Doxorubicin hydrochloride (DOX),
1,3,5-triaza-7-phosphaadamantane (PTA). Cancer: Breast Cancer (BC), Glioblastoma (GBM), Prostate Cancer (PC),
Lung Cancer (LC), Colorectal Cancer (CRC), Ovarian Cancer (OC), Hodgkin’s Lymphoma (HL), Papillary Thyroid
Cancer (PTC), Prostate Carcinoma (PC), Cervical Cancer (CC), Hepatocarcinoma (HC).

7. Targeted SLNs
One of the challenges of cancer therapy is the management of adverse side effects
caused by conventional chemotherapy that affect not only the cancer cells but also the
healthy cells. In order to solve this problem, different approaches to specifically target
tumor cells have been strongly explored in recent years. NanoDDS are one of the adopted
strategies since their surface can be functionalized with several targeting moieties to
increase the uptake of the delivery system by the target cells. In the case of SLNs, different
molecules have been used to introduce active targeting moieties, and a summary of the
most recent and relevant works is shown in Table 4.
It is widely known that some cancer cells overexpress certain receptors in compar-
ison to healthy cells; thus, by targeting these receptors, it is expected to obtain a higher
uptake by cancerous cells, as demonstrated by E. Souto et al. [96] and S. Shi et al. [97].
E. Souto et al. [96] developed a Compritol® -based SLN with active targeting against HER2
receptor by conjugating the compact antibody CAB51. The SLNs showed higher cellular
uptake in BT-474 (HER2 positive cells) cells than in MCF-7 (HER2 negative cells), proving
the active targeting of the HER2 receptor. S. Shi et al. [97] proposed dual-targeting by
functionalizing the SLN’s surface with hyaluronic acid and tetraiodothyoacetic acid as lig-
ands of CD44 and αvβ3 receptors, respectively. Functionalized SLNs had a higher cellular
uptake in cells expressing those receptors and increased the therapeutic effect of docetaxel
in vivo. Another example is the SLNs conjugated with the antibody against the receptor for
advanced glycation end products (RAGE) developed by V. T. Siddhartha et al. [98]. These
SLNs loaded with di-allyl-disulfide were taken up more efficiently and induced higher
cytotoxicity than the unconjugated SLNs in triple-negative breast cancer cells. The higher
cytotoxicity was due to a combined effect of intracellular accumulation of di-allyl-disulfide
and the promotion of pro-apoptotic proteins by the inhibition of the RAGE receptor.
Targeting the folate receptor is also a widely used approach for increasing the tumoral accu-
mulation/internalization of SLNs, as demonstrated by R. Rosière et al. [99], J.S. Baek et al. [100],
and K. Rajpoot et al. [101], among others. In the case of R. Rosière et al. [100], they developed
an SLN coated with a folate-grafted copolymer of PEG and chitosan for lung tumors. They
observed that this nanoformulation loaded with PTX had a higher penetrating capacity
into lung tumors when administrated by inhalation rather than the conventional treatment.
Due to folate functionalization, the SLN does not have to rely on tumor vascularization to
reach the tumor site. K. Rajpoot et al. [101] encapsulated oxaliplatin into SLNs conjugated
with folic acid for colorectal cancer treatment and observed that the SLNs functionalized
Pharmaceutics 2023, 15, 831 14 of 28

had a higher cytotoxicity effect in the HT29 cell line compared to the unfunctionalized
SLNs. They believed this higher cytotoxicity was due to the higher cellular uptake of the
nanoformulation mediated by the folate receptor. SLNs are also useful for transporting
plant essential oils (fatty nature) due to their ability to encapsulate hydrophobic com-
pounds. Based on this, S.F. Tabatabaeain et al. [102] successfully loaded Satureja khuzistanica
essential oil into SLNs modified using a chitosan coating attached to folic acid to improve
drug accumulation into breast cancer cells (MCF-7 cells). J.S. Baek et al. [100] developed
SLNs coated with folic acid and conjugated to stearic acid for the treatment of MDR breast
cancer. These SLNs loaded with curcumin and PTX showed a higher cellular internalization
and synergic cytotoxicity partially due to the capacity of curcumin to inhibit P-gp, thus
increasing the PTX intracellular accumulation.
The use of sugars has also been widely studied for targeting cancer cells due to their
higher energetic metabolism. For that, N. Soni et al. [103] and N.K. Garg et al. [104]
functionalized their SLN’s surface with mannose and fucose. N. Soni et al. [103] loaded
gemcitabine in a stearyl amide-based SLNs for lung cancer. Adding mannose to the SLN’s
surface increased the cellular uptake through the mannose receptors overexpressed in
the macrophages. Also, in biodistribution studies, the SLNs functionalized showed more
accumulation in the lungs than the basal SLNs. N. K. Garg et al. [104] used fucose-coated
SLNs loaded with methotrexate for breast cancer treatment, achieving approximately 70%
of tumor reduction.
Several treatments and targeting actives can be combined in the same SLNs.
M.Y. Shen et al. [105] developed SLNs loaded with Dox and SPIONs with a double coating
of folic acid and dextran for colon cancer treatment. The folic acid increased the cellular
uptake through the folate receptors, and the dextran increased the tissue-specificity of SLNs
since the enzyme capable of degrading dextran is only present in the colon. Besides, the
coating also allowed the oral administration of SLNs by protecting them from degradation
at harsh gastric conditions. This nanoformulation showed promising results in vitro and
in vivo, not only by the high tumor cytotoxicity but by the lack of side effects. This is an ex-
ample of a multifunctional nanoparticle that is expected to be the future of nanomedicine by
combining different components and functions in the same vehicle for improved biological
behavior and clinical outcome.
Another widely used approach to improve cancer treatment is the functionalization of
nanoDDS with cell-penetrating peptides (CPP), as reported by B. Liu et al. [106]. They have
modified the SLNs surface with a trans-activating transcriptional activator (TAT) peptide
and studied how the functionalization can increase the accumulation of SLNs loaded with
PTX and α-tocopherol succinate-cisplatin prodrug. They report a higher accumulation of
the SLNs in the tumorous cells, increasing the drugs’ therapeutic index. They discuss that
this higher accumulation is due to the presence of TAT. However, since the function of CPP
is to translocate through the plasmatic membrane, not only to the tumor cells but also the
healthy cells, the use of CPP should not be considered active targeting, contrary to what
has been described in some literature. The use of CPP as moieties for nanoDDS surface
functionalization relies on the improvement of cellular uptake and consequent improve-
ment of drug effectiveness without tumor specificity. Even without this cell-specificity,
the use of CPP is of major interest in brain tumors that require crossing the BBB. The use
of SLNs modified with moieties that increase the permeability of drugs through the BBB
has been proposed by Y.C. Kuo et al. [107,108] and A. Kadari et al. [109], among others.
Y.C. Kuo et al. [107,108] developed different Compritol® -based SLNs formulations for the
encapsulation of etoposide as a chemotherapeutic drug. One of the formulations was com-
posed of a double surface conjugation with an 83–14 monoclonal antibody (83–14 MAb) and
the anti-epithelial growth factor receptor (AEGFR) [107]. The double targeting facilitated
the BBB crossing due to the recognition of the α-subunit insulin receptor by the 83–14 MAb,
and the active targeting of cancerous cells was achieved by the AEGFR. Another formula-
tion developed by the same authors included an anti-melanotransferrin antibody attached
to the surface of SLNs to increase the BBB crossing [108]. Both studies were tested in an
Pharmaceutics 2023, 15, 831 15 of 28

in vitro model of BBB and glioblastoma and successfully decreased the glioblastoma cells
proliferation without causing cytotoxicity to the BBB. A. Kadari et al. [109] have developed
an SLN loaded with docetaxel with an angiopep-2 linked to its surface. Angiopep-2 is a
specific ligand for lipoprotein receptor-related protein 1 (LRP1), a receptor overexpressed
in the BBB and the glioma cells. The in vivo results demonstrated a higher accumulation of
the SLNs in the brain and an increase in the survival rate of the animals compared with the
current treatment, thus arising as a promising alternative for the treatment of glioblastoma.

Table 4. Summary of targeted SLNs for different cancer types in different stages of development.
N.A.—not applicable.

Lipid Method Drug Targeting Cancer Phase Ref

Compritol® HSH N.A. Antibody against HR2 BC In vitro [96]
Glyceryl stearate &
Nanoprecipitation PTX Folic acid coated LC In vivo [99]
Chol
Satureja khuzistanica
Essential Oil &
SA and lecithin HHPH Folic acid BC In vitro [102]
folate-bound
chitosan
Behenic acid Coacervation Methotrexate Apoemimkin Chimera GBM In vivo [110]
GMS and SA SEE Docetaxel Angiopep-2 GBM In vivo [109]
PA SED di-allyl-disulfide RAGE antibody BC In vitro [98]
DSPE SED Oxaliplatin Folic acid CRC In vitro [101]
GMS and TPGS SEE PTX and Curcumin SA-folate BC In vitro [100]
GMS, SPC, and Film-ultrasonic
Docetaxel HA-Te BC In vivo [97]
Oda method
Tristearin SED Irinotecan Folic acid CRC In vivo [111]
GMS SEE PTX and TSC TAT CC In vivo [106]
Trilaurin and TPGS Microemulsion DOX and SPIONs Folic acid CRC In vivo [105]
Glyceryl Emulsification-
PTX Anti CD44v6 antibody BC In vitro [112]
palmitostearate solidification
Stearyl amine SEE Gemcitabine Mannose LC In vivo [103]
Gelucire® 50/13 Microemulsion Methotrexate Fucose BC In vivo [104]
GMS HHPH PTX Hyaluronic acid CC & BC In vivo [113]
Resveratrol and
SA SI (modified) Folic acid CRC In vitro [114]
Ferulic acid
Hot melted
SA PTX HP-β-CD BC In vivo [115]
sonication
GMS and Hot
Dox and Curcumin Folic acid BC In vivo [116]
Compritol® melt-emulsification
Compritol® , Melanotransferr-in
tripalmitin, SA, and SEE ETP antibody and GBM In vitro [108]
Chol Tamoxifen
GMS SEE PTX Wheat germ agglutinin LC In vivo [117]
Compritol® , CL, 83–14 MAb and
Microemulsion ETP GBM In vitro [107]
and SA AEGFR
Pharmaceutics 2023, 15, 831 16 of 28

Table 4. Cont.

Lipid Method Drug Targeting Cancer Phase Ref

Behenic acid,
Tamoxifen and
tripalmitin, and SEE Carmustine GBM In vitro [118]
Lectoferrin
cacao butter
Tristearin & HSPC SI PTX Lactoferrin LC In vitro [39]
PA and Dynasan® N.A. Saquinavir 83–14 MAb GBM In vitro [119]
Compritol® 888
Sonication of AS1411 anti-nucleolin
ATO and Precirol® DTX CRC In vivo [120]
pre-emulsion aptamers
ATO
Hot ultrasonication
Cetyl palmitate Mitoxantrone Folate receptor BC In vitro [121]
method
Abbreviations: Lipid: Stearic Acid (SA), Glycerol Monostearate (GMS), Palmitic acid (PA), 1,2-distearoyl-sn-
glycero-3-phosphoethanolamine (DSPE), DL-α-Tocopherol methoxypolyethylene glycol succinate (TPGS), Soy
phosphatidylcholine (SPC), Octadecylamine (Oda), Cardiolipin (CL), Hydrogenated soya phosphatidylcholine
(HSPC). Method: High Shear Homogenization (HSH), Hot High-Pressure Homogenization (HHPH), Solvent
Emulsification-Evaporation (SEE), Solvent Emulsification-Diffusion (SED), Solvent Injection (SI). Drug: Paclitaxel
(PTX), α-tocopherol succinate-cisplatin (TSC), Doxorubicin hydrochloride (DOX), Superparamagnetic iron oxide
nanoparticles (SPIONs), Etoposide (ETP), Docetaxel (DTX). Cancer: Breast Cancer (BC), Lung Cancer (LC),
Glioblastoma (GBM), Colorectal Cancer (CRC), Cervical Cancer (CC), Prostate Cancer (PC), Ovarian Cancer (OC).

8. SLNs for Gene Delivery

Gene therapy gained a huge interest in the field of cancer treatment to overcome the
high toxicity and the low specificity associated with conventional drugs. Gene therapy
allows the expression of an exogenous oligonucleotide, encoding for a missing or defective
gene or achieving the silence of a particular gene [122,123]. The exogenous expression is
usually mediated by plasmid DNA (pDNA) which consists of a small circular sequence of
DNA that can replicate after entering the nucleus [124]. Gene silencing, on the other hand,
is usually performed by technologies of RNA interference (RNAi). There are three types
of RNAi: short hairpin RNA (shRNA), small interfering RNA (siRNA), and microRNA
(miRNA). The shRNA, like the pDNA, has its function in the nucleus, where it is transcribed
to small RNA and binds to the complementary mRNA, thus inhibiting the expression
of the protein [125]. On the other hand, siRNA and miRNA do not have to enter the
nucleus since they exert activity in the cytoplasm [126]. In the case of the siRNA, it
is a 20–25 base nucleotide with a specific sequence that targets and degrades specific
mRNAs [127]. Regarding miRNA is not as specific as siRNA since the same miRNA can
bind to different mRNAs [128,129].
The major issue regarding gene therapy is the delivery of genetic material into the
cells. The oligonucleotide’s physicochemical properties make its entrance into the cell
difficult without a proper vector. Despite their low packaging capacity, high production
costs, and immunogenicity, viral vectors are still the preferred vectors for gene delivery in
the clinical setting. In order to overcome all the drawbacks associated with the viral vectors,
considerable investment and efforts have been made to develop non-viral vectors [130,131],
including some of the recent vaccines against the SARS-CoV-2 virus [14]. In this review, we
are focused on the application of SLNs for gene therapy in oncological diseases.
Many formulations have been proposed with differences regarding the components
and the physicochemical properties of the SLNs enjoying the lipidic nature of the particles
to promote cell internalization. However, many of them have at least one cationic lipid
and/or phospholipid, such as 1,2-dioleoyl-3-trimethylammonium propane (DOTAP), in
the composition to facilitate the complexation of genetic material. Table 5 summarizes
different SLNs developed for cancer gene therapy, where the main components used for its
formulation can be observed. J. Jin et al. [132] developed an SLN complexed with c-Met
siRNA for glioblastoma. The c-Met complexation with SLNs increased its accumulation in
the brains of mice, leading to a decrease in tumor growth. C. Botto et al. [133] have success-
Pharmaceutics 2023, 15, 831 17 of 28

fully loaded the shNUPR1 in a Precirol® -based SNL and delivery it to the cells. Moreover,
SLNs/shNUPR1 downregulated the NUPR1 gene, which is known to cause chemoresis-
tance and cancer proliferation in hepatocellular carcinoma. Several works describe the use
of SLNs to downregulate the expression of signal transducer and activator of transcription
3 (STAT 3). M. Kotmakçi et al. [134] used shRNA against STAT3 to reduce STAT3 levels
and re-sensitize resistant lung cancer cells (CR-Calu1) to cisplatin. Zhang et al. used decoy
oligodeoxynucleotides (ODN) to target STAT-3. The results were promising, showing
an inhibition of tumor growth activating the apoptotic cascade, regulating autophagy,
and reversing the epithelial-mesenchymal transition program with no obvious toxicity
on nude mice [135].
In many studies, gene therapy is combined with chemotherapeutic drugs within the same
nanoparticle to potentiate their synergy, as reported by G. Büyükköroglu [136], Y.H. Yu et al. [137]
and T. Li et al. [138], among many others. In the case of G. Büyükköroglu [136], they loaded
SLNs with Bcl-2 siRNA and PTX for the treatment of cervical cancer. Their results show
higher cytotoxicity with the combination of siRNA and PTX than with individual treat-
ments. Also, they propose a local administration by encapsulating the SLNs in a PEG
suppository to reduce the systemic exposure of the pharmacologic compounds and thus
reduce their side effects [139]. Y.H. Yu et al. [137] developed cationic SLNs for breast cancer
treatment loaded with PTX and MCL1-siRNA that successfully reduced tumor growth
in vivo. T. Li et al. [138] studied the synergetic anticancer activity of sorafenib and all-trans
retinoic acid (ATRA) combined with miRNA-542-3p loaded in SLNs. Again, the SLNs
showed a much higher cell growth inhibition than individual treatments, such as free drugs
or in SLNs. Moreover, in vivo, it also showed promising results by an increased reduction
of tumor growth and increased blood circulation time compared to the free drugs. They
believe this high antitumor efficacy is due to the combined therapeutic effects of drugs with
the microRNA.
Targeted SLNs have also been developed for gene delivery. D.M. Yu 2016 et al. [140]
loaded SLNs with PTX and pDNA and attached hyaluronic acid (HA) with a pH-sensitive
linker to promote release at low pH. This nanoformulation not only efficiently released
the chemotherapeutic drug and the pDNA in breast cancer cells but also increased the
accumulation and preferential release of the compounds in the tumor tissue by actively
targeting HA to CD44 receptors.
Finally, different nanoDDS can be successfully combined for improved therapy, as
demonstrated by V. Juang et al. [141]. They developed an SLN and a liposome loaded with
miRNA200 and irinotecan for colon cancer treatment. Both nanoformulations had their
surface modified with three different peptides (including one cell-penetrating peptide, one
peptide targeting tumor neovasculature undergoing angiogenesis, and one mitochondria-
targeting peptide) that increased the cellular uptake and provided an active target to
tumoral cells. Moreover, this nanoformulation was coated with a pH-sensitive PEG-lipid
that enhanced the release of the miRNA in tumor sites due to the acidic environment.
The combination therapies of different delivery systems promoted the synergetic activity
between irinotecan and miR-200 since miR-200 increased the cancer cell sensitivity to
irinotecan. The in vivo studies showed a highly effective inhibition of tumor growth caused
by suppressing several proteins such as Rac-1, KRAS, and β-catenin, among others, being a
promising study for further development.
Pharmaceutics 2023, 15, 831 18 of 28

Table 5. SLNs with different genetic material for different cancer types in different stages of develop-
ment. N.A.—not applicable.

Lipid Method Drug Genetic Material Cancer Phase Ref

Gelucire® 50/13 SEE PTX Bcl-2 siRNA CC In vitro [136]
Precirol ATO5 and Microemulsion
N.A. pDNA stat3 LC In vitro [134]
Compritol® (modified)
Sorafenib/
Steryalmide Microemulsion miR-542-3p GC In vivo [138]
ATRA
DSPE, DOTAP, and αPC SED Irinotecan miR200 CRC In vivo [141]
DOPE, Chol, and DC-Chol SEE N.A. c-Met siRNA GBM In vivo [132]
emulsification
DOPC PTX MCL-1 siRNA BC In vivo [137]
solidification methods
film-ultrasonic
GMS PTX pDNA BC In vivo [140]
dispersion method
ethanolic precipitation
Precirol ATO5 N.A. shNUPR1 HC In vitro [133]
technique & HPH
DOTAP and GMS SED N.A. miR200 BC In vitro [142]
GMS, SPC, and Chol film-ultrasonic method N.A. miR-34a LC In vivo [143]
GMS and SPC SED N.A. AMO LC In vitro [144]
STAT3 decoy
solvent diffusion
GMS and soya lecithin N.A. oligodeoxynu- OC In vivo [135]
method
cleotides
Cetyl palmitate and
melt-emulsification siRNA-EGFR
Cremephor RH 40, Peceol, N.A. GBM In vivo [145]
technique siRNA-PD-L1
and propylene glycol
Abbreviations: Lipid: 3β-[N-(N0 ,N0 -dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol), 1,2-distearoyl-
sn-glycero-3-phosphoethanolamine (DSPE), 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP), l-α-
Phosphatidylcholine (αPC), 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), Glycerol Monostearate (GMS),
Soy phosphatidylcholine (SPC). Stearic Acid (SA), Glycerol Monostearate (GMS), Palmitic acid (PA), DL-α-
Tocopherol methoxypolyethylene glycol succinate (TPGS), Soy phosphatidylcholine (SPC), Octadecylamine (Oda),
Cardiolipin (CL), Hydrogenated soya phosphatidylcholine (HSPC). Method: High Shear Homogenization (HSH),
Hot High-Pressure Homogenization (HHPH), Solvent Emulsification-Evaporation (SEE), Solvent Emulsification-
Diffusion (SED), Solvent Injection (SI). Drug: Paclitaxel (PTX), α-tocopherol succinate-cisplatin (TSC), Doxorubicin
hydrochloride (DOX), Superparamagnetic iron oxide nanoparticles (SPIONs), Etoposide (ETP). Cancer: Cervical
Cancer (CC), Lung Cancer (LC), Gastric Cancer (GC), Colorectal Cancer (CRC), Glioblastoma (GBM), Breast
Cancer (BC), Hepatocarcinoma (HC), Ovarian Cancer (OC).

9. Other Applications
9.1. Immunotherapy
The idea of using a patient’s immune system to fight cancer lead to the concept of
cancer immunotherapy. In the last years, this approach increased exponentially, becoming
an important and promising alternative at the clinical level.
Cancer cells have the capacity to make themselves invisible to the immune system
by selecting for certain genetic changes, by having proteins on their surface that turn off
immune cells (e.g., PD-L1), or by inducing changes in the surrounding stroma. Different
approaches have been proposed in this scenario to activate the immune response. This
includes monoclonal antibodies, immune checkpoint inhibitors, adaptive T-cell transfer,
and cancer vaccination [146]. Specifically, here are limited studies in the literature related
to cancer immunotherapy with SLNs.
G. Erel-Akbaba et al. [145] developed an iRGD (CCRGDKGPDC)-conjugated SLN
to deliver siRNA against both epidermal growth factor receptor (EGFR) and PD-L1 for
glioblastoma treatment. Moreover, 5 Gy radiation pre-treatment led to enhanced trans-
 Pharmaceutics 2023, 15, 831 19 of 28

, x FOR PEER REVIEW 20 of 29

portation of SLNs to glioblastomas, yielding activation of an immune response, slower
tumor growth, and prolonged mouse survival (Figure 4).

Figure 4. Cont.
Pharmaceutics 2023, 15, 831 20 of 28

Figure 4. RadiationFigure
primes glioblastoma
4. Radiation for SLNs for
primes glioblastoma targeted delivery.
SLNs targeted (a)(a)
delivery. Mice
Micebearing GL261-Fluc
bearing GL261-Fluc
tumors were irradiated
tumors (or not
were as control)
irradiated (or notand, threeand,
as control) days later,
three daysreceived retro-orbital
later, received administration
retro-orbital administration
of f(SLNs)-iRGD:Cy5.5 or PBS control. Twenty-four hours
of f(SLNs)-iRGD:Cy5.5 or PBS control. Twenty-four hours post-injection, tumor volume post-injection, tumor volume was first eval-first
was
uated by Fluc imaging (left), and brains were removed and imaged ex vivo for Cy5.5 (middle). The
evaluated by Fluc imaging (left), and brains were removed and imaged ex vivo for Cy5.5 (middle).
mean fluorescence intensity was calculated and normalized to tumor volume (right; n = 3, * p < 0.05).
The mean fluorescence intensity
(b–f) Mice bearing was calculated
GL261-Fluc and irradiated
tumors were normalized (or nottoas tumor
a control)volume (right; ninjected
and retro-orbitally = 3, * p <
0.05). (b–f) Mice bearing GL261-Fluc
with either tumors were
f(SLNs)-iRGD:siCTRL, irradiated (or not as
f(SLNs)-iRGD:siEGFR/PDL1, or a control) and retro-orbitally
f(SLNs)-scriRGD:siEGFR/PDL1
injected with eitheraccording to f(SLNs)-iRGD:siCTRL,
the scheme in (b). Tumor growthf(SLNs)-iRGD:siEGFR/PDL1,
was monitored weekly by Fluc imaging, or f(SLNs)-
and survival
was recorded. Images from a representative mouse from each
scriRGD:siEGFR/PDL1 according to the scheme in (b). Tumor growth was monitored weekly by group are shown over time (c). Quan-
tification ofwas
Fluc imaging, and survival tumor-associated
recorded. ImagesFluc radiance
from intensity with data presented
a representative mouse from±each
as mean SD; * pgroup
< 0.05 are
control vs. f(SLNs)-iRGD:siRNA and control vs. IR + f(SLNs)-scriRGD:siRNA; ** p < 0.01 control
shown over time (c). Quantification of tumor-associated Fluc radiance intensity with data presented
vs. IR + f(SLNs)-iRGD:siRNA by ANOVA (d). Kaplan–Meier survival curves are shown (n = 5–12);
as mean ± SD; *** pp <<0.01 0.05 control
control vs. f(SLNs)-iRGD:siRNA
vs. f(SLNs)-iRGD:siRNA; ** p < 0.01 controland vs. control vs. IR + f(SLNs)-
IR + f(SLNs)-scriRGD:siRNA;
scriRGD:siRNA; *****p p<<0.010.001 control
control [Link].
IR +IR + f(SLNs)-iRGD:siRNA
f(SLNs)-iRGD:siRNA; ** p < 0.01 IRby+ ANOVA (d). Kaplan–Meier
f(SLNs)-scriRGD:siRNA vs. IR
+ f(SLNs)-iRGD:siRNA; by Mantel–Cox (log-rank) test (e). H&E staining and immunohistological
analysis using anti-PD-L1 and anti-CD8 antibodies on brain sections of a representative mouse from
each group (DAPI, blue; PD-L1, green; and CD8, red) (f). Reprinted with permission of American
Chemical Society from [145].

9.2. Imaging
The advances in imaging techniques acquired major importance in the cancer field
since they allow the achievement of an accurate early diagnosis and monitoring of the
patient during and after the treatment. This can substantially impact the treatment efficacy
and patient survival [147]. There are multiple techniques for imaging, and some of them
need contrast agents for better differentiation between the tissues. The contrast agents
are administered intravenously, being one of their major issues the lack of specificity
to the site of interest. J. Sun et al. [55] have developed SLNs loaded with gadolinium
diethylenetriaminepentaacetic acid (Gd-DTPA), a widely used contrast agent in magnetic
resonance imaging (MRI), for colon cancer imaging. Due to the encapsulation of the Gd-
DTPA, they have been able to increase its cellular uptake and the tumor’s resolution and
differentiation, and limits. Also, an in vivo biodistribution of SLNs-Gd-DTPA showed a
high accumulation in the tumor site.

9.3. Theragnostic
Theragnostic consists of the combination of treatment and diagnosis in the same
system. Cancer treatment is a promising new strategy that will contribute not only to
early tumor diagnosis but also allow constant monitoring of the treatment’s effective-
Pharmaceutics 2023, 15, 831 21 of 28

ness [148,149]. J. Kulbacka et al. [150] and Y. Kuang et al. [151] developed SLNs for cancer
theragnostics. J. Kulbacka et al. [150] developed cetyl palmitate-based SLNs loaded with
cyanine IR-780 and flavonoid derivates for colon cancer. The flavonoid was used as the
drug in this nanoformulation and the cyanine IR-780 as a diagnostic agent and a photo-
sensitizer. The encapsulation of cyanine IR-780 decreased its cytotoxicity and increased its
efficacy. Y. Kuang et al. [151] also loaded IR-780 in SLNs for phototherapy and imaging.
This nanoformulation enabled the specific treatment due to the guided imaging that allows
light activation in the area of interest. Finally, K.H. Bae et al. [152] developed SLNs loaded
with quantum dots PTX and siRNA-bcl2 for the synergistic treatment and in situ lung
cancer imaging, paving the way for SLNss to be used as multifunctional and optically
traceable nanocarriers for anticancer theragnostics.

10. Conclusions
SLNs have been reported to be effective multitasking nanoDDS for cancer treatment
since they are demonstrated to be a promising approach to increasing the therapeutic index
of the delivered cargo. Currently, multiple SLNs-based formulations are proposed for
different cancer treatments with various loading cargos, such as chemotherapeutic drugs
and genetic material. Also, modifying the SLNs surface enables effective active targeting
against the cells/tissues of interest, increasing the specificity of the treatment and reducing
the secondary adverse effects.
Apart from the treatment applications, SLNs also demonstrated great potential as diag-
nostic tools, openings the possibility of creating multifunctional nanoDDS for theragnostics.
One of the biggest advantages of using SLNs is the possibility of using biocompatible,
non-immunogenic, low-cost materials and production methods easily scalable for industrial
scale. On the other hand, some limitations related to SLNs, mainly cargo and stability issues,
should be overcome. In this sense is expected that the research in the field of SLNs-based
nanosystems will keep evolving and that, in the future, more formulations will reach the
clinical phases.

Author Contributions: Conceptualization, D.R. and F.A.; writing—original draft preparation, J.G.-C.,
M.V.-H., D.R. and F.A.; writing—review and editing, D.R., F.A. and I.A.; funding acquisition, I.A. All
authors have read and agreed to the published version of the manuscript.
Funding: The present work as supported by the SGR grant from the Catalan Government (2021
SGR 01173), the Spanish Ministry of Science and Innovation (MICINN, RTC2019-006809-1), and
the Networking Research Centre on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN)
which is financed by the Instituto de Salud Carlos III (ISCIII) with assistance from the European
Regional Development Fund (ERDF, “A way to make Europe”/“Investing in your future”). FA was
supported by an investigator grant from Asociación Española Contra el Cáncer (AECC), Spain.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Wei, G.; Wang, Y.; Yang, G.; Ju, R. Recent progress in nanomedicine for enhanced cancer chemotherapy. Theranostics 2021, 11,
6370–6392. [CrossRef] [PubMed]
2. Bayón-Cordero, L.; Alkorta, I.; Arana, L. Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs.
Nanomaterials 2019, 9, 474. [CrossRef] [PubMed]
3. Müller, R.H.; Mäder, K.; Gohla, S. Solid lipid nanoparticles (SLN) for controlled drug delivery–a review of the state of the art. Eur.
J. Pharm. Biopharm. 2000, 50, 161–177. [CrossRef]
4. Mishra, V.; Bansal, K.K.; Verma, A.; Yadav, N.; Thakur, S.; Sudhakar, K.; Rosenholm, J.M. Solid Lipid Nanoparticles: Emerging
Colloidal Nano Drug Delivery Systems. Pharmaceutics 2018, 10, 191. [CrossRef]
Pharmaceutics 2023, 15, 831 22 of 28

5. Musicanti, C.; Gasco, P. Solid Lipid Nanoparticles–SLN. In Encyclopedia of Nanotechnology; Bhushan, B., Ed.; Springer: Dordrecht,
The Netherlands, 2012; pp. 2471–2487.
6. Mehnert, W.; Mäder, K. Solid lipid nanoparticles: Production, characterization and applications. Adv. Drug Deliv. Rev. 2001, 47,
165–196. [CrossRef] [PubMed]
7. Hernández-Esquivel, R.-A.; Navarro-Tovar, G.; Zárate-Hernández, E.; Aguirre-Bañuelos, P. Solid Lipid Nanoparticles (SLN). In
Nanocomposite Materials for Biomedical and Energy Storage Applications; Sharma, A., Ed.; IntechOpen Limited: London, UK, 2022.
8. Prabhakaran, E.; Hasan, A.; Karunanidhi, P. Solid lipid nanoparticles: A review. Sci. Revs. Chem. Commun. 2012, 2, 80–102.
9. Suk, J.S.; Xu, Q.; Kim, N.; Hanes, J.; Ensign, L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene
delivery. Adv. Drug Deliv. Rev. 2016, 99, 28–51. [CrossRef] [PubMed]
10. Satapathy, M.K.; Yen, T.L.; Jan, J.S.; Tang, R.D.; Wang, J.Y.; Taliyan, R.; Yang, C.H. Solid Lipid Nanoparticles (SLNs): An Advanced
Drug Delivery System Targeting Brain through BBB. Pharmaceutics 2021, 13, 1183. [CrossRef]
11. Thi, T.T.H.; Suys, E.J.A.; Lee, J.S.; Nguyen, D.H.; Park, K.D.; Truong, N.P. Lipid-Based Nanoparticles in the Clinic and Clinical
Trials: From Cancer Nanomedicine to COVID-19 Vaccines. Vaccines 2021, 9, 359. [CrossRef]
12. Ghasemiyeh, P.; Mohammadi-Samani, S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery
systems: Applications, advantages and disadvantages. Res. Pharm. Sci. 2018, 13, 288–303.
13. Souto, E.B.; Baldim, I.; Oliveira, W.P.; Rao, R.; Yadav, N.; Gama, F.M.; Mahant, S. SLN and NLC for topical, dermal, and
transdermal drug delivery. Expert Opin. Drug Deliv. 2020, 17, 357–377. [CrossRef] [PubMed]
14. Fiolet, T.; Kherabi, Y.; MacDonald, C.J.; Ghosn, J.; Peiffer-Smadja, N. Comparing COVID-19 vaccines for their characteristics, efficacy
and effectiveness against SARS-CoV-2 and variants of concern: A narrative review. Clin. Microbiol. Infect. 2022, 28, 202–221. [CrossRef]
15. Zieneldien, T.; Kim, J.; Cao, J.; Cao, C. COVID-19 Vaccines: Current Conditions and Future Prospects. Biology 2021, 10, 960.
[CrossRef] [PubMed]
16. Khairnar, S.V.; Pagare, P.; Thakre, A.; Nambiar, A.R.; Junnuthula, V.; Abraham, M.C.; Kolimi, P.; Nyavanandi, D.; Dyawanapelly,
S. Review on the Scale-Up Methods for the Preparation of Solid Lipid Nanoparticles. Pharmaceutics 2022, 14, 1886. [CrossRef]
[PubMed]
17. Sastri, K.T.; Radha, G.V.; Pidikiti, S.; Vajjhala, P. Solid lipid nanoparticles: Preparation techniques, their characterization, and an
update on recent studies. JAPS 2020, 10, 126–141. [CrossRef]
18. Schwarz, C.; Mehnert, W.; Lucks, J.S.; Müller, R.H. Solid lipid nanoparticles (SLN) for controlled drug delivery. I. Production,
characterization and sterilization. J. Control. Release 1994, 30, 83–96. [CrossRef]
19. Jenning, V.; Thünemann, A.F.; Gohla, S.H. Characterisation of a novel solid lipid nanoparticle carrier system based on binary
mixtures of liquid and solid lipids. Int. J. Pharm. 2000, 199, 167–177. [CrossRef]
20. Zur Mühlen, A.; Schwarz, C.; Mehnert, W. Solid lipid nanoparticles (SLN) for controlled drug delivery–drug release and release
mechanism. Eur. J. Pharm. Biopharm. 1998, 45, 149–155. [CrossRef]
21. Pooja, D.; Tunki, L.; Kulhari, H.; Reddy, B.B.; Sistla, R. Optimization of solid lipid nanoparticles prepared by a single emulsification-
solvent evaporation method. Data Brief 2016, 6, 15–19. [CrossRef]
22. Mukherjee, S.; Ray, S.; Thakur, R.S. Solid Lipid Nanoparticles: A Modern Formulation Approach in Drug Delivery System. Indian
J. Pharm. Sci. 2009, 71, 349–358. [CrossRef]
23. Sjöström, B.; Bergenståhl, B. Preparation of submicron drug particles in lecithin-stabilized o/w emulsions I. Model studies of the
precipitation of cholesteryl acetate. Int. J. Pharm. 1992, 88, 53–62. [CrossRef]
24. Hu, F.Q.; Yuan, H.; Zhang, H.H.; Fang, M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent
diffusion method in aqueous system and physicochemical characterization. Int. J. Pharm. 2002, 239, 121–128. [CrossRef] [PubMed]
25. Schubert, M.A.; Müller-Goymann, C.C. Solvent injection as a new approach for manufacturing lipid nanoparticles–evaluation of
the method and process parameters. Eur. J. Pharm. Biopharm. 2003, 55, 125–131. [CrossRef] [PubMed]
26. Wang, T.; Wang, N.; Zhang, Y.; Shen, W.; Gao, X.; Li, T. Solvent Injection-Lyophilization of Tert-Butyl alcohol/water Cosolvent
Systems for the Preparation of Drug-Loaded Solid Lipid Nanoparticles. Colloids Surf. B Biointerfaces 2010, 79, 254–261. [CrossRef]
[PubMed]
27. Battaglia, L.; Gallarate, M.; Cavalli, R.; Trotta, M. Solid Lipid Nanoparticles Produced Through a Coacervation Method. J.
Microencapsul. 2010, 27, 78–85. [CrossRef]
28. Shah, R.; Eldridge, D.; Palombo, E.; Harding, I. Production Techniques. In Lipid Nanoparticles: Production, Characterization and
Stability; Springer International Publishing: Cham, Switzerland, 2015; pp. 23–43.
29. Liu, X.; Meng, H. Consideration for the scale-up manufacture of nanotherapeutics—A critical step for technology transfer. View
2021, 2, 1–11. [CrossRef]
30. Arduino, I.; Liu, Z.; Rahikkala, A.; Figueiredo, P.; Correia, A.; Cutrignelli, A.; Denora, N.; Santos, H.A. Preparation of cetyl
palmitate-based PEGylated solid lipid nanoparticles by microfluidic technique. Acta Biomater 2021, 121, 566–578. [CrossRef]
31. Andrade, L.N.; Oliveira, D.M.L.; Chaud, M.V.; Alves, T.F.R.; Nery, M.; da Silva, C.F.; Gonsalves, J.K.C.; Nunes, R.S.; Corrêa, C.B.;
Amaral, R.G.; et al. Praziquantel-Solid Lipid Nanoparticles Produced by Supercritical Carbon Dioxide Extraction: Physicochemical
Characterization, Release Profile, and Cytotoxicity. Molecules 2019, 24, 3881. [CrossRef]
Pharmaceutics 2023, 15, 831 23 of 28

32. Montoto, S.S.; Muraca, G.; Ruiz, M.E. Solid Lipid Nanoparticles for Drug Delivery: Pharmacological and Biopharmaceutical
Aspects. Front. Mol. Biosci. 2020, 7, 587997. [CrossRef]
33. Pardeike, J.; Hommoss, A.; Müller, R.H. Lipid Nanoparticles (SLN, NLC) in Cosmetic and Pharmaceutical Dermal Products. Int. J.
Pharm. 2009, 366, 170–184. [CrossRef]
34. Schäfer-Korting, M.; Mehnert, W.; Korting, H.C. Lipid Nanoparticles for Improved Topical Application of Drugs for Skin Diseases.
Adv. Drug Deliv. Rev. 2007, 59, 427–443. [CrossRef] [PubMed]
35. Jose, J.; Netto, G. Role of Solid Lipid Nanoparticles as Photoprotective Agents in Cosmetics. J. Cosmet. Dermatol. 2019, 18, 315–321.
[CrossRef] [PubMed]
36. Ozeki, T.; Beppu, S.; Mizoe, T.; Takashima, Y.; Yuasa, H.; Okada, H. Preparation of Two-Drug Composite Microparticles to
Improve the Dissolution of Insoluble Drug in Water for Use With a 4-fluid Nozzle Spray Drier. J. Control. Release Off. J. Control.
Release Soc. 2005, 107, 387–394. [CrossRef] [PubMed]
37. Üner, M.; Yener, G. Importance of solid lipid nanoparticles (SLN) in various administration routes and future perspectives. Int. J.
Nanomed. 2007, 2, 289–300.
38. Jawahar, N.; Reddy, G. Nanoparticles: A novel pulmonary drug delivery system for tuberculosis. J. Pharm. Sci. Res. 2012, 4,
1901–1906.
39. Pandey, V.; Gajbhiye, K.R.; Soni, V. Lactoferrin-appended Solid Lipid Nanoparticles of Paclitaxel for Effective Management of
Bronchogenic Carcinoma. Drug Deliv. 2015, 22, 199–205. [CrossRef] [PubMed]
40. Weber, S.; Zimmer, A.; Pardeike, J. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for Pulmonary
Application: A Review of the State of the Art. Eur. J. Pharm. Biopharm. Off. J. Arb. Fur Pharm. Verfahr. E.V 2014, 86, 7–22.
[CrossRef] [PubMed]
41. Videira, M.; Almeida, A.J.; Fabra, A. Preclinical Evaluation of a Pulmonary Delivered Paclitaxel-Loaded Lipid Nanocarrier
Antitumor Effect. Nanomed. Nanotechnol. Biol. Med. 2012, 8, 1208–1215. [CrossRef] [PubMed]
42. Hu, L.; Jia, Y.; WenDing. Preparation and Characterization of Solid Lipid Nanoparticles Loaded With Epirubicin for Pulmonary
Delivery. Die Pharm. 2010, 65, 585–587. [CrossRef]
43. Dharmala, K.; Yoo, J.W.; Lee, C.H. Development of chitosan-SLN Microparticles for Chemotherapy: In Vitro Approach Through
Efflux-Transporter Modulation. J. Control. Release Off. J. Control. Release Soc. 2008, 131, 190–197. [CrossRef]
44. Liu, J.; Gong, T.; Fu, H.; Wang, C.; Wang, X.; Chen, Q.; Zhang, Q.; He, Q.; Zhang, Z. Solid Lipid Nanoparticles for Pulmonary
Delivery of Insulin. Int. J. Pharm. 2008, 356, 333–344. [CrossRef] [PubMed]
45. Makled, S.; Nafee, N.; Boraie, N. Nebulized Solid Lipid Nanoparticles for the Potential Treatment of Pulmonary Hypertension via
Targeted Delivery of phosphodiesterase-5-inhibitor. Int. J. Pharm. 2017, 517, 312–321. [CrossRef]
46. Negi, J.S.; Chattopadhyay, P.; Sharma, A.K.; Ram, V. Development of Solid Lipid Nanoparticles (SLNs) of Lopinavir Using Hot
Self Nano-Emulsification (SNE) Technique. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2013, 48, 231–239. [CrossRef] [PubMed]
47. Silva, A.C.; Kumar, A.; Wild, W.; Ferreira, D.; Santos, D.; Forbes, B. Long-term Stability, Biocompatibility and Oral Delivery
Potential of Risperidone-Loaded Solid Lipid Nanoparticles. Int. J. Pharm. 2012, 436, 798–805. [CrossRef]
48. Singh, H.; Bhandari, R.; Kaur, I.P. Encapsulation of Rifampicin in a Solid Lipid Nanoparticulate System to Limit Its Degradation
and Interaction With Isoniazid at Acidic pH. Int. J. Pharm. 2013, 446, 106–111. [CrossRef] [PubMed]
49. Cirri, M.; Mennini, N.; Maestrelli, F.; Mura, P.; Ghelardini, C.; Di Cesare Mannelli, L. Development and in Vivo Evaluation of
an Innovative "Hydrochlorothiazide-in Cyclodextrins-in Solid Lipid Nanoparticles" Formulation With Sustained Release and
Enhanced Oral Bioavailability for Potential Hypertension Treatment in Pediatrics. Int. J. Pharm. 2017, 521, 73–83. [CrossRef]
50. Strettoi, E.; Gargini, C.; Novelli, E.; Sala, G.; Piano, I.; Gasco, P.; Ghidoni, R. Inhibition of Ceramide Biosynthesis Preserves
Photoreceptor Structure and Function in a Mouse Model of Retinitis Pigmentosa. Proc. Natl. Acad. Sci. USA 2010, 107, 18706–18711.
[CrossRef]
51. Liu, S.; Han, X.; Liu, H.; Zhao, Y.; Li, H.; Rupenthal, I.; Lv, Z.; Chen, Y.; Yang, F.; Ping, Q.; et al. Incorporation of Ion Exchange
Functionalized-Montmorillonite Into Solid Lipid Nanoparticles With Low Irritation Enhances Drug Bioavailability for Glaucoma
Treatment. Drug Deliv. 2020, 27, 652–661. [CrossRef]
52. Chetoni, P.; Burgalassi, S.; Monti, D.; Tampucci, S.; Tullio, V.; Cuffini, A.M.; Muntoni, E.; Spagnolo, R.; Zara, G.P.; Cavalli, R. Solid
Lipid Nanoparticles as Promising Tool for Intraocular Tobramycin Delivery: Pharmacokinetic Studies on Rabbits. Eur. J. Pharm.
Biopharm. Off. J. Arb. Fur Pharm. Verfahr. E.V 2016, 109, 214–223. [CrossRef]
53. Soni, S.; Ruhela, R.K.; Medhi, B. Nanomedicine in Central Nervous System (CNS) Disorders: A Present and Future Prospective.
Adv. Pharm. Bull. 2016, 6, 319–335. [CrossRef]
54. Gasco, M.R.; Priano, L.; Zara, G.P. Chapter 10—Solid Lipid Nanoparticles and Microemulsions for Drug Delivery The CNS. Prog.
Brain Res. 2009, 180, 181–192. [CrossRef] [PubMed]
55. Sun, J.; Zhang, S.; Jiang, S.; Bai, W.; Liu, F.; Yuan, H.; Ji, J.; Luo, J.; Han, G.; Chen, L.; et al. Gadolinium-Loaded Solid Lipid
Nanoparticles as a Tumor-Absorbable Contrast Agent for Early Diagnosis of Colorectal Tumors Using Magnetic Resonance
Colonography. J. Biomed. Nanotechnol. 2016, 12, 1709–1723. [CrossRef]
Pharmaceutics 2023, 15, 831 24 of 28

56. Amiri, M.; Jafari, S.; Kurd, M.; Mohamadpour, H.; Khayati, M.; Ghobadinezhad, F.; Tavallaei, O.; Derakhshankhah, H.; Sadegh
Malvajerd, S.; Izadi, Z. Engineered Solid Lipid Nanoparticles and Nanostructured Lipid Carriers as New Generations of
Blood-Brain Barrier Transmitters. ACS Chem. Neurosci. 2021, 12, 4475–4490. [CrossRef] [PubMed]
57. Costa, C.P.; Moreira, J.N.; Sousa Lobo, J.M.; Silva, A.C. Intranasal delivery of nanostructured lipid carriers, solid lipid nanoparticles
and nanoemulsions: A current overview of. Acta Pharm. Sin. B 2021, 11, 925–940. [CrossRef]
58. Shah, R.M.; Rajasekaran, D.; Ludford-Menting, M.; Eldridge, D.S.; Palombo, E.A.; Harding, I.H. Transport of stearic acid-based
solid lipid nanoparticles (SLNs) into human epithelial cells. Colloids Surf. B Biointerfaces 2016, 140, 204–212. [CrossRef]
59. El-Housiny, S.; Shams Eldeen, M.A.; El-Attar, Y.A.; Salem, H.A.; Attia, D.; Bendas, E.R.; El-Nabarawi, M.A. Fluconazole-loaded
solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: Formulation and clinical study. Drug Deliv. 2018, 25, 78–90.
[CrossRef] [PubMed]
60. University, M. Clinical Assessment of Oxiconazole Nitrate Solid Lipid Nanoparticles Loaded Gel. NCT03823040. Available online:
[Link] (accessed on 20 February 2023).
61. Mistraletti, G.; Paroni, R.; Umbrello, M.; Moro Salihovic, B.; Coppola, S.; Froio, S.; Finati, E.; Gasco, P.; Savoca, A.; Manca, D.; et al.
Different routes and formulations of melatonin in critically ill patients. A pharmacokinetic randomized study. Clin. Endocrinol.
(Oxf.) 2019, 91, 209–218. [CrossRef] [PubMed]
62. Insights, F.B. Lipid Nanoparticles Market Research Report. Available online: [Link]
segmentation/lipid-nanoparticles-market-106960 (accessed on 19 February 2023).
63. Xie, B.; Wang, H.; Wang, H.; Liu, Y.; Yu, M. Sorafenib Solid Lipid Nanoparticles and Preparation Method Thereof. CN105326812A,
28 October 2015. Available online: [Link] (accessed on 19 February 2023).
64. Yu, L.; Tian, L.; Zhao, Y.; Yang, C.; Su, J.; Sun, W.; Du, Y.; Zhou, T. Folic Acid Targeting Silymarin Solid Lipid Nanosphere
Preparation Method. CN105708803A, 4 December 2014. Available online: [Link]
(accessed on 19 February 2023).
65. Kim, J.; Kim, H.; Cha, J.; Jeb, A.; Quresh, O.S. Solid Lipid Nanoparticles Composition Comprising Docetaxel for Oral Formulation.
KR101799539B1, 7 February 2014. Available online: [Link] (accessed on
19 February 2023).
66. Paliwal, R.; Paliwal, S.R.; Kenwat, R.; Kurmi, B.D.; Sahu, M.K. Solid lipid nanoparticles: A review on recent perspectives and
patents. Expert Opin. Pat. 2020, 30, 179–194. [CrossRef]
67. Leiva, M.C.; Ortiz, R.; Contreras-Cáceres, R.; Perazzoli, G.; Mayevych, I.; López-Romero, J.M.; Sarabia, F.; Baeyens, J.M.; Melguizo,
C.; Prados, J. Tripalmitin Nanoparticle Formulations Significantly Enhance Paclitaxel Antitumor Activity against Breast and Lung
Cancer Cells in Vitro. Sci. Rep. 2017, 7, 13506. [CrossRef]
68. 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]
69. Kapse-Mistry, S.; Govender, T.; Srivastava, R.; Yergeri, M. Nanodrug delivery in reversing multidrug resistance in cancer cells.
Front. Pharmacol. 2014, 5, 159. [CrossRef] [PubMed]
70. Kartal-Yandim, M.; Adan-Gokbulut, A.; Baran, Y. Molecular mechanisms of drug resistance and its reversal in cancer. Crit. Rev.
Biotechnol. 2016, 36, 716–726. [CrossRef] [PubMed]
71. Wang, W.; Zhou, M.; Xu, Y.; Peng, W.; Zhang, S.; Li, R.; Zhang, H.; Cheng, S.; Wang, Y.; Wei, X.; et al. Resveratrol-Loaded TPGS-
Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer. Front. Bioeng. Biotechnol. 2021, 9, 762489.
[CrossRef] [PubMed]
72. Guney Eskiler, G.; Cecener, G.; Dikmen, G.; Egeli, U.; Tunca, B. Solid Lipid Nanoparticles: Reversal of Tamoxifen Resistance in
Breast Cancer. Eur. J. Pharm. Sci. Off. J. Eur. Fed. Pharm. Sci. 2018, 120, 73–88. [CrossRef] [PubMed]
73. Stella, B.; Peira, E.; Dianzani, C.; Gallarate, M.; Battaglia, L.; Gigliotti, C.L.; Boggio, E.; Dianzani, U.; Dosio, F. Development and
Characterization of Solid Lipid Nanoparticles Loaded With a Highly Active Doxorubicin Derivative. Nanomaterials 2018, 8, 110.
[CrossRef]
74. Grillone, A.; Battaglini, M.; Moscato, S.; Mattii, L.; de Julián Fernández, C.; Scarpellini, A.; Giorgi, M.; Sinibaldi, E.; Ciofani,
G. Nutlin-loaded Magnetic Solid Lipid Nanoparticles for Targeted Glioblastoma Treatment. Nanomedicine 2019, 14, 727–752.
[CrossRef]
75. Liu, T.I.; Lu, T.Y.; Chang, S.H.; Shen, M.Y.; Chiu, H.C. Dual Stimuli-Guided Lipid-Based Delivery System of Cancer Combination
Therapy. J. Control. Release Off. J. Control. Release Soc. 2020, 318, 16–24. [CrossRef] [PubMed]
76. Rehman, M.; Ihsan, A.; Madni, A.; Bajwa, S.Z.; Shi, D.; Webster, T.J.; Khan, W.S. Solid Lipid Nanoparticles for Thermoresponsive
Targeting: Evidence From Spectrophotometry, Electrochemical, and Cytotoxicity Studies. Int. J. Nanomed. 2017, 12, 8325–8336.
[CrossRef] [PubMed]
77. Zheng, G.; Zheng, M.; Yang, B.; Fu, H.; Li, Y. Improving Breast Cancer Therapy Using Doxorubicin Loaded Solid Lipid
Nanoparticles: Synthesis of a Novel Arginine-Glycine-Aspartic Tripeptide Conjugated, pH Sensitive Lipid and Evaluation of the
Nanomedicine in Vitro and in Vivo. Biomed. Pharm. 2019, 116, 109006. [CrossRef]
Pharmaceutics 2023, 15, 831 25 of 28

78. Baek, J.S.; Na, Y.G.; Cho, C.W. Sustained Cytotoxicity of Wogonin on Breast Cancer Cells by Encapsulation in Solid Lipid
Nanoparticles. Nanomaterials 2018, 8, 159. [CrossRef]
79. Wang, W.; Chen, T.; Xu, H.; Ren, B.; Cheng, X.; Qi, R.; Liu, H.; Wang, Y.; Yan, L.; Chen, S.; et al. Curcumin-Loaded Solid Lipid
Nanoparticles Enhanced Anticancer Efficiency in Breast Cancer. Molecules 2018, 23, 1578. [CrossRef] [PubMed]
80. Guorgui, J.; Wang, R.; Mattheolabakis, G.; Mackenzie, G.G. Curcumin Formulated in Solid Lipid Nanoparticles Has Enhanced
Efficacy in Hodgkin’s Lymphoma in Mice. Arch. Biochem. Biophys. 2018, 648, 12–19. [CrossRef] [PubMed]
81. Chirio, D.; Peira, E.; Dianzani, C.; Muntoni, E.; Gigliotti, C.L.; Ferrara, B.; Sapino, S.; Chindamo, G.; Gallarate, M. Development
of Solid Lipid Nanoparticles by Cold Dilution of Microemulsions: Curcumin Loading, Preliminary In Vitro Studies, and
Biodistribution. Nanomaterials 2019, 9, 230. [CrossRef] [PubMed]
82. Serini, S.; Cassano, R.; Corsetto, P.A.; Rizzo, A.M.; Calviello, G.; Trombino, S. Omega-3 PUFA Loaded in Resveratrol-Based Solid
Lipid Nanoparticles: Physicochemical Properties and Antineoplastic Activities in Human Colorectal Cancer Cells In Vitro. Int. J.
Mol. Sci. 2018, 19, 586. [CrossRef]
83. Rahiminejad, A.; Dinarvand, R.; Johari, B.; Nodooshan, S.J.; Rashti, A.; Rismani, E.; Mahdaviani, P.; Saltanatpour, Z.; Rahiminejad,
S.; Raigani, M.; et al. Preparation and Investigation of Indirubin-Loaded SLN Nanoparticles and Their Anti-Cancer Effects on
Human Glioblastoma U87MG Cells. Cell Biol. Int. 2019, 43, 2–11. [CrossRef]
84. Chen, Z.J.; Zhang, Z.; Xie, B.B.; Zhang, H.Y. Development and Evaluation of Topotecan Loaded Solid Lipid Nanoparticles: A
Study in Cervical Cancer Cell Lines. J. Photochem. Photobiol. B Biol. 2016, 165, 182–188. [CrossRef]
85. Guney Eskiler, G.; Cecener, G.; Egeli, U.; Tunca, B. Synthetically Lethal BMN 673 (Talazoparib) Loaded Solid Lipid Nanoparticles
for BRCA1 Mutant Triple Negative Breast Cancer. Pharm. Res. 2018, 35, 218. [CrossRef]
86. Rodenak-Kladniew, B.; Islan, G.A.; de Bravo, M.G.; Durán, N.; Castro, G.R. Design, Characterization and in Vitro Evaluation of
Linalool-Loaded Solid Lipid Nanoparticles as Potent Tool in Cancer Therapy. Colloids Surf. B Biointerfaces 2017, 154, 123–132.
[CrossRef]
87. Zhou, M.; Li, X.; Li, Y.; Yao, Q.; Ming, Y.; Li, Z.; Lu, L.; Shi, S. Ascorbyl Palmitate-Incorporated Paclitaxel-Loaded Composite
Nanoparticles for Synergistic Anti-Tumoral Therapy. Drug Deliv. 2017, 24, 1230–1242. [CrossRef]
88. Khallaf, R.A.; Salem, H.F.; Abdelbary, A. 5-Fluorouracil Shell-Enriched Solid Lipid Nanoparticles (SLN) for Effective Skin
Carcinoma Treatment. Drug Deliv. 2016, 23, 3452–3460. [CrossRef]
89. Bhushan, S.; Kakkar, V.; Pal, H.C.; Mondhe, D.M.; Kaur, I.P. The Augmented Anticancer Potential of AP9-cd Loaded Solid Lipid
Nanoparticles in Human Leukemia Molt-4 Cells and Experimental Tumor. Chem.-Biol. Interact. 2016, 244, 84–93. [CrossRef]
[PubMed]
90. Brezaniova, I.; Hruby, M.; Kralova, J.; Kral, V.; Cernochova, Z.; Cernoch, P.; Slouf, M.; Kredatusova, J.; Stepanek, P. Temoporfin-
loaded 1-tetradecanol-based Thermoresponsive Solid Lipid Nanoparticles for Photodynamic Therapy. J. Control. Release Off. J.
Control. Release Soc. 2016, 241, 34–44. [CrossRef] [PubMed]
91. Sguizzato, M.; Cortesi, R.; Gallerani, E.; Drechsler, M.; Marvelli, L.; Mariani, P.; Carducci, F.; Gavioli, R.; Esposito, E.; Bergamini, P.
Solid Lipid Nanoparticles for the Delivery of 1,3,5-triaza-7-phosphaadamantane (PTA) Platinum (II) Carboxylates. Mater. Sci.
Eng. C Mater. Biol. Appl. 2017, 74, 357–364. [CrossRef] [PubMed]
92. Arranja, A.; Gouveia, L.F.; Gener, P.; Rafael, D.F.; Pereira, C.; Schwartz, S.; Videira, M.A. Self-assembly PEGylation Assists
SLN-paclitaxel Delivery Inducing Cancer Cell Apoptosis Upon Internalization. Int. J. Pharm. 2016, 501, 180–189. [CrossRef]
[PubMed]
93. Alajami, H.N.; Fouad, E.A.; Ashour, A.E.; Kumar, A.; Yassin, A.E.B. Celecoxib-Loaded Solid Lipid Nanoparticles for Colon
Delivery: Formulation Optimization and In Vitro Assessment of Anti-Cancer Activity. Pharmaceutics 2022, 14, 131. [CrossRef]
94. Pi, C.; Zhao, W.; Zeng, M.; Yuan, J.; Shen, H.; Li, K.; Su, Z.; Liu, Z.; Wen, J.; Song, X.; et al. Anti-lung cancer effect of paclitaxel solid
lipid nanoparticles delivery system with curcumin as co-loading partner in vitro and in vivo. Drug Deliv. 2022, 29, 1878–1891.
[CrossRef]
95. Beg, S.; Malik, A.K.; Ansari, M.J.; Malik, A.A.; Ali, A.M.A.; Theyab, A.; Algahtani, M.; Almalki, W.H.; Alharbi, K.S.; Alenezi,
S.K.; et al. Systematic Development of Solid Lipid Nanoparticles of Abiraterone Acetate with Improved Oral Bioavailability and
Anticancer Activity for Prostate Carcinoma Treatment. ACS Omega 2022, 7, 16968–16979. [CrossRef]
96. Souto, E.B.; Doktorovova, S.; Campos, J.R.; Martins-Lopes, P.; Silva, A.M. Surface-tailored anti-HER2/neu-solid Lipid Nanoparti-
cles for Site-Specific Targeting MCF-7 and BT-474 Breast Cancer Cells. Eur. J. Pharm. Sci. 2019, 128, 27–35. [CrossRef]
97. Shi, S.; Zhou, M.; Li, X.; Hu, M.; Li, C.; Li, M.; Sheng, F.; Li, Z.; Wu, G.; Luo, M.; et al. Synergistic Active Targeting of Dually
Integrin αvβ3/CD44-targeted Nanoparticles to B16F10 Tumors Located at Different Sites of Mouse Bodies. J. Control. Release Off.
J. Control. Release Soc. 2016, 235, 1–13. [CrossRef]
98. Siddhartha, V.T.; Pindiprolu, S.K.S.S.; Chintamaneni, P.K.; Tummala, S.; Nandha Kumar, S. RAGE Receptor Targeted Bioconjuguate
Lipid Nanoparticles of Diallyl Disulfide for Improved Apoptotic Activity in Triple Negative Breast Cancer: In Vitro Studies. Artif.
Cells Nanomed. Biotechnol. 2018, 46, 387–397. [CrossRef]
99. Rosière, R.; Van Woensel, M.; Gelbcke, M.; Mathieu, V.; Hecq, J.; Mathivet, T.; Vermeersch, M.; Van Antwerpen, P.; Amighi, K.;
Wauthoz, N. New Folate-Grafted Chitosan Derivative To Improve Delivery of Paclitaxel-Loaded Solid Lipid Nanoparticles for
Lung Tumor Therapy by Inhalation. Mol. Pharm. 2018, 15, 899–910. [CrossRef]
Pharmaceutics 2023, 15, 831 26 of 28

100. Baek, J.S.; Cho, C.W. A Multifunctional Lipid Nanoparticle for Co-Delivery of Paclitaxel and Curcumin for Targeted Delivery and
Enhanced Cytotoxicity in Multidrug Resistant Breast Cancer Cells. Oncotarget 2017, 8, 30369–30382. [CrossRef] [PubMed]
101. Rajpoot, K.; Jain, S.K. Colorectal Cancer-Targeted Delivery of Oxaliplatin via Folic Acid-Grafted Solid Lipid Nanoparticles:
Preparation, Optimization, and in Vitro Evaluation. Artif. Cells Nanomed. Biotechnol. 2018, 46, 1236–1247. [CrossRef] [PubMed]
102. Tabatabaeain, S.F.; Karimi, E.; Hashemi, M. Satureja khuzistanica Essential Oil-Loaded Solid Lipid Nanoparticles Modified With
Chitosan-Folate: Evaluation of Encapsulation Efficiency, Cytotoxic and Pro-apoptotic Properties. Front. Chem. 2022, 10, 904973.
[CrossRef]
103. Soni, N.; Soni, N.; Pandey, H.; Maheshwari, R.; Kesharwani, P.; Tekade, R.K. Augmented Delivery of Gemcitabine in Lung Cancer
Cells Exploring Mannose Anchored Solid Lipid Nanoparticles. J. Colloid Interface Sci. 2016, 481, 107–116. [CrossRef] [PubMed]
104. Garg, N.K.; Singh, B.; Jain, A.; Nirbhavane, P.; Sharma, R.; Tyagi, R.K.; Kushwah, V.; Jain, S.; Katare, O.P. Fucose Decorated
Solid-Lipid Nanocarriers Mediate Efficient Delivery of Methotrexate in Breast Cancer Therapeutics. Colloids Surf. B Biointerfaces
2016, 146, 114–126. [CrossRef]
105. Shen, M.Y.; Liu, T.I.; Yu, T.W.; Kv, R.; Chiang, W.H.; Tsai, Y.C.; Chen, H.H.; Lin, S.C.; Chiu, H.C. Hierarchically Targetable
Polysaccharide-Coated Solid Lipid Nanoparticles as an Oral Chemo/Thermotherapy Delivery System for Local Treatment of
Colon Cancer. Biomaterials 2019, 197, 86–100. [CrossRef]
106. Liu, B.; Han, L.; Liu, J.; Han, S.; Chen, Z.; Jiang, L. Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid
nanoparticles with synergistic antitumor activity against cervical cancer. Int. J. Nanomed. 2017, 12, 955–968. [CrossRef]
107. Kuo, Y.C.; Lee, C.H. Dual Targeting of Solid Lipid Nanoparticles Grafted With 83-14 MAb and anti-EGF Receptor for Malignant
Brain Tumor Therapy. Life Sci. 2016, 146, 222–231. [CrossRef]
108. Kuo, Y.C.; Wang, I.H. Enhanced Delivery of Etoposide Across the Blood-Brain Barrier to Restrain Brain Tumor Growth Using
Melanotransferrin Antibody—And Tamoxifen-Conjugated Solid Lipid Nanoparticles. J. Drug Target. 2016, 24, 645–654. [CrossRef]
109. Kadari, A.; Pooja, D.; Gora, R.H.; Gudem, S.; Kolapalli, V.R.M.; Kulhari, H.; Sistla, R. Design of Multifunctional Peptide
Collaborated and Docetaxel Loaded Lipid Nanoparticles for Antiglioma Therapy. Eur. J. Pharm. Biopharm. Off. J. Arb. Fur Pharm.
Verfahr. E.V 2018, 132, 168–179. [CrossRef] [PubMed]
110. Battaglia, L.; Muntoni, E.; Chirio, D.; Peira, E.; Annovazzi, L.; Schiffer, D.; Mellai, M.; Riganti, C.; Salaroglio, I.C.; Lanotte, M.;
et al. Solid Lipid Nanoparticles by Coacervation Loaded With a Methotrexate Prodrug: Preliminary Study for Glioma Treatment.
Nanomedicine 2017, 12, 639–656. [CrossRef] [PubMed]
111. Rajpoot, K.; Jain, S.K. Oral Delivery of pH-responsive Alginate Microbeads Incorporating Folic Acid-Grafted Solid Lipid
Nanoparticles Exhibits Enhanced Targeting Effect Against Colorectal Cancer: A Dual-Targeted Approach. Int. J. Biol. Macromol.
2020, 151, 830–844. [CrossRef] [PubMed]
112. Cavaco, M.C.; Pereira, C.; Kreutzer, B.; Gouveia, L.F.; Silva-Lima, B.; Brito, A.M.; Videira, M. Evading P-glycoprotein Mediated-Efflux
Chemoresistance Using Solid Lipid Nanoparticles. Eur. J. Pharm. Biopharm. Off. J. Arb. Fur Pharm. Verfahr. E.V 2017, 110, 76–84.
[CrossRef]
113. Wang, F.; Li, L.; Liu, B.; Chen, Z.; Li, C. Hyaluronic Acid Decorated Pluronic P85 Solid Lipid Nanoparticles as a Potential Carrier
to Overcome Multidrug Resistance in Cervical and Breast Cancer. Biomed. Pharm. 2017, 86, 595–604. [CrossRef]
114. Senthil Kumar, C.; Thangam, R.; Mary, S.A.; Kannan, P.R.; Arun, G.; Madhan, B. Targeted Delivery and Apoptosis Induction of
Trans-Resveratrol-Ferulic Acid Loaded Chitosan Coated Folic Acid Conjugate Solid Lipid Nanoparticles in Colon Cancer Cells.
Carbohydr. Polym. 2020, 231, 115682. [CrossRef]
115. Baek, J.S.; Kim, J.H.; Park, J.S.; Cho, C.W. Modification of Paclitaxel-Loaded Solid Lipid Nanoparticles With 2-hydroxypropyl-β-
cyclodextrin Enhances Absorption and Reduces Nephrotoxicity Associated With Intravenous Injection. Int. J. Nanomed. 2015, 10,
5397–5405. [CrossRef]
116. Pawar, H.; Surapaneni, S.K.; Tikoo, K.; Singh, C.; Burman, R.; Gill, M.S.; Suresh, S. Folic Acid Functionalized Long-Circulating
Co-Encapsulated Docetaxel and Curcumin Solid Lipid Nanoparticles: In Vitro Evaluation, Pharmacokinetic and Biodistribution
in Rats. Drug Deliv. 2016, 23, 1453–1468. [CrossRef]
117. Pooja, D.; Kulhari, H.; Kuncha, M.; Rachamalla, S.S.; Adams, D.J.; Bansal, V.; Sistla, R. Improving Efficacy, Oral Bioavailability,
and Delivery of Paclitaxel Using Protein-Grafted Solid Lipid Nanoparticles. Mol. Pharm. 2016, 13, 3903–3912. [CrossRef]
118. Kuo, Y.C.; Cheng, S.J. Brain Targeted Delivery of Carmustine Using Solid Lipid Nanoparticles Modified With Tamoxifen and
Lactoferrin for Antitumor Proliferation. Int. J. Pharm. 2016, 499, 10–19. [CrossRef] [PubMed]
119. Kuo, Y.C.; Ko, H.F. Targeting Delivery of Saquinavir to the Brain Using 83-14 Monoclonal Antibody-Grafted Solid Lipid
Nanoparticles. Biomaterials 2013, 34, 4818–4830. [CrossRef] [PubMed]
120. Shakib, Z.; Mahmoudi, A.; Moosavian, S.A.; Malaekeh-Nikouei, B. PEGylated solid lipid nanoparticles functionalized by aptamer
for targeted delivery of docetaxel in mice bearing C26 tumor. Drug Dev. Ind. Pharm. 2022, 48, 69–78. [CrossRef] [PubMed]
121. Granja, A.; Nunes, C.; Sousa, C.T.; Reis, S. Folate receptor-mediated delivery of mitoxantrone-loaded solid lipid nanoparticles to
breast cancer cells. Biomed. Pharm. 2022, 154, 113525. [CrossRef]
122. Kanasty, R.; Dorkin, J.R.; Vegas, A.; Anderson, D. Delivery Materials for siRNA Therapeutics. Nat. Mater. 2013, 12, 967–977.
[CrossRef] [PubMed]
123. Mohr, S.E.; Smith, J.A.; Shamu, C.E.; Neumüller, R.A.; Perrimon, N. RNAi Screening Comes of Age: Improved Techniques and
Complementary Approaches. Nat. Rev. Mol. Cell Biol. 2014, 15, 591–600. [CrossRef]
Pharmaceutics 2023, 15, 831 27 of 28

124. Bathula, S.R.; Huang, L. Gene Therapy with Plasmid DNA. Burg. Med. Chem. Drug Discov. 2010, 457–499. [CrossRef]
125. Moore, C.B.; Guthrie, E.H.; Huang, M.T.H.; Taxman, D.J. Short Hairpin RNA (shRNA): Design, Delivery, and Assessment of Gene
Knockdown. Methods Mol. Biol. 2010, 629, 141–158. [CrossRef]
126. Bartel, D.P. MicroRNAs: Genomics, Biogenesis, Mechanism, and Function. Cell 2004, 116, 281–297. [CrossRef]
127. Kapoor, M.; Burgess, D.J.; Patil, S.D. Physicochemical Characterization Techniques for Lipid Based Delivery Systems for siRNA.
Int. J. Pharm. 2012, 427, 35–57. [CrossRef]
128. Pillai, R.S.; Bhattacharyya, S.N.; Filipowicz, W. Repression of Protein Synthesis by miRNAs: How Many Mechanisms? Trends Cell
Biol. 2007, 17, 118–126. [CrossRef]
129. Alvarez, J.P.; Pekker, I.; Goldshmidt, A.; Blum, E.; Amsellem, Z.; Eshed, Y. Endogenous and Synthetic microRNAs Stimulate
Simultaneous, Efficient, and Localized Regulation of Multiple Targets in Diverse Species. Plant Cell 2006, 18, 1134–1151. [CrossRef]
[PubMed]
130. Jackson, A.L.; Linsley, P.S. Recognizing and Avoiding siRNA Off-Target Effects for Target Identification and Therapeutic
Application. Nat. Rev. Drug Discov. 2010, 9, 57–67. [CrossRef] [PubMed]
131. Whitehead, K.A.; Langer, R.; Anderson, D.G. Knocking Down Barriers: Advances in siRNA Delivery. Nat. Rev. Drug Discov.
2009, 8, 129–138. [CrossRef]
132. Jin, J.; Bae, K.H.; Yang, H.; Lee, S.J.; Kim, H.; Kim, Y.; Joo, K.M.; Seo, S.W.; Park, T.G.; Nam, D.H. In Vivo Specific Delivery of c-Met
siRNA to Glioblastoma Using Cationic Solid Lipid Nanoparticles. Bioconjugate Chem. 2011, 22, 2568–2572. [CrossRef] [PubMed]
133. Botto, C.; Augello, G.; Amore, E.; Emma, M.R.; Azzolina, A.; Cavallaro, G.; Cervello, M.; Bondì, M.L. Cationic Solid Lipid
Nanoparticles as Non Viral Vectors for the Inhibition of Hepatocellular Carcinoma Growth by RNA Interference. J. Biomed.
Nanotechnol. 2018, 14, 1009–1016. [CrossRef] [PubMed]
134. Kotmakçı, M.; Çetintaş, V.B.; Kantarcı, A.G. Preparation and Characterization of Lipid nanoparticle/pDNA Complexes for STAT3
Downregulation and Overcoming Chemotherapy Resistance in Lung Cancer Cells. Int. J. Pharm. 2017, 525, 101–111. [CrossRef]
135. Zhang, X.; Lu, T.; Ma, Y.; Li, R.; Pang, Y.; Mao, H.; Liu, P. Novel Nanocomplexes Targeting STAT3 Demonstrate Promising
Anti-Ovarian Cancer Effects in vivo. Onco Targets 2020, 13, 5069–5082. [CrossRef]
136. Büyükköroğlu, G.; Şenel, B.; Başaran, E.; Yenilmez, E.; Yazan, Y. Preparation and in Vitro Evaluation of Vaginal Formulations
Including siRNA and Paclitaxel-Loaded SLNs for Cervical Cancer. Eur. J. Pharm. Biopharm. Off. J. Arb. Fur Pharm. Verfahr. E.V
2016, 109, 174–183. [CrossRef]
137. Yu, Y.H.; Kim, E.; Park, D.E.; Shim, G.; Lee, S.; Kim, Y.B.; Kim, C.W.; Oh, Y.K. Cationic Solid Lipid Nanoparticles for Co-Delivery
of Paclitaxel and siRNA. Eur. J. Pharm. Biopharm. Off. J. Arb. Fur Pharm. Verfahr. E.V 2012, 80, 268–273. [CrossRef]
138. Li, T.; Zhang, Y.; Meng, Y.P.; Bo, L.S.; Ke, W.B. miR-542-3p Appended Sorafenib/All-trans Retinoic Acid (ATRA)-Loaded Lipid
Nanoparticles to Enhance the Anticancer Efficacy in Gastric Cancers. Pharm. Res. 2017, 34, 2710–2719. [CrossRef]
139. Büyükköroğlu, G.; Şenel, B.; Yenilmez, E. Vaginal Suppositories with siRNA and Paclitaxel-Incorporated Solid Lipid Nanoparticles
for Cervical Cancer: Preparation and In Vitro Evaluation. Methods Mol. Biol. 2019, 1974, 303–328. [CrossRef] [PubMed]
140. Yu, D.; Li, W.; Zhang, Y.; Zhang, B. Anti-tumor Efficiency of Paclitaxel and DNA When Co-Delivered by pH Responsive Ligand
Modified Nanocarriers for Breast Cancer Treatment. Biomed. Pharm. 2016, 83, 1428–1435. [CrossRef] [PubMed]
141. Juang, V.; Chang, C.H.; Wang, C.S.; Wang, H.E.; Lo, Y.L. pH-Responsive PEG-Shedding and Targeting Peptide-Modified
Nanoparticles for Dual-Delivery of Irinotecan and microRNA to Enhance Tumor-Specific Therapy. Small 2019, 15, e1903296.
[CrossRef] [PubMed]
142. Liu, J.; Meng, T.; Yuan, M.; Wen, L.; Cheng, B.; Liu, N.; Huang, X.; Hong, Y.; Yuan, H.; Hu, F. MicroRNA-200c Delivered by Solid
Lipid Nanoparticles Enhances the Effect of Paclitaxel on Breast Cancer Stem Cell. Int. J. Nanomed. 2016, 11, 6713–6725. [CrossRef]
[PubMed]
143. Shi, S.; Han, L.; Deng, L.; Zhang, Y.; Shen, H.; Gong, T.; Zhang, Z.; Sun, X. Dual Drugs (microRNA-34a and Paclitaxel)-Loaded
Functional Solid Lipid Nanoparticles for Synergistic Cancer Cell Suppression. J. Control. Release Off. J. Control. Release Soc.
2014, 194, 228–237. [CrossRef] [PubMed]
144. Shi, S.J.; Zhong, Z.R.; Liu, J.; Zhang, Z.R.; Sun, X.; Gong, T. Solid Lipid Nanoparticles Loaded With anti-microRNA Oligonu-
cleotides (AMOs) for Suppression of microRNA-21 Functions in Human Lung Cancer Cells. Pharm. Res. 2012, 29, 97–109.
[CrossRef]
145. Erel-Akbaba, G.; Carvalho, L.A.; Tian, T.; Zinter, M.; Akbaba, H.; Obeid, P.J.; Chiocca, E.A.; Weissleder, R.; Kantarci, A.G.; Tannous,
B.A. Radiation-Induced Targeted Nanoparticle-Based Gene Delivery for Brain Tumor Therapy. ACS Nano 2019, 13, 4028–4040.
[CrossRef]
146. Qiu, H.; Min, Y.; Rodgers, Z.; Zhang, L.; Wang, A.Z. Nanomedicine approaches to improve cancer immunotherapy. Wiley
Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, 10. [CrossRef]
147. Fass, L. Imaging and cancer: A review. Mol. Oncol. 2008, 2, 115–152. [CrossRef]
148. Chen, X.; Wong, S. (Eds.) Cancer Theranostics: An introduction. In Cancer Theranostics; Academic Press, Elsevier: Amesterdam,
The Netherlands, 2014; pp. 3–8.
Pharmaceutics 2023, 15, 831 28 of 28

149. Sudhakar, C.K.; Upadhyay, N.; Verma, A.; Jain, A.; Narayana Charyulu, R.; Jain, S. Nanomedicine and Tissue Engineering.
In Nanotechnology Applications for Tissue Engineering; Thomas, S., Grohens, Y., Ninan, N., Eds.; Elsevier: Amesterdam, The
Netherlands, 2015; pp. 1–19.
150. Kulbacka, J.; Pucek, A.; Kotulska, M.; Dubińska-Magiera, M.; Rossowska, J.; Rols, M.P.; Wilk, K.A. Electroporation and
Lipid Nanoparticles With Cyanine IR-780 and Flavonoids as Efficient Vectors to Enhanced Drug Delivery in Colon Cancer.
Bioelectrochemistry 2016, 110, 19–31. [CrossRef]
151. Kuang, Y.; Zhang, K.; Cao, Y.; Chen, X.; Wang, K.; Liu, M.; Pei, R. Hydrophobic IR-780 Dye Encapsulated in cRGD-Conjugated
Solid Lipid Nanoparticles for NIR Imaging-Guided Photothermal Therapy. ACS Appl. Mater. Interfaces 2017, 9, 12217–12226.
[CrossRef] [PubMed]
152. Bae, K.H.; Lee, J.Y.; Lee, S.H.; Park, T.G.; Nam, Y.S. Optically Traceable Solid Lipid Nanoparticles Loaded With siRNA and
Paclitaxel for Synergistic Chemotherapy With in Situ Imaging. Adv. Healthc. Mater. 2013, 2, 576–584. [CrossRef] [PubMed]

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.