Structure-Property Relationship for Different Mesoporous Silica Nanoparticles and its Drug Delivery Applications: A Review

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Structure-Property Relationship for
Different Mesoporous Silica
Nanoparticles and its Drug Delivery
Applications: A Review
Parya Kazemzadeh
1
, Khalil Sayadi
2
, Ali Toolabi
3
, Jalil Sayadi
4
, Malihe Zeraati
5
,
Narendra Pal Singh Chauhan
6
* and Ghasem Sargazi
7
*
1
Department of Chemistry, Lorestan University, Khorramabad, Iran,
2
Department of Chemistry, Young Researchers Society,
Shahid Bahonar University of Kerman, Kerman, Iran,
3
Department of Environmental Health Engineering, School of Public Health,
Bam University of Medical Sciences, Bam, Iran,
4
Department Environmental Engineering, University of Zabol, Zabol, Iran,
5
Department of Materials Engineering, Shahid Bahonar University of Kerman, Kerman, Iran,
6
Department of Chemistry, Faculty of
Science, Bhupal Nobles’University, Udaipur, India,
7
Noncommunicable Diseases Research Center, Bam University of Medical
Sciences, Bam, Iran
Mesoporous silica nanoparticles (MSNs) are widely used as a promising candidate for drug
delivery applications due to silica’s favorable biocompatibility, thermal stability, and
chemical properties. Silica’s unique mesoporous structure allows for effective drug
loading and controlled release at the target site. In this review, we have discussed
various methods of MSNs’mechanism, properties, and its drug delivery applications.
As a result, we came to the conclusion that more in vivo biocompatibility studies, toxicity
studies, bio-distribution studies and clinical research are essential for MSN advancement.
Keywords: mesoporous, silica, nanoparticles, properties, drug delivery
INTRODUCTION
One of the most important purposes pursued by nanotechnology is the production of
nanoparticles that have the desired distribution of drug in the body (El-Boubbou, 2018;
Tandel et al., 2018). Over the past two decades, researchers have concluded that a vital step
in the development of drugs is to focus on designing new drug delivery systems (NDDS)
(Martínez-Ortega et al., 2019). Ideally, all new systems should improve the stability, absorption,
drug concentration, and long-term release of the drug in the target tissue. In addition (Djekic
et al., 2019), reducing the number of drug injections to increase patient comfort (Reibaldi et al.,
2019), advanced drug delivery systems (Bhatia, 2016), pharmacokinetics of proteins (Turner and
Balu-Iyer, 2018), and peptides (Hughes, 2005) that are usually low in half-time should be
considered. The ultimate goal of the drug research is to safely transfer the drug to the suitable
location in the body at the right time (Jahangirian et al., 2017;Yin and Zhang, 2020). However,
for many drugs, these ideals are often impossible. For example, the oral method is usually the
best way to use a drug due to non-invasiveness, but peptides and proteins will be absorbed and
effectiveness will be reduced due to the acidic properties of the stomach, as well as the effects of
the first transfer of the liver, such as drug loss due to metabolic processes prior to systemic
rotation and resistance by the intestine (Ahmed and Aljaeid, 2016;Khdair et al., 2016). Finally,
its accessibility will be greatly diminished. Nanotechnology, with the elimination of many
problems with traditional drugs, allows the application of oral drugs that were previously not
usable. In some cases, co-administration of the drug with nanoparticles can increase the
Edited by:
Sudip Mukherjee,
Rice University, United States
Reviewed by:
Ravindra Pratap Singh,
Indira Gandhi National Tribal
University, India
Vijay Sagar Madamsetty,
Mayo Clinic Florida, United States
*Correspondence:
Ghasem Sargazi
g.sargazi@gmail.com
Narendra Pal Singh Chauhan
narendrapalsingh14@gmail.com
Specialty section:
This article was submitted to
Nanoscience,
a section of the journal
Frontiers in Chemistry
Received: 29 November 2021
Accepted: 25 January 2022
Published: 14 March 2022
Citation:
Kazemzadeh P, Sayadi K, Toolabi A,
Sayadi J, Zeraati M, Chauhan NPS and
Sargazi G (2022) Structure-Property
Relationship for Different Mesoporous
Silica Nanoparticles and its Drug
Delivery Applications: A Review.
Front. Chem. 10:823785.
doi: 10.3389/fchem.2022.823785
Frontiers in Chemistry | www.frontiersin.org March 2022 | Volume 10 | Article 8237851
REVIEW
published: 14 March 2022
doi: 10.3389/fchem.2022.823785

bioavailability of the drug in a way that is useful for oral use
(Chen et al., 2018). Nanoparticles protect the drugs that are
susceptible to degradation in the body and give more durability
to the drug’s presence in the blood, attach the drug to the target
tissue, release the drug in the target site, and increase the
efficacy of the drug several times over (McClements, 2018;
Paunovska et al., 2018). The main roles of the preparation of
nano-drug delivery systems are to control particle size (Cooley
et al., 2018), surface properties (Banerjee et al., 2016)and
release of the drug in a good therapeutic dose (Kamaly et al.,
2016). Generally, by fabricating silica, the micelles self-
assemble around a template and then remove the template
using a suitable method such as calcination The design and
manufacture of controlled drug release systems can be very
helpful in cancer drug therapies. So far, many substances have
been introduced as drug release systems, among which
biodegradable polymer materials (Goetjen et al., 2020),
ceramic materials such as hydroxyapatite (Martínez-
Vázquez et al., 2015), and calcium phosphates (Kapoor
et al., 2015) can be mentioned. Recently, mesoporous
materials have attracted the most attention in this regard.
In fact, the porosity of silica mesoporous materials allows
biologically active molecules of different sizes to locate in
the cavities of these materials (Vallet-Regí et al., 2007).
Also, the regular porosity of these materials makes it
possible to achieve a convenient loading and release rate
(Anglin et al., 2008). Conversely, as the adsorption of
molecules into mesoporous (Manzano and Vallet-Regí,
2019) is a surface phenomenon and the specificsurfaceof
these materials also results in the absorption of more active
biological molecules (Manzano and Vallet-Regí, 2019). What
is important in designing a drug release system is
biocompatibility and biodegradability (Jindal et al., 2019).
Recent research is based on the development of drug
delivery systems that are stable in structure and capable of
carrying large volumes of drugs without the problem of early
release to target tissues or even small intracellular organs
(Manzano and Vallet-Regí, 2019).Amongmanyofthe
materials that have been investigated in terms of their
stable structure for drug delivery, silica mesoporous
nanomaterials are known to be biocompatible with defined
structures and certain surface specific properties (Dudarko
et al., 2019). Silica mesoporous is known as a selective material
for the biological applications of inorganic nanoparticles.
Typically, silica meso-nanostructure coated with
semiconductor quantum dots, such as high-stability
cadmium sulfide and selenide (Sharma et al., 2019;Tarrahi
et al., 2019), has the potential for chemical change and high
biocompatibility that can be used for many diagnostic
biomedical applications. In addition, meso silica
nanoparticle can be applied to increase the biocompatibility
of several drug delivery systems, such as magnetic
nanoparticles (Vallet-Regí et al., 2018), biopolymers (Nairi
et al., 2018) and micelles (Zhang et al., 2019). In this article, we
have reviewed and studied the introduction of various types of
silica mesostructure and their application in various drug
delivery processes, the advantages of the application of
silica nanoparticles in drug delivery systems, and
biocompatibility and mechanism reception by the host cell.
MESOPOROUS SILICA MATERIALS AND
ITS SYNTHETIC METHOD
In general, the porous nanoparticles are divided into three groups
according to their size: Microporous (pore size: <2 nm),
mesoporous (pore size: 2–50 nm) and macroporous (pore size:
>50 nm) (Vallet-Regí, 2012). The mesoporus silica was produced
in two steps: first, the micelles self-assembled around a template
and then the template was removed via calcination (Figure 1).
Mesoporous nanomaterials with a well-defined architecture have
a high density of silanol (Si-OH) functional groups at their
surface that can be modified with a wide range of organic
groups to stabilize biomolecules and other applications (Wang,
2009).
Chen and coworkers developed the “DOX@MSNs-CAIX”
targeted and redox-responsive drug delivery system, in which
MSNs were used as the vehicle for loading chemotherapeutic drug
doxorubicin (DOX) and CAIX grafted on MSNs by disulfide
bonds. MSNs-CAIX are a promising medication delivery method
for cancer treatment with a specific target (Meynen et al., 2009).
In some cases, additional functional groups penetrate into the
mesoporous nanoparticles due to fills the silica walls, and
consequently reducing the size of the pore and drug loading,
despite the fact that this controls drug release. Modification of the
nanoparticles surface with a variety of functional groups can
cause changes in electrostatic forces, hydrophilic or hydrophobic
forces, and internal reactions of the drug and the matrix (Meynen
et al., 2009). Various methods for producing silica mesoporous
nanomaterials have been reported that show, with sufficient
knowledge of preparation methods, pore size engineering,
morphological control, and structural properties, that these
materials can be of good quality. In addition, the
manufacturing of these materials by modifying different of
agents, such as a diversity of surfactants, acquires the specific
mechanism and the internal reaction of silica with template
molecules (Wang et al., 2016;Yi, 2021). For example, through
direct reaction of S
+
I
−
, they occur between a positively charged
molecular based organized system (MOS) activating surface ion
by and a negatively charged silicate source. Two kinds of
mechanisms including liquid crystal templating, self-assembly
mechanisms have been proposed for mesoporous synthesis
(Meynen et al., 2009). Figure 2 presents an overview of
possible pathways for their synthesis.
These materials can also be manufactured using surface
activators called polymeric based organized systems (POS)
through the indirect reaction of template with a silicate source
in an acidic media. Conversely, the interaction between the MOS
and the inorganic silicate source (S
0
I
0
) leads to the formation of
hollow mesoporous silica (HMS) materials (Meynen et al., 2009).
Many factors such as pH, salts, inflammasome, co-solvents, co-
surfactants, concentration, specific silicate source, solvent, and
temperature are involved in the organization of mesopores (Zhao
et al., 2000). In a typical method of preparation of mesosilica
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Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

materials, the dissolution of template molecules in the solvent and
the addition of a silicate source such as tetraethoxy ortho silane
(TEOS), meta silicate (Na
2
SiO
3
), and gaseous silica are
performed. After some time at a certain temperature, the
hydrolysis and condensation processes begin. Finally, the
resulting product is washed and dried, and by removing the
mold using calcining, the silica mesoporous is obtained (Kim
et al., 2000).
Mesoporus silica nanoparticles have shown to have excellent
properties for biomedical applications. These properties includes
porous ordered and well aligned structure, which shows fine
control of drug delivery and release kinetics; larger surface area
and pore volume, which shows high potential for molecule
loading and dissolution enhancement; tunable particle size in
between 50 and 300 nm which is suitable for facile endocytosis by
living cells; and silanol-contained surfaces have two functional
surfaces with cylindrical pore surface, exhibit better control over
drug loading and release; and have excellent biocompatibility.
The oral route is the most popular route for drug delivery,
despite the fact that many medicines, particularly highly pH- and/
or enzymatic biodegradable peptide substances, are extremely
difficult to manufacture and obtain efficient intestine absorption.
Only if the drug 1) is substantially present as a solution in the
gastrointestinal tract, 2) is able to penetrate through the intestinal
mucus, 3) overcomes the various gastrointestinal barriers, and 4)
provides an effective therapeutic dose that is efficient for
systematic absorption of an active substance, is oral ingestion
possible. As a result, improving the oral bioavailability of poorly
soluble medications is still a major challenge for the
pharmaceutical industry. Despite the fact that several
traditional drug carriers have solved some of the problems
associated with the oral delivery of poorly soluble medicines,
only a few have fulfilled commercialization requirements. Due to
these limitations, scientists have begun to rethink their methods
for targeted drug delivery systems and researchers have begun
looking for alternate vectorized carriers (Florek et al., 2017).
Lee et al. synthesized MSNs with varying concentrations of
positive surface charges (Lee et al., 2008). The positive surface
charge was achieved by directly co-condensing a TA-silane and
tetraethoxysilane (TEOS) in the presence of a base as a catalyst
and inserting trimethylammonium (TA) functional groups into
the framework of MSN (MSN–TA). These MSN–TA samples
have well-defined hexagonal structures with an average particle
diameter of 100 nm, pore size of 2.7 nm, and surface area of about
1,000 m
2
g
−1
. Anionic drug molecules, Orange II (a fluorescent
tracing molecule), and sulfasalazine (an anti-inflammatory
FIGURE 1 | Preparation route for CAIX guided mesoporous silica nanoparticles (Chen et al., 2020).
FIGURE 2 | Possible pathways for the synthesis of mesoporous materials (A) Liquid crystal templating and (B) self-assembly.
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Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

prodrug used for bowel disorders) were successfully loaded into
these MSN–TA samples and persisted within the MSN–TA in an
acidic environment (pH 2–5) (Li et al., 20211196). Guha and
others developed poly (methacrylic acid-co-vinyl
triethoxylsilane) coated MSN with better hypoglycemic effect
for insulin delivery (Guha et al., 2016). Ang and coworkers
have reported the synthesis of MCM-41 nanoparticles using
sol-gel method for oral delivery of MCC7433 and pretomanid
and its surface was modified with phosphonate and amino groups
(Ang et al., 2021). The impact of various structural features of
MSNs on protein loading, protection, and delivery performance
have been reviewed by Xu and coworkers. They also discussed the
current state of MSN research in enzyme mobilization, catalysis,
intracellular delivery, extracellular delivery, and antimicrobial
protein delivery (Xu et al., 2019). Janjua and coworkers have
developed a room temperature procedure for synthesizing ultra-
small silica nanoparticles with large pore sizes that can load high
amounts of chemotherapeutic medicines and attach a targeting
moiety to their surface for the first time. To accomplish additional
active targeting, the nanoparticles were coupled with lactoferrin
(>80 kDa), whose receptors are overexpressed by both the blood-
brain barrier and glioblastoma (Janjua et al., 2021).
Meka et al. studied the solubility, permeability, and anti-
cancer activity of vorinostat encapsulated within MSNs with
various functional groups. When vorinostat was encapsulated
in pristine MSNs, its solubility was increased by 2.6 fold when
compared to the free drug (MCM-41-VOR). When MSNs were
treated with silanes with amino (3.9 fold) or phosphonate (4.3
fold) terminal functional groups and solubility were increased
even further. Also, MSN-based formulations considerably
improved vorinostat permeability into Caco-2 human colon
cancer cells, particularly MSNs modified with an amino
functional group (MCM-41-NH
2
-VOR), where it increased by
fourfold (Meka et al., 2018).
TYPES OF SILICA MESOPOROUS
SYSTEMS
The meso-silica, due to their high thermality, chemical stability,
high surface area, and good compatibility with other materials
meso-silica systems, they have found wide applications in
adsorption, enzyme stabilization and particularly drug delivery.
These structures are MCM (Mobile Composition of Matter), SBA
(Santa Barbara Amorphous), TUD (Technische Universiteit
Delft), HMS (Hollow Mesoporous Silica) and MCF (Meso
Cellular Form) (Yue et al., 2000;Heikkilä et al., 2007;
Martínez-Edo et al., 2018;Wang et al., 2018).
Mobile Composition of Matter
These adsorbents are the first material in the mesopores
generation that were synthesized in1992, which was the first
step in the design of novel silica meso-carriers (Vadia and Rajput,
2011). The two groups identified from this family are MCM-41
(Chen et al., 1993) and MCM-48 (Kim et al., 2010). The synthesis
of these materials is based on the creation of a liquid crystalline
mesophase of surfactants that takes place in an acidic or base
media (Janicke et al., 1999). Their appearance, shape, and pore
size can be changed by manipulating pH and adding co-solvent.
During the synthesis of MCM, from CTAB (Cethyl trimethyl
ammonium Bromide) cationic surfactant, which is strongly
stirred in a high-temperature in a basic solution are apply.
TEOS is then added and the resulting solution is heated at
high temperature to be stirred for 2 h. After the reaction is
complete, the product is filtered, rinsed with water and
ethanol and then dried under vacuum. The surfactant is then
removed by acid wash (Figure 3)(Janicke et al., 1999).
Depending on the synthesis conditions, inorganic silica
templates can be hexagonal, irregular, cubic, and so on. The
first case was reported in the release of silica porous mesoporous
to carriers of MCM-41 with ibuprofen (Salonen et al., 2008).
Kavallaro et al. used Al Si- MCM-41 mesoporous silica for drugs
such as difflonisal and its sodium salt and naproxen. Qiu and et al.
investigated the Si-MCM-41 system as carrier of the drug
captopril in water. They obtained a cavity size of 4.3 nm and a
loading of 32.5%, while Kavrallo et al. obtained a cavity size of
2.79 nm and a total of 15.6% loading. The lower drug loading for
Al Si-MCM-41 is presence of Al and Si metals of loaded in the
MCM-41 pores, so if the size of the pore is less, the amount of
drug loading is increases (Cavallaro et al., 2004).
Zeng et al. synthesized MCM-41 with the organic group of
aminopropyl as carriers of aspirin and the results showed its release
properties were influenced by the amount and distribution of
aminopropyl groups in the pores wall and their regular structure
(Zeng et al., 2005). MCM-48 is another mesoporous carrier from
MCM group that has the three-dimensional shape group and cubic
cavities, and the delayed release of the erythromycin antibiotic from
this adsorbent was observed (Izquierdo-Barba et al., 2005). Lz-
quierdo-Barba et al. conducted synthesis of MCM-48/erythromycin
and MCM-48/ibuprofen nanocarriers. They illustrate that both have
good release (Izquierdo-Barba et al., 2005). Also, these matters have
been reported to increase the dissolution rate of piroxicam analgesic
(Patil et al., 2019).
Santa Barbara Amorphous
In1998, silica materials with regular meso pores synthesized in
acidic conditions using non-ionic copolymers were
synthesized with high amounts of polyethylene oxide and
polypropylene oxide such as F-127 and P-123 pluronic
(Speybroeck et al., 2009).Thenamingofthesebatchesis
based on their shape, such that the SBA-1 has a cage shape
with cube circular pores (Che et al., 2001), SBA-11 (cubic)
(Che et al., 2001), SBA-3 has a six-sided cylindrical porosity
shape (Chen et al., 2004), SBA-14 (sheet) (Yu et al., 2018),
SBA-15 has a two-dimensional hexagon shape (Margolese
et al., 2000)andSBA-16hasacubiccagestructure(Rivera-
Muñoz and Huirache-Acuña, 2010). Among these
mesostructures, the SBA-15, followed by the SBA-16,
quickly became the focus of attention. Because they have
desirable surfaces, physicochemical properties such as low
toxicity, biocompatibility, biodegradability, low-cost sources
for synthesis, and are widespread their daily applications
(Speybroeck et al., 2009). The SBA mesoporous pore wall is
thicker than the MCM; although their specific surface area and
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Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

porevolumearesmallerthantheMCMgroup,buttheyhavea
high mechanical and thermal stability (Speybroeck et al.,
2009). Recently, the use of SBA-15 as a drug carrier has
been evaluated and proven to have a structural shape and
pore size effect on atenolol release. The appearance of the
properties can be changed by altering the synthesis
temperature. It also appears that SBA-15 is leading to the
slow release of drugs (Speybroeck et al., 2009). Wang et al.
showed that the choice of aqueous and non-aqueous solvents
for loading into the SBA-15 had a significant effect on the rate
of drug dissolution (Wang, 2009). An acceptable therapeutic
target of hybrid porous mesoporous silica to which amine
functional groups were added was also observed in folic acid
loading (Figure 4)(Freitas et al., 2016).
Melaerts et al. locate itraconazole, a low-soluble antifungal
drug in porous SBA-15, which increased its release. Zelenak et al.
stabilized two Zn
3
(benzoate)
6
(nicotinamide)
2
ZnNIA and Zn
(benzoate)
2
(3-pyridinemethanol)
2
]
n
(ZnPCB) antibacterial drug
complexes on SBA-16 and examined their release (Zeleňák
et al., 2005).
Other Silica Mesopores
TUD-1 is similar to foam because of its three-dimensional
structure, where ibuprofen loading has led to improved drug
release rates. Its synthesis conditions are slightly different from
that of porous silica nanoparticles and the manufacturing
process is carried out without the presence of surfactants,
which is essential in terms of toxicity reduction and
economic feasability. It has a high absorption capacity and
is suitable for loading water-soluble drugs (Heikkilä et al.,
2007). HMS has been reported as another meso-silica with a
porous structure, the central part of which is hollow, which has
given it the potential to load the drug as a nano-carrier (Zhu
et al., 2005). The loading of ibuprofen and vancomycin by
MCFs has been reported to have resulted in their dissolution
rate increasing and as a good candidate for drug delivery (Zhu
et al., 2009).
The incorporation of magnetic nanoparticles with
mesoporous nanoparticles with a particle diameter of about
150 nm and pore size of 4 nm also showed slow drug release,
similar to ibuprofen (Kim et al., 2006).
FIGURE 3 | Synthesis of MCM-41 in basic media (Janicke et al., 1999).
FIGURE 4 | Loading of folic acid into SBA-15/NH
2
.
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Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

FUNCTIONALIZATION OF MESOPOROUS
SILICA
Modification of the surface of the porous silica nanoparticles is
carried out to enhance their different physical and chemical
attributes. As mentioned, porous silica materials have an
unusually broad surface area. Their surface is covered with
silanol groups, which makes their cavities surface functional to
be adjustable, which dramatically enhances the various physical
and chemical properties (Kim et al., 2006). For example, the
mesoporous surface of the silica can be modified by sulfonic acid
groups derived from oxidized mercapto. Modified mesosilica
can also be obtained with the aldehyde functional group by
reaction with the amine and glutaraldehyde functional groups.
Therefore, the various groups are capable of generating internal
reactions such as hydrogen bonding, electrostatic adsorption,
and covalent bonding with host molecules. Also, an
organoalkoxy silane can be replaced with the cyano group
present in the mesoporous surface, and the modified groups
in the presence of sulfuric acid as catalysts were variated through
hydrolysis by acidic groups.
Post-synthesis Grafting
Grafting is a type of post-fabrication process used to modify the
surface of pre-fabricated porous silica material which bonds the
functional groups connected to their surface after removing the
surfactant (Zhang et al., 2004;Lesaint et al., 2005). The
abundant silanol groups present on the surface of the silica
porous material are applied as suitable junctions for
functionalization with organic functional groups (Figure 5)
(Barczak, 2019).
After removal of the surfactant, the organosilanes can be
attached to the silanol channels using trichloro organosilanes
or trialkoxy organosilanes (Barczak, 2019). A series of
organosilanes including amine (Aguado et al., 2009), thiol (Li
et al., 2011), chloride (Han et al., 2003), cyano (Prouzet et al.,
1999), ester (Prouzet et al., 1999), aldehyde (Yin et al., 2020),
epoxy (Yeganeh et al., 2019), anhydride (Park et al., 2019),
isocyanate (Ratirotjanakul et al., 2019), phosphor (Yamada
et al., 2019), imidazole (Nuri et al., 2019), ammonium
(Lagarde et al., 2019), acryl (Xiao Song et al., 2019), alkyl
(Nuntang et al., 2019), and phenyl (Gao et al., 2019) are
available for application in the grafting procedure. The
grafting is done by silicification so that the reaction is carried
out on free (Si-OH) and attached silanol (HO-Si-OH) groups
(Barczak, 2019). To diversify the surface or cavity walls of silica
nanoparticles, silanol groups bonded hydrogen have limited
access because they form hydrophilic networks between
themselves (Barczak, 2019). It is worth noting that the main
structure of the mesoporous does not change after applying the
grafting procedure (Zhang et al., 2004). Silica mesostructures
have two inner and exterior parts. Functional groups on the outer
part will be more accessible than the inner part but the presence of
these patches will diminish the use of pores space (Lesaint et al.,
2005). To minimize the barriers of the outer surface in reaction
and selective optimization, the outer surfaces may be coated to
reduce chemical reactions before the functionalization of the
inner surfaces occurs (Zhang et al., 2004;Lesaint et al., 2005).
It is also possible to modify the surface in a controlled manner
through site-selective grafting methods. Thus, in the first step, the
cavities are filled with surfactants, and the exterior modification is
accomplished by the proximity of the template to a solution such
as a trimethylsilyl chloride (Lesaint et al., 2005). Then, template
and finally the interior pore surfaces, for example, are
functionalized with the phenyl propyl dimethyl chlorosilane
sample (Zhang et al., 2004).
Co-Condensation
The co-condensation matter is, in fact, sol-gel chemistry
between tetraalkoxysilanes and one or more of the
organoalkoxy silanes with Si-C bonds (Gao et al., 2019). In
its mechanism of operation, silica precursor with a
organotrialkoxy silanes (R
/
(Si(OR)
3
) precursor in neutral,
acidic media that the organosilane precursor plays two
important roles in silica-based skeletal formation and
binding of an organic group to the skeleton (Hamoudi and
Kaliaguine, 2002). Due to the presence of organic groups in the
synthesized nanoparticles, template removal should be
performed under appropriate conditions in terms of
temperature and pH (Wu et al., 2013). Template removal is
generally preferred by chemical extraction, and depending on
the nature of the template and the manufacturing
process, chemical extraction of the surfactant molecules is
carried out by refluxing with ethanol or ethanol/HCl under
highly acidic H
2
SO
4
conditions. Functional groups such as
FIGURE 5 | Functionalization of mesoporous silica by grafting.
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Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

polypropylene glycol, trimethylbenzene and tetradecane can
also be used to achieve modified ordered mesoporous
(Diagboya and Dikio, 2018). One of the advantages of this
method, compared to the post-synthesis grafting, is the
applicability of a wide range of organoalkoxy silanes (Jeelani
et al., 2020) suitable for a wide range of reaction conditions
(Fukuda and Yoshitake, 2019), homogeneous coverage of
functional groups (Putz et al., 2019), and high loading of
functional groups without destructing the regular structure
of the pores (Nguyen et al., 2019).
SILICA MESOPOROUS FOR DRUG
DELIVERY
The use of nanosilica materials for controlled drug delivery and
release has been reported since the beginning of 1983 (He and Shi,
2011). To date, silica nanoparticles are widely used as drug carriers due
to their easy compatibility and formulation with drugs (Yamada et al.,
2019). Advantages of using mesoporous silica to transport bioactive
molecules include protecting cargo from physiological destruction of
controlled release of drugs (Tang et al., 2012), longer durability in the
bloodstream (Privettetal.,2011), improving targeted drug delivery
(Wang et al., 2010), and reducuction of side effects to healthy tissues
(Zhou et al., 2017). In recently years, non-steroidal Analgesics (NSA)
have been considered. Non-steroidal painkillers, which are analgesic
(Aiello et al., 2002), fever-inducing (N et al., 2019), and
platelet-inhibiting (Brogan et al., 2019), are one of the most
widely used medical drugs whose biological target is the
cyclooxygenase (COX) enzyme (Voiriot et al., 2019). These
drugs actually suppress prostaglandins, which are chemical
messengers for pain, fever, and inflammation (Mahalanobish
et al., 2019). Their strategy of action is to inactivate the
performance of the COX, which has the potential to convert
fatty acid to prostaglandin, or in other words, overcome the
production of prostaglandin by COX (FitzGerald, 2003). In
addition to the advantages of these drugs, they have side
effects, including excessive body retention (Marsh et al.,
1972) and low solubility (Rives et al., 2013), which disrupt
the treatment. As a result, in recent years, silica porous
nanoparticles have been proposed to address these
problems. Increasing the solubility of NSA drugs can be
justified by the size of the cavities (Mellaerts et al., 2008),
easy dispersion, indirect transfer of the drug into the aqueous
media (Li et al., 2007), utilization of surfactants (Chen et al.,
2010), and long durability in the body by biodegradable
coatings such as polyethylene glycol (PEG) (Morelli et al.,
2011). Research has reported the release of a number of drugs
such as ibuprofen (Charnay et al., 2004), diclofenac (Barczak,
2018), melasamine (Mes) (Tiwari et al., 2019), naproxen
(Halamová et al., 2010), piroxicam (Ambrogi et al., 2007),
celecoxib (Zhao et al., 2012) and mefenamic acid (Mustafa and
Hodali, 2015) and etc.
Yoncheva et al. synthesized MCM-41/carbopol/indomethacine
nanocarrier. They reported that this meso-carrier showed little
cytotoxicity due to carbopol coating (Tzankov et al., 2013).
Naproxen (Nap) is a potent Cox enzyme inhibitor that reduces
prostaglandin production and exhibits analgesic and anti-
inflammatory effects (Lejal et al., 2013). Therefore, Halamova
et al. two mesostructures used amine- non-amine functionalized
hexagonal MCM-41 to release Nap. Comparison of these two
carriers showed that after 72 h, the efficiency of release of MCM-
41/Nap was 95% and with MCM-41/amine/Nap 90%, respectively.
Their groups’research also showed that the release of the Nap using
SBA-15 with a larger cavity size was less than MCM-41 with a
smaller cavity size (Halamová and Zeleňák, 2012). The preparation
of SBA-15 decorated by glycidyl methacrylate (GMA) as nanocarrier
for release of ibuprofen and Mes was carried out by Rehman and
coworkers. Copper was modified with hydrophobic ligands to slow
and adjust the release of the two drugs and increase the ibuprofen
and Mes- SBA-15 interaction. The impact of pH in their research
revealed interesting results. The in vitro releaseratefromthe
functionalized SBA-15 was slow in simulated gastric fluid where
pH=1.2waslessthan10%ofMesandibuprofenwasreleasedin
initial time 8 h, while comparatively high release rates were observed
in simulated intestinal (pH = 6.8) and simulated body fluids (pH =
7.2) (Rehman et al., 2016).
CONCLUSION AND CLINICAL
TRANSLATION
MSNs are one-of-a-kind nanoparticles that combine the chemical
and physical stability of silica with the potential of the
mesoporous structure’s network of cavities. MSNs’unique
properties, such as pore-volume, their great loading capability,
their controllable particle size and shape, and their high drug
loading capacity, make them an excellent carrier for nano-drug
delivery systems. MSNs can be anchored with many polymers,
proteins, enzymes and due to their ease of functionalization,
make them a good candidate for drug delivery applications.
Standardization of manufacturing techniques is vital for
achieving reproducibility in MSN synthesis. It is also critical
that the generated nanoparticles have the proper stability,
dispersibility; and any surface functionalization method should
be standardized before reaching the clinic. More importantly,
additional MSN biodistribution studies on various animal models
should be conducted to be certain of the MSNs’ultimate fate.
From a broad view, it is clear that significant progress has been
made in the design and development of MSNs for biological
applications. However, much more work needs to be done before
clinical translation can be accomplished.
Based on their efficacy in clinical studies, silica nanoparticles
are developing as a viable diagnostic and delivery platform, and
might play a crucial role in the development of next-generation
theranostics, nanovaccines, and formulations to orally transport
peptides and proteins. However, establishing safety from chronic
exposure, establishing long-term toxicological profiles from
various routes of administration, investigating reliable scale-up
methods, and synthesizing reproducible silica nanoparticles with
minimal batch-to-batch variation, are all major obstacles that
must be overcome before silica nanoparticles can be used in
clinical trials. Furthermore, only solid silica nanoparticles with no
or small pores have been clinically evaluated to date. These
Frontiers in Chemistry | www.frontiersin.org March 2022 | Volume 10 | Article 8237857
Kazemzadeh et al. MSN and its Drug Delivery Applications: A Review

nanoparticles have a low cargo-loading capacity which is
particularly problematic for nucleic-acid-based medicines.
AUTHOR CONTRIBUTIONS
KS: writing—original draft methodology, software, validation,
formal analysis, data curation, visualization JS:
writing—original draft methodology, software, validation,
formal analysis, data curation. AT: writing—original draft
methodology, software, validation, MZ: writing—original
draft methodology, software, validation, formal analysis,
visualization NC: conceptualization, methodology, software,
validation, formal analysis, investigation, resources, data
curation, writing—original draft, review and editing,
visualization. GS: conceptualization, methodology, software,
validation, formal analysis, investigation, resources, data
curation, writing—original draft, review and editing,
visualization, supervision, project administration.
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