diagnostic applications

Biomedicine & Pharmacotherapy 109 (2019) 1100–1111

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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Mesoporous silica nanoparticles for therapeutic/diagnostic applications a

a,⁎

b

T

a

Samira Jafari , Hossein Derakhshankhah , Loghman Alaei , Ali Fattahi , ⁎ Behrang Shiri Varnamkhastia, Ali Akbar Sabouryb, a b

Pharmaceutical Sciences Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran

A R T I C LE I N FO

A B S T R A C T

Keywords: Mesoporous silica nanoparticles Safety Drug delivery Bioimaging Biosensing Quantum dots Cargo loading

Based on unique intrinsic properties of mesoporous silica nanoparticles (MSNs) such as high surface area, large pore size, good biocompatibility and biodegradability, stable aqueous dispersion, they have received much attention in the recent decades for their applications as a promising platform in the biomedicine field. These porous structures possess a pore size ranging from 2 to 50 nm which make them excellent candidates for various biomedical applications. Herein, at first we described the common approaches of cargo loading and release processes from MSNs. Then, the intracellular uptake, safety and cytotoxicity aspects of MSNs are discussed as well. This review also highlights the most recent advances in the biomedical applications of MSNs, including 1) MSNs-based carriers, 2) MSNs as bioimaging agents, 3) MSNs-based biosensors, 4) MSNs as therapeutic agents (photodynamic therapy), 5) MSN based quantum dots, 6) MSNs as platforms for upconverting nanoparticles, and 6) MSNs in tissue engineering.

1. Introduction During recent decades, porous materials have shown a great promise to offer sustainable solutions to global issues, including increasing energy demands and simultaneously standards for industrial pollutants, exhaustion of resources and health improvement [1,2]. Indeed, the ability of these particles to provide the driving forces for physical and chemical processes is related to the different local environment of atoms exposed at solid surfaces compared to those in the bulk. Therefore, the greater number of surface atoms can increase the specific surface area of porous solids, leading to higher material’s reactivity as well as improved efficacy in relevant applications [3,4]. According to the literature, can be classified based on their pore size into three groups including microporous, mesoporous and macroporous particles which have the pore sizes less than 2 nm, between 2–50 nm and greater than 50 nm, respectively. Owing to unique structural property of mesoporous particles like uniform pore size and a long-range ordered pore structure, these porous structures have been employed and studied in wide variety of different fields from catalysis, adsorption, separation, sensing to biomedical applications [5–9]. Among various mesoporus materials, mesoporous silica nanoparticles, MSNs, are a promising class of porous materials with exceptional surface properties including high specific surface area as well as pore size [10,11]. Silica nanoparticles, the submicron sized range structures which carry a silica adduct, are

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nanostructures with a high amount of pores in order to load the various molecules inside them. Moreover, the silica body further provides an external surface between pore openings and anionic molecules attached to the outer surface of the silica. These anionic links grant hydrophilicity to the submicron structure and are suitable to provide repulsion between other submicron structures. These fabricated structures have a maximum surface to volume ratio than bare particles, which makes them a good agent for cargo loading purposes and so on [12]. In addition to appropriate surface properties, these mesoporous materials possess good biocompatibility, controllable size, easy surface modification and etc, which make them excellent candidates for various biomedical applications [10,11]. Owing to these unique merits, the number of research studies on the MSNs has increased dramatically. Large specific surface area and pore volume make MSNs as suitable reservoir for loading therapeutic/diagnostic agents. On the other hand, MSNs are able to protect their cargos from premature release and subsequently undesired degradation in stomach and intestines before arriving to the target location. Numerous researches have investigated the internalization of MSNs in various cell lines [9,13,14]. Different parameters including morphology and size of mesostructures, electrostatic interactions between MSNs and the cell membrane and the surface functionalization can affect the uptake mechanisms of MSNs. In agreement with published literatures in this regard, a common mechanism for translocation of MSNs is via endocytosis. To achieve an

Corresponding authors. E-mail addresses: [email protected] (H. Derakhshankhah), [email protected] (A.A. Saboury).

https://doi.org/10.1016/j.biopha.2018.10.167 Received 20 August 2018; Received in revised form 26 October 2018; Accepted 26 October 2018 0753-3322/ © 2018 Published by Elsevier Masson SAS.

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effective therapeutic effect, MSNs should be able to release their cargo on the cytoplasm using different endosomal escape approaches [15–17]. Furthermore, physical and chemical surface modifications are used to enlarge the range of biomedical (diagnostic/therapy) applications for MSNs. These modifications lead to enhancement of biocompatibility, inhibition of specific adsorption and also providing functional groups for further biomolecule conjugation aims. The prevalent physical and chemical approaches to modify the surface of MSNs are layer by layer self-assembly (LSA) and chemical surface functionalization, respectively [18]. In addition to size and shape, surface properties such as charge, functional groups and the presence of some molecules can influence the biocompatibility of MSNs. Nanoparticles with positive charges on their surface can induce a more significant immune response and cytotoxicity compared with the neutral and anion species. MSNs with negative zeta potential can be associated with serum opsonin. They rapidly removed from the extracellular or intracellular environments by macrophages in the reticuloendothelial (ER) systems [19]. Another critical issue is the number of (-SiOH) groups at the surface layer of MSNs. These functional groups can negatively interact with biological molecules, such as cellular membrane lipids and plasma proteins that subsequently destroy the structure of these molecules. Therefore, surface modification is an essential step in modifying surface reactivity to enhance biocompatibility and further broaden the biomedical applications of MSNs [20]. The routine way to synthesize MSNs uses the sol-gel method and the starting materials will be tetraalkoxysilanes such as tetra-ethyl-orthosilicate (TEOS). Other tetraalkoxy silicates aren’t widely used because of fast reaction and low controllability. Kurdo et al. for the first time reported the production of porous structures using hexadecyltrimethylammonium bromide (CTAB) and normal octane in 1988. The addition of these surfaces activating agents during the synthesis process, produces structures with a lot of fine pores between 2–50 nm based on the IUPAC definition (mesoporous). Recent reports have proposed using of other templates like chitosan because of its amine and hydroxyl functional groups. These two functional groups ease the further modifications on MSNs in order to expand their applications range [21–23]. This manuscript is structured as follow: firstly it highlights the common approaches of cargo loading and release processes from MSNs. Then, it provides a short overview of safety and cytotoxicity aspects of MSNs. In the next section, the exciting progresses of MSNs for the above mentioned biomedical applications are discussed. Fig. 1 depicts schematically some of biomedical applications of MSNs.

Fig. 1. A scheme of biomedical applications of MSNs.

diagnostic agents into pores of MSNs. For this group of cargo, the amount of adsorbate can be increased through functionalization of MSNs with different functional groups, which probably leads to additional interactions between adsorbate and adsorbent. While, adsorbed hydrophobic molecules from organic solvents, vacuum drying is applied to remove the solvent. In the case of hydrophobic agents, pore size is another main manipulatable parameter used to increase the extent of adsorption, if the molecular size of the payload is in the range of the pore diameter of carrier. Based on physicochemical properties of the drugs such as polarity, circulation time, the degradation rate of the carrier itself, weak interactions of the drug and the pore surface cause premature release of the therapeutic molecules prior to arriving at the site of action. Thus, numerous recent studies have concentrated on designing and developing the novel drug delivery systems which can be triggered through either exterior intracellular processes or stimuli in order to target delivery and also controlled release. In this regard, two main approaches are reported in the literature: 1) covalent attachment of drug to carrier via cleavable bonds, 2) functionalization of the outside surface of the MSNs with different functional groups. Most of the drugs recently presented in the market, suffer from poor water solubility, so-called poorly water-soluble drugs (PWSD). Accordingly, these drugs lack therapeutic efficacy in vivo, mainly because of not reaching a high enough concentration in the site of absorption, i.e., gastrointestinal (GI) lumen. Therefore, it is remaining a challenge to enhance the dissolution of the drug in the GI [24]. New trends in combinatorial chemistry and novel drug design have resulted in drugs with higher lipophilicity, poorer water solubility, and higher molecular weight, all of which notbeing beneficial for oral absorption. Far from the abovementionedproblems, drugs that can form stable crystals are an emerging challenge for pharmaceutical researchers as well. Newer drug molecules possess several functional groups, which makes them able to crystallize into stable crystals with high melting points. These drugs are not necessarily lipophilic, but the energy needed to overcome the forces attaching the drug molecule within the crystalline lattice is higher than the metastable or amorphous ones, thus making the dissolution in GI fluids more difficult [25,26]. In order to find the best solutions for the oral bioavailability, the biopharmaceutics classification system classifies drugs intended for oral administration into four different groups based on the aqueous

2. Cargo loading and release process from MSNs The novel drug delivery systems particularly nanostructures which are designed with the aim of improvement of drug solubility, change the drug metabolism and pharmacokinetics to increase drug accumulation in the target sites, as well as minimize the associate adversary effects. Two essential parameters to determine the performance of a drug delivery system are loading capacity and drug release profiles. Various payloads into pores of MSNs can be performed through two main routes; 1) in situ loading during fabrication 2) adsorption of cargo onto mesopores of MSNs (either as physisorption or chemisorptions) (Fig. 2). Table 1 provides some types of MSNs along with their cargo loading, capacity loading and also release rate. The most common approach for the loading of therapeutic molecules into pores of MSNs is adsorption method via soaking of the MSNs in a drug solution, especially poor water-soluble drugs. The surface silanol groups, at least 2–4 ^Si−OH groups/nm, on the surface of MSNs play a key role in cargo loading as adsorption sites. Since the point of zero charge for MSNs is 2–3, their surface is negatively charged in the absence of specific ion adsorption under biological conditions; therefore electrostatic adsorption payloads with a positive charge is a promising approach for accommodation of water soluble therapeutic/ 1101

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Fig. 2. Different approaches of payload (small molecule drugs, protein drugs, contrast agent, bio-sensing agent and so on) loading into mesopores of MSNs.

can release from MSN at low pH environment within the tumor cells. There are several strategies for cargo loading and controlled release of drugs in target sites. These strategies are resulting from surface chemistry and physical parameters and may be listed as follow: pH sensitive MSNs, Red-ox trigger MSNs, Enzyme trigger MSNs, Light trigger MSNs, Magnetic trigger, Ultrasound trigger, which the first three ones are called internal actuations and the last three ones are named external actuations [33].

solubility/dissolution as well as the intestinal epithelium permeability. In class 1, drugs with both, high permeability and high solubility are found; those with high permeability but low solubility are assigned to class two; drugs with lowpermeability, but high solubility are classified as class 3, and finally,class 4 includes the drugs with both low solubility and permeability [27,28]. Several studies have highlighted triggerable MSNs for controlled release of various therapeutic agents [29–31]. For example, a prevalent and promising strategy for anti-tumor and anti-inflammatory system is synthesis of pH-responsive carriers in which covalent bonds between drug and carrier can be cleaved into tumor and inflammatory tissues. Li et al., developed a pH-sensitive MSN to enhance anticancer efficacy of ursolic acid (UA) in hepatocellular carcinoma cancer. UA is a nature product with good anti-cancer activity that possesses low toxicity as well as good liver protection properties. However, its clinical application is constrained due to the low-solubility and poor bioavailability. In the mentioned research, a pH-sensitive pro-drug delivery system was fabricated to overcome this problem, using MSN, which UA molecules was either conjugated to the surface of MSN via an acid-sensitive linkage or incorporated into pores of MSN through non-covalent interactions [32]. Both of these interactions could result in enhancing the solubility and bioavailability of UA. Subsequently, the UA molecules

2.1. pH directed delivery Controlled release of drugs via a pH trigger is one of the most promising ways to treat diseases via nanoparticles since pH changes occur upon particle internalization into cancer cells. One of the earliest reports of the pH-controlled delivery of cargo via surface engineered MSNs, reported by Zink and co-workers with rotaxane grafted MSNs. The rotaxane could change its configuration as a function of the pH to release from nearly zero at pH 6.5 in a pH-dependent manner from pH 5 to 3.4. Lee et al., reported the intracellular pH-responsive controlled delivery of doxorubicin drugs via a pro–drug strategy using pH-cleavable hydrazine linkers in the MSN pores [34]. The surface coating strategy of MSNs also investigated to control the delivery of loaded

Table 1 Some MSNs types along with their cargo loading, capacity loading and release rate. MSN Type

Cargo

Capacity Loading (wt. %)

Release Rate

References

MCM-41 HMSNs MCM-41 HMSNs HMSNs HMSNs-NH2 HMSNs-COOH HMSNs-CN HMSNs-CH3 MCM-41(C12) MCM-41(C16) SBA-15 MCM-41 SBA-15 SBA-15 (C8) SBA-15 (C18) MCM-41 MCM-41-NH2 SBA-15-NH2

Ibuprofen

35.9 74.5 48.16 112.12 18.54 28.89 20.73 22.54 12.13 23.6 34 22.6 29 34 13 18 14 37 8 22 34 42

Complete release in 10 h Initial burst release of 50% in 10 h followed by 100% release in 3 days 40% in 8 h, stagnant release beyond 8 h 10% in first 24 h, sustained beyond 160 h

[130–132]

61% within 3 h, total release over 19 h 57% within 4 h, total release > 50 h 43% within 1 h, total release over 12 h 48% within 6 h, total release over 24 h Complete release in 36 h 45% within 2 h, total release over 16 h 47.47% within 2 h, total release > 30 h 60% within 0.5 h, total release over 16 h 60% release within 5 h total release within 14 h Complete release in 10 h 25% in first 24 h, sustained beyond 80 h 50% release within 7 h, total release within 11 h Complete release in 12 h 35% in first 20 h, sustained beyond 45 h

[135–137]

10% in first 24 h, sustained beyond 160 h Complete release in 24 h

[145,146]

MSN-C0 MSN-C10

Doxorubicin 5-fluorouracil

Captopril

Erythromycin

Alendronate

Lysozyme

1102

[92,133,134]

[136–139]

[138–141]

[142–144]

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reported for biomedical applications [48,49]. Upconversion-siliceous hybrid nanovectors can be excited in the NIR for the controlled release and delivery of loaded materials through different proposed mechanisms. MSN containing Gd2O3: Yb/Er upconversion nanocrystal shown to release their content faster under NIR light, however, the loaded guests were passively releasing from the mesopores [50].

guests via a pH change. Yang and co-workers reported the coating of MSNs with a pH-responsive chitosan/polymethacrylic acid polymer to deliver doxorubicin to HeLa cancer cells [35]. Modification of the MSN surface via nanoparticles, capping the pores applied for pH-sensitive nanovectors. A pH-sensitive nanovector designed by Zhu and coworkers with regard of the dissolution of ZnO NPs functionalized onto the surface of MSNs for the delivery of doxorubicin to HeLa cells. A pHdegradable calcium phosphate coating of drug-loaded MSNs was also described [36,37].

2.5. Magnetic based delivery Thomas et al., designed mesoporous silica nanovalves encapsulating superparamagnetic zinc- doped iron oxide nanocrystal cores for drug delivery using magnetic actuation [51]. The design was based on the fact, that the binding constant of the diamine inclusion complex of the nanovalves could be disrupted with thermal energy and thus under magnetic actuation. Half of the cargos could be released in solution after an initial one minute pulse with an alternating current (AC) magnetic field with a 500 kHz frequency and a current amplitude of 37.4 k Am−1, whereas nearly all the payload could be released under multiples pulses over time. Khashab and co-workers recently designed magnetic iron oxide–silica hybrid 100 nm wide nanovectors with pores ranging from 20 to 60 nm in diameters [52].

2.2. Redox-based delivery Similarly, the pH parameter of the redox actuation is another suitable strategy to use that takes advantage of intracellular conditions, the presence of GSH biological reducers to cleave redox-cleavable groups and trigger the bioactive agents. The GSH concentration difference between the extracellular (2–20 × 10−6 M) and intracellular (2–10 × 10-3M) media allows the autonomous delivery of cargos via redox-responsive nanocarriers. Moreover, GSH is typically more concentrated in cancer cells than that in normal cells [38,39]. In this regard, Kim et al., reported the designing of the MSN surface with disulfide redox-cleavable groups connecting β-cyclodextrin with a multistep synthesis process. The control of the cargo release kinetics from mesoporous silica species also tuned by hindering disulfides by various surface engineering strategies. A study successfully regulated the release rate of loaded cargos from MSNs by hindering disulfide linking β-cyclodextrin nanocaps on the surface silica. Redox-responsive disulfide or tetrasulfide groups also have been inserted into the silica framework to control the delivery upon the nanoparticle degradation. This approach was applied to delivery of small-and large-sized cargos such as anticancer drugs and proteins, respectively [38,40–42].

2.6. Ultrasound based delivery The design and application of silica hybrids for high intensity focused ultrasound (HIFU) tumor ablation was firstly reported by Shi and co-workers using manganese oxide-doped hollow MSNs designed for MRI particle tracking in vivo so as to selectively actuate the ablation of tumors under HIFU [53]. The same group also prepared ultrasoundresponsive perfluorohexane doped and Au NPs-coated hollow mesoporous silica nanovectors [54,55]. In order to increase the control of the release of the cargos via HIFU, Vallet-Regí and co-workers designed the surface of MSNs with the ultrasound-responsive copolymer(poly(2-(2methoxy-ethoxy) ethylmethacrylate-co-2-tetrahydropyranyl methacrylate) [56].

2.3. Enzyme based delivery Enzymes also can use mesoporous silica and organosilica nanoparticles via ester, peptide, urea, and oxamide bond cleavages. The enzymatic role obtained via an ester bond between the stalk and the adamantine stopper so that the addition of porcine liver esterase triggers the controlled release of cargos [43,44]. A similar system developed with calix[4]arene molecular rings capping complexed with esteror urea-linked stalks so as to generate three stimuli roles (enzyme, pH, competitive binding) in aqueous solutions [45]. The release of loaded cargos from MSNs monitored in solution upon the addition of the elastase protease enzyme. Bein and co-workers designed protease-responsive biotin–avidin to cap the MSN pores and monitored the controlled release of cargos in the presence of trypsin as a model enzyme, while Raichuret al., used arginine-rich protamine proteins for the same trypsin-mediated release strategy [46].

3. Intracellular uptake of MSNs Since the biological membrane is the most important barrier for intracellular delivery, it needs to pay special attention to the mechanisms of internalization and translocation of MSNs as carriers for therapeutic/diagnostic agents. Up to now, a wide variety of pathways to penetrate the external materials into cellular membrane were reported [33,57,58]. In general, the uptake mechanisms can be categorized into two main groups: phagocytosis and pinocytosis (macropinocytosis and endocytosis) (Fig. 3). It is known that the surface properties of any material have a key role in determination of its biological fate (e.g., toxicity, biocompatibility, drug loading and release, biodistribution, and cellular internalization). In the case of biomedical applications, MSNs are designed to play a specific role, with minimal non-specific or adverse effects. Silica is generally considered as a biocompatible substance. However, MSNs biocompatibility needs to be assessed with regard to individual size, shape, and surface chemistry. Here, we discuss the current advances in investigations of the effects of size, shape, and surface properties on MSNs interactions with live cells [59,60].

2.4. Light based delivery According to the delivery strategy, one can divide the light mediated mesoporous silica and organo silica nanostructures into several categories involved: (a) photolysis-responsive nanovectors, (b) photoisomerization-responsive nanovectors, (c) photoredox-responsive nanovectors, and (d) photothermal-responsive upconversion or plasmonicnanovectors. A selection of the pioneering works is as below: Photolysis-responsive nanovectors: Lin and co-workers reported MSNs electrostatically capped with gold nanospheres–oligomer– nitrobenzyl–alkyl ammonium. Zhao et al., reported the photodimerization-cleavage cycle of thymine-modified MSNs [47]. Photoisomerization-responsive nanovectors: The incorporation of photoisomerizable azobenzene groups into the mesopores of siliceous materials reported by Zink et al., to allow the photo driven expulsion of dyes physically entrapped into mesoporous organosilica nanoparticles. A wide variety of upconversion mesoporous silica and organosilica shell nanocarriers

3.1. Effect of surface chemistry, shape, and size of MSNs According to the literature, the major pathway of toxicity associated with silica is due to its surface chemistry (silanol groups) which can interact with the membrane components leading to the lysis of the cells and consequently leaking of the cellular components. Besides, mesoporous silica exhibits a lower hemolytic effect compared to non-porous silica that could be attributed to the lower density of silanol groups on the surface of these structures. Surface properties of MSNs also have a 1103

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Fig. 3. Possible mechanisms of MSNs for internalization into cells: phagocytosis and pinocytosis (macropinocytosis and endocytosis).In the case of MSN, the common pathway of internalization is endocytosis.

However, no pathological abnormalities reported at the end of 1 month. Smaller sized MSNs undergo slower degradation as it can escape the degradation by the liver and spleen [61]. The particle size plays a key role in determining the internalization process. The observed uptake of particles larger than 1 μm is found to involve phagocytosis that particles can be engulfed into specific cells such as monocytes, neutrophils, macrophages, and dendritic cells, whereas the smaller particles (< 200–300 nm) are taken up through endocytosis pathway in the majority of cases. This mechanism involves some routes such as clathrin dependent, caveolin-dependent, receptormediated, as well as clathrin- and caveolin-independent endocytosis, which depending on the cell types and their culture conditions as well as some of structural properties of particles like particle size, shape and surface charge can be occurred via one of the specific endocytic pathways [67,68]. To date, extensive researches have rendered on internalization of MSNs into cells. According to previous reports on the intracellular uptake of MSNs, endocytosis pathway is the most common approach for translocation of these mesostructures [29,69,70]. A study on the uptake pathway of the MSNs into Hela cancer cells found that efficiency and also the uptake mechanism can be regulated by the surface functionalization of MSNs [9]. For instance, functionalization of MSNs with groups that cells can express related specific receptors, e.g. folic acid, considerably improved the cellular uptake of MSNs. A trend was also conducted about the correlation between internalization of MSNs and their surface charge.

great impact on the biodistribution and biocompatibility of MSNs. For an instance, modification of the surface features through functionalization with PEG helps the MSNs to escape from being degraded by liver, spleen and lung tissues due to the longer circulation time of PEG-MSNs. Yu et al., studied the impact of pore size, shape and surface features of silica nanoparticles on the cellular toxicity. The cellular toxicity was evaluated on macrophages (RAW 264.7) and cancer epithelial (A549) cells [19,61]. The morphology of MSNs influences the biocompatibility, biodistribution, and clearance. Huang et al., have shown that Short-rod MSNs distribute mainly in the liver, while long-rod MSNs are easily trapped in the spleen and display a slower clearance rate than sortrodones using animal models. The shape of MSNs also affects cellular uptake, which has been a major recent research concern. In vitro studies reported independency of shape on endocytosis rates and dependency to endocytosis rate. The large aspect ratio of MSN can result in a more extended circulation time and therefore, different biocompatibility. The biodegradation and toxicity of MSNs also depend on the shape of the MSNs. The effect of shape on in vivo toxicity of MSNs after oral administration was studied by Li et al., for MSNs with different aspect ratios of 1, 1.75 and 5. These results suggest that the degradation of MSNs depends on the shape and biological environment [62,63]. Controversy has arisen regarding the impact of particle size on the biocompatibility of MSNs. Particle size can manipulate biological factors such as in vivo distribution, blood-circulation time, and clearance. With intravenous delivery, MSNs were found to be mainly distributed in the liver and spleen, with a minority of them in the lung, and a few in the kidney and heart. A longer blood circulation lifetime was observed for particles with smaller size [61]. The excretion of MSNs from urine increased by the elevation of particle size may affect the degradation rate and therefore biocompatibility. in vitro assays have suggested a degree of toxicity for spherical MSNs at the particle size of 1220 nm at > 25 mg/ml concentration [64], while another study demonstrated the sizedependent hemolytic activity [65]. However, Hudson et al. showed no sizeindependent toxicity using an in vivo mouse model [66]. Size of the nanoparticles also has a profound influence on the biodistribution and excretion of MSNs. These mesoporous structures with a varying particle size from 80 to 360 nm was prepared, and their biodistribution assessed in mice. An increase in particle size led to an increase in its accumulation in the liver and spleen following intravenous administration.

4. Toxicity and safety of MSNs According to the literature, silica-based nanostructures have acceptable biocompatibility to utilize in biomedical applications. As compared with nonporous silica nanoparticles, MSNs reveal the welldefined structures with high specific surface area as well as large pore size, resulting in alter the biological manner. Owing to the declined silanol density by the existence of pores, MSNs exhibit lower hemolytic effect rather than nonporous silica. Besides, MSNs because of comparatively their large hydrodynamic size in serum, demonstrated high accumulation in lung [71,72]. Some of advantages and disadvantages of MSNs are summarized in Fig. 4. 1104

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Fig. 4. Some of important advantages and disadvantages of MSNs.

other porous material, silica-based mesoprous materials have been successfully investigated as an appropriate carrier for drug delivery, especially in the delivery of hydrophobic therapeutic agents due to attractive structural properties as mentioned above [11,29,83]. Poor water solubility of hydrophobic drugs and subsequently their poor absorption cause to restrict applications of these classes of therapeutic agents after oral dosing. In literature, oral improvement absorption of insoluble drugs using design of suitable carriers for efficient drug delivery has been widely reported [84–87]. Among all of the available carriers, numerous research studies have been employed MSNs to design an efficient drug reservoir for loading the hydrophobic drugs. In general, the large surface area and high pore volume provide encapsulation of drugs with a high payload. Drug molecules remain in the amorphous or non-crystalline state within the pores of MSNs due to the presence of mesoporous channels which facilitates drug dissolution [88–90]. On the other hand, chemical stability and inert manner of these mesoporous structures provide controllable drug loading and release. For the absorption of hydrophobic drugs, the dissolution process is the rate-limiting step; factors like drug loading method, pore morphology and pore size, have considerable effect on the drug loading and dissolution rate [91–93] (Fig. 5). In a recent investigation, Zhang et al. applied mesoporous silica for the improved oral absorption of Telmisartan (TEL), as a model hydrophobic drug [94]. The obtained results depicted that TEL loading within pores of MSNs resulted in improvement of its dissolution rate as well as bioavailability compared with pure drug powder. Furthermore, the findings suggested that the possible mechanism of oral absorption improvement of TEL could be because of the entrapment of TEL in the pores of MSNs which significantly enhanced the permeability of TEL as well as decreased the rate of drug efflux. Furthermore, most of anticancer therapeutic agents have poor water solubility and belong to the class of hydrophobic drugs. Their low solubility in aqueous media is a critical obstacle for bioavailability of these drugs which can limit their administration via intravenous path [83,95,96]. Therefore, it is a vital issue to improve the aqueous

In most scientific reports have denoted that MSNs possess low toxicity in vitro against the various cell lines. Nonetheless, evaluation of safety and toxicity of MSNs is an important issue that needs to be considered at using MSNs in clinical applications [73,74]. Surface chemistry and the particle size are two critical parameters for evaluation of the behavior of the particulate systems in biological conditions. Indeed, all critical factors of cytotoxicity and also biological behavior including particles aggregation, protein adsorption to particles, interactions at the nano-bio interface, and intracellular particle trafficking, cellular toxicity and biological behavior are influenced by these two parameters [75]. In this connection, a recent research has been reported size-dependency of MSNs toxicity in endothelial cells [76]. The authors demonstrated that particles with size of above 100 nm have low cytotoxicity, whilst the particles sub-50 nm exhibited greatly induced necrotic cell death. Surface charge is another determinant of cellular toxicity. In this regard, researchers demonstrated MSNs with positive charge display the lower cytotoxicity than bare MSNs. For instance, Pasqua et al., compared cytotoxicity of native MSN with thiol- or amino-functionalized MSNs [77]. The obtained results displayed that unmodified MSN was more cytotoxic than modified MSNs. Furthermore, PEGylation of MSNs can considerably reduce their non-specific attachment to serum proteins and also decrease hemolysis of human red blood cells in comparison with native MSNs, improving the blood compatibility; this issue should be considered in the nanoformulations which supposed to be intravenously injected [61,78]. 5. Biomedical applications of MSNs 5.1. MSNs-based carrier for drug delivery The ability to transport the therapeutic molecules to the specific site without any loss in their functions as well as structure is a significant prerequisite for designing of an efficient carrier for targeting drug delivery [79–82]. For achieving this objective, the carrier should be able to release the cargo molecules in a controlled manner. Compared with 1105

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Fig. 5. A schematically figure from drug loading of MSNs to their clinical applications.

non-fluorescent dye molecule, Förster resonance energy transfer (FRET) quenches QD luminescence. However, the release of the quencher can recover the photoluminescence of QD [103,104]. Pillai et al., reported the quenching of QD photoluminescence after conjugation with a non-fluorescent dye molecule, called black hole quencher 1 (BHQ-1), intermediated with a molecular sensing target peptide. Based on steady state and time-resolved photoluminescence measurements of QD and the QD-peptide-BHQ-1 sensor assemblies, they attributed the quenching of photoluminescence intensity and lifetime to induce FRET from the quantum dot to BHQ-1molecules [105]. A multifunctional design reported for synergistic therapy with controlled drug release, magnetic hyperthermia, and photothermal therapy, which is composed of graphene quantum dots (GQDs) as caps and local photothermal generators and magnetic mesoporous silica nanoparticles (MMSN) as drug carriers and magnetic thermoseeds. The structure, drug release behavior, magnetic hyperthermia capacity, photothermal effects and synergistic therapeutic efficiency of the MMSN/GQDs nanoparticles investigated by Yao and co-workers. The results showed that magnetic MSN/GQDs with the particle size of 100 nm could load doxorubicin (DOX) and trigger DOX release in low pH. More importantly, in the case of breast cancer 4T1 cells as a model system, the results indicated that compared with chemotherapy, magnetic hyperthermia or photothermal therapy alone, the combined chemo-magnetic hyperthermia therapy or chemo-photothermal therapy with the DOX-loaded magnetic MSN/GQDs nanosystem exhibits a significant synergistic effect, resulting in a higher efficacy to kill cancer cells. Therefore, the magnetic MSN/GQDs multifunctional platform has great potential in cancer therapy for enhancing the therapeutic efficiency [70,106].

solubility of these therapeutic molecules without the use of organic solvents. In order to overcome the insolubility problem of Camptothecin (CPT), an anticancer drug, Lu and co-workers applied a fluorescent mesoporous silica nanoparticle (FMSN) for delivery of CPT into cancerous cells to induce the cells death with aim of minimizing of adverse effect on normal cells. FEMSNs were fabricated through a basecatalyzed sol-gel method. The results revealed that incorporation of CPT into pores of FMSNs lead to enhance the solubility of CPT and subsequently improvement of its antitumor efficacy [83]. 5.2. MSNs as bioimaging agents Owing hydrophilic surface of MSNs, these mesoporous structures become well distributed in aqueous solution. Besides, the high surface area/pore volume of MSN can provide compartmental reservoirs for multiple functionalities, which constitutes MSN as promising options for various medical imaging applications [97,98]. It has been also reported that MSNs possess high optical transparency because of their small particle size. There are numerous reports for bioimaging applications of MSNs through modification of these materials with various fluorescent dyes both in vitro and in vivo. In order to measure the intracellular pH values in the cytosol and endosome-lysosome regions,a modified MSN with two different pH-sensitive dyes, Fluorescein isothiocyanate (FITC) and Rhodamine B isothiocyanate (RITC) was fabricated by Tsou and coworker [99]. Bioimaging approach based on MSNs is achieved using upconverting nanoparticles and quantum dot methods. These two techniques are discussed as follow: 5.2.1. Upconverting nanoparticles Upconverting nanoparticles (UCNPs) refer to nanoscale particles that do photon upconversion. They are usually composed of lanthanideor actinide-doped transition metals and are preferred to use in bioimaging and bio-sensing. They also have potential applications in photovoltaics and security, such as infrared detection of hazardous materials. In this phenomenon, two or more photons with low energy are absorbed and converted into one emitted higher energy photon. Generally, absorption occurs in the IR, while emission occurs in the visible or UV regions of the electromagnetic spectrum [100].There are many reports from their use in nanoparticle synthesis and clinical applications as below. For example, mesoporous-silica-coated NaYF4: Yb/ Er successfully fabricated. Vitamin B12, a widely present vitamin, used as a photosensitizing drug. Near-IR light provides deep penetration and avoids damage to normal cells. All reagents involved are nontoxic, environmentally safe, and biocompatible [101,102].

5.3. MSNs-based biosensors Owing to unique features of nanostructures such as small size, large specific surface area, versatile chemistry can be used as the attractive sensors with high sensitivity for detection of various analytes in both in vitro and in vivo conditions [107,108]. Among different nanoparticlebased biosensors, MSNs because of high porosity as well as optical transparency are excellent options for biosensing applications. The former feature provides large areas to immobilize the sensing agents in both outside surface and inside of pores, which leads to fast responses and also low detection limits. The latter feature allows the optical detection via the layers of materials. Due to these unique properties, until now a wide variety of MSNs-based structures have been designed and investigated for generation of biosensors [109,110]. For instance, Wei et al., fabricated an MSN-based biosensor, in which glucose oxidase and horseradish peroxidase were loaded into pores of silica nanoparticles [111]. In another research study, H2O2 and NO2 were detected using immobilization of myoglobin and hemoglobin in mesoporous silicamodified electrodes [112]. Martínez and coworkers synthesized an MSN with amino methyl anthracene groups grafted on it for the

5.2.2. Quantum dots Quantum dots (QDs) are powerful probes for detecting single-molecules and imaging live cells. Despite several reports on bioimaging and biosensing applications of QDs, controlled and targeted detection of biomolecules using quantum dots is remained a challenge. When a QD conjugates with an ideal chromophore, which can be a fluorescent or a 1106

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Table 2 Some of biomedical applications of MSNs with their status. Applications

MSN type

Status (Invitro/Invivo)

Ref.

Drug Delivery

Spherical mesoporous silica nanoparticles (MSNs) Magnetic mesoporous silica nanoparticles (MMSNs) Folic Acid-Modified Mesoporous Silica Nanoparticles

[147–149] [150–153] [83,154,155]

Bio-imaging

Mesoporous silica oxide micro-particles (meso-SiO2)/C-dot Graphene Oxide (GO)-enwrapped mesoporous silica nanoparticles MSNPs Trimethylammonium groups modified MSN (MSN‐TA) Stimulus-response mesoporous silica nanoparticle Different size range of SiO2 particles Poly(phenyleneethynylene) (PPE)/silica composite particles

Improve dissolution rate and bioavailability of hydrophobic Telmisartan (TEL) after oral administration In vitro delivering of hydrophilic/hydrophobic DOX-PTX and DOX-RAPA combinations simultaneously Camptothecin (CPT) in vitro For biological imaging/In vitro For bioimaging applications/Invitro NIR contrast agent for in vivo optical imaging

[156–158] [159–161] [162–164]

Chemiluminescence biosensor for cocaine determination glucose biosensor for physiological condition/Invitro For nucleic acid detection

[47,165–167] [168–170] [171–173]

Bio-sensing

high number of photosensitizers incorporated into a single MSN. They covalently linked the compound inside the particles and the particles further functionalized with mannose for cancer cell specific uptake [122]. Incorporating the photosensitizers into MSNs also prevented unwanted excitation by UV/visible light and the MSNs demonstrated no toxicity under standard illumination and the mentioned design led to selectivity and efficiency as well. Particles with a hydrodynamic diameter of 118 nm efficiently internalized in two breast cancer cell lines, MCF-7 and MDA-MB-231 in vitro with successful therapeutic outcome upon irradiation. The design further evaluated in vivo on nude mice bearing HCT-116 subcutaneous xeno-grafts [123].

recognition of some onions such as chloride, bromide and phosphate [113]. A number of recent biomedical applications of MSNs are summarized in Table 2. 5.4. MSNs theranostics: where therapy and diagnostic meet Theranostics is a field of medicine, which combines specific targeted therapy based on specific targeted diagnostic tests. The theranostics paradigm involves using nanoscience to unite diagnostic and therapeutic applications to form a single agent, allowing for diagnosis, drug delivery and treatment response monitoring [114]. A specific diagnostic test shows a particular molecular target on a tumor, allowing a therapy agent specifically to target that receptor on the tumor, rather than more broaden the disease and locate it presents. Employing theranostic nanoparticles, which combine both therapeutic and diagnostic capabilities in one dose, has promise to propel the biomedical field toward personalized medicine. Therapeutic strategies such as nucleic acid delivery, chemotherapy, hyperthermia (photothermal ablation), photodynamic, and radiation therapy are combined with one or more imaging functionalities for both in vitro and in vivo studies. Different imaging probes, such as MRI contrast agents, fluorescent markers, and nuclear imaging agents, can add onto therapeutic agents or therapeutic delivery tools to facilitate their imaging and, in so doing, gain information about the trafficking pathway, kinetics of delivery, and therapeutic efficacy [115]. In contrast to the development and use of separate materials for these two objectives, theranostics combine these features into one class, which has the potential to overcome undesirable differences in biodistribution and selectivity between distinct imaging and therapeutic agents. The most promising aspects of utilizing nanoparticles as therapeutics, diagnostics, and theranostics are their potential to localize in a specific manner to the site of disease and reduce or eliminate the possible numerous untoward side effects [116]. Theranostic nanomedicine can work better than other ones, since they have advanced capabilities in a single platform. This united platform includes sustained/controlled release, targeted delivery, higher transport efficiency by endocytosis [117], stimulus responsive agent release (i.e., smart delivery), synergetic performance (e.g., combination therapy, siRNA co-delivery) [118], multimodality diagnosis and/or therapies and quality performances (e.g., oral delivery, escape from multi drug resistance (MDR) protein, autophagy inhibition, etc.) [119,120].

5.5. MSNs application in tissue engineering Successful treatments in regenerative medicine will involve different combinations of factors to target Stem Cells and other cells in the niche, applied at different times according to the dynamics of stem cell–niche interactions. This can be achieved at high precision with nanoparticles [124].MSNs are designed for cell-targeted uptake and temporally and spatially controlled drug delivery of various classes of drugs, due to their high chemical flexibility [125]. The incorporation of such refined drug delivery vehicles in stem cell scaffolds offers a possibility for targeted and controlled delivery of biological cues. The application of MSNs in tissue engineering will allow for the development of advanced technologies to track stem cells, guide stem cell transplantation (diagnostics/imaging) and to obtain controlled and targeted delivery of stem cell signals (therapy) (126). Most of the research on MSN in tissue engineering has focused on osteogenic differentiation and bone tissue formation. One of the first reports of MSNs in tissue engineering was the attachment of MSNs on titanium substrates by layer-by-layer assembly as implant technology. The modified surface improved the bio behavior of osteoclasts [127]. Various silica composite scaffolds and particles generated to enhance drug delivery kinetics to obtain efficient and sustained drug release [127]. Amine functionalized MSNs, loaded with bisphosphonate drugs, incorporated in collagen hydrogels and MSNs with enlarged pores loaded with bone forming peptides, have been generated for prolonged and efficient drug release to support osteogenic differentiation. Dexamethasone loaded MSNs to which a bone morphogenetic protein-2 peptide was covalently grafted improved osteogenic differentiation of mesenchymal stem cells [128]. Aminated MSNs with large pores and a positively charged surface have been demonstrated to function as efficient gene delivery vehicles in mesenchymal stem cells to be used in bone tissue engineering. The application of MSNs in tissue engineering will drive new developments in the design of the technology, as well as the introduction of new methods and models for analyzing bio functionality and behavior. Advances in drug discovery and molecular stem cell research will further promote MSN research and medical applicability. Tissue engineering interconnects research within different disciplines, which will spur MSN technology development within drug

5.4.1. MSNs as therapeutic agents: photodynamic therapy Photodynamic therapy (PTD) has appeared as a competitive alternative to radio- and chemotherapy. The basic principal for PDT is the use of a photosensitizer that leads to the generation of cytotoxic species and cell death upon irradiation at specific wavelengths. There are numerous reports about using MSNs for therapeutic agents. For example, Gary-Bobo et al., used mannose-functionalized mesoporous silica nanoparticles for tumor-targeted cells [121]. In this work, the authors used MSNs to gain tumor specific targeting of the photosensitizer by the 1107

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delivery, diagnostics and molecular sensing which in turn gives rise to new tools for enhanced understanding of stem cell biology and stem cell-based tissue engineering [129].

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