Mesoporous Silica as Carrier for Drug-Delivery Systems

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Mesoporous Silica as Carrier for Drug-Delivery Systems

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Raul-Augustin Mitran1, Mihaela Deaconu2, Cristian Matei2, Daniela Berger2 "Ilie Murgulescu” Institute of Physical Chemistry, Bucharest, Romania1; University “Politehnica” of Bucharest, Bucharest, Romania2

1. INTRODUCTION Nowadays, human health is one of the highest priorities worldwide, and many efforts are focused on the improvement of treatment regarding cost, duration, and drug efficacy. Mesoporous silica nanoparticles (MSN) have received attention due to the possibility of their use as reservoirs for many biologically active molecules. Among the features that make mesoporous silica a versatile nanocarrier in drug-delivery and imaging applications, the most important are the high porosity and the possibility of modulating the surface properties via functionalization [1e3]. The most well known silica-type carriers include MCM-41 and SBA-15, with 2D hexagonal empty mesopore channels, or MCM-48, with a 3D cubic interconnected pores network. Silica nanoparticles were approved by the US Food and Drug Administration (FDA) for phase I human clinical trials in 2011. This represents an important step toward the clinical acceptance of silica nanoparticles [4]. Starting with the seminal work of Vallet-Regi on using MCM-41 mesoporous silica as a matrix for ibuprofen [5], MSN materials have shown great potential in this field. Mesoporous silica nanomaterials present a host of beneficial properties, which enable them to act as matrices for drug-delivery systems (DDSs), including excellent adsorption properties, biosafety, and ease of modifying the material’s textural and morphological properties through chemical synthesis. The large surface area and pore volumes of MSNs, often in excess of 1000 m2/g and 1 cm3/g, respectively, enable the storage and release of drug molecules through carrieretherapeutic agent supramolecular interactions. Both the MSN pores and the particles are easily adjustable and monodisperse. Furthermore, there are a number of chemical strategies available to tailor the surface MSN properties, which play a crucial role in drug adsorption and release. For instance, the acidity or basicity of the mesopore surface can be adjusted by the introduction of heteroatoms into the silica matrix (Al, Fe, Zn, Ti, etc.), while the hydrophobicehydrophilic

Nanocarriers for Drug Delivery. https://doi.org/10.1016/B978-0-12-814033-8.00011-4 Copyright © 2019 Elsevier Inc. All rights reserved.

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balance can be modified by chemically grafting organic groups. Moreover, the pore size, shape, and spatial arrangement (for example, hexagonal parallel pores, interconnected spherical pores, interconnected “wormhole” cylindrical pores) can be changed based on the synthesis reagents and conditions. The capacity of MSNs to carry cargo molecules was proven for various active pharmaceutical ingredients (APIs), including antibiotics [6,7], cytostatic agents [8e10], antiinflammatory drugs [11], peptides [12,13], etc. On the other hand, the size of mesoporous silica particles is very important for biomedical applications, and studies on their toxicity and biocompatibility have demonstrated that the large particles are accumulated in the liver, spleen, and bone marrow. It was also shown that the microvasculature of tumors is permeable to MSN and hence, they should have the right diameter to passively accumulate in tumors via an enhanced permeability and retention effect [14]. Not only the size, but also the shape of MSNs seems to alter their biocompatibility. He et al. reported significantly reduced A375 cell viability and apoptosis for long rod-shaped particles in comparison with spherical or small rod-shaped particles [15]. MSNs should have the right shape to be readily internalized by nonspecific cellular uptake, playing an active role in mediating biological effects. Another important issue is MSN biodegradability, which is higher than that of nonporous silica nanoparticles because of the higher surface exposed to the biological medium, and therefore a good colloidal dispersity is required for better degradability [16e18]. Yamada et al. [16] reported that the degradation of MSNs simultaneously proceeds from both outer and inner surfaces. The colloidal stability of MSNs increases when a high degree of siloxane network condensation is reached, usually when a hydrothermal treatment is performed. One method to control MSN biodegradability is through their surface functionalization. For example, Cauda et al. [18] reported a faster degradation rate for phenyl-functionalized silica than for MSNs modified with polyethylene groups. Nowadays, about 40% of approved drugs on the market are poorly water soluble, leading to low bioavailability, especially via oral administration; suboptimal dosing; and improper therapeutic response. A solution for this problem could be the utilization of a mesoporous silica nanocarrier, the drug molecules being in an amorphous state due to their nanoconfinement in the mesopores of the silica matrix. The amorphous phase has advantages over the crystalline form with respect to the drug’s solubility and dissolution rate. MSN encapsulation has been reported as a good strategy for increasing the drug dissolution rate and solubility in the cases of naproxen [19], carbamazepine [20], ibuprofen [21], etc. Generally, MSN-based vehicles that carry cytostatic agents and/or imaging probes should exhibit good colloidal stability in physiological fluids, especially when they are administered intravascularly. Therefore, the size, shape, structure, and surface characteristics of MSNs should be carefully controlled during their synthesis.

2. Synthesis of Mesoporous Silica Nanoparticle Carriers

FIGURE 11.1 Strategies for controlling mesoporous silica properties through synthesis.

2. SYNTHESIS OF MESOPOROUS SILICA NANOPARTICLE CARRIERS In the literature, there are reported several procedures based on the solegel method for obtaining MSNs, but frequently they have a large diameter, around 200 nm, and a significant tendency to aggregate. Thus, for biomedical applications, a careful selection of MSN synthesis methods is required to obtain nanoparticles with adequate dimensions for each specific application. Fig. 11.1 illustrates the common synthesis strategies for controlling the MSN properties. The most-used MSNs are MCM-41-type materials with a hexagonal pore array, which are usually synthesized using cetyltrimethylammonium (CTAþ) cations as the structure-directing agent, in basic solutions that are appropriate for the formation of spherical particles. In basic medium, cationic surfactants form micelles, which react effectively with negatively charged inorganic species by electrostatic interactions. The formation of pore geometry and its dimensions are strongly dependent on the supramolecular self-assembling of surfactant micelles and silicate species. The transformation of spherical to rodlike micelles is induced by charge neutralization of CTAþ cations with anions with higher polarizability [22]. The surfactant content also influences the mesostructure; a high surfactant/silicon molar ratio reduces the particles’ size and increases their colloidal stability. It was shown that a cetyltrimethylammonium bromide (CTAB)/alkoxysilane molar ratio of 0.13 or higher is required for obtaining highly dispersed MSNs [23].

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FIGURE 11.2 Morphology of mesoporous silica nanoparticles. (A) Stellate, (B) raspberry, and (C) wormlike.

The surfactant counterion, nature of the catalyst used for alkoxysilane hydrolysis and condensation reactions, pH of the reaction medium, and surfactant/silica precursor molar ratio are key parameters in controlling the morphology of MSNs. Both the surfactant counterion and the use of small organic amines (triethylamine, triethanolamine, 2-amino-2-(hydroxymethyl)propane-1,3-diol) instead of ammonia as the catalyst influence the MSN morphology. For example, under the same mild synthesis conditions, at pH 7, tosylate anions favored the formation of spherical particles with stellate channel morphology (Fig. 11.2A), while bromide anions led to raspberry-like particles (Fig. 11.2B). The pH value of the reaction mixture affects the MSN properties, a higher pH resulting in a wormlike morphology for MCM-41 particles (Fig. 11.2C) [24]. Other authors have shown evidence that a low surfactant/ silica precursor molar ratio favored the formation of a wormlike mesostructure, while a high value yielded an extended one [23]. Du and He [25] reported the synthesis of MCM-41 with sizes ranging from 72  19 to 96  16 nm using dodecanethiol (C12eSH) as a co-structure-directing agent in addition to CTAB, and trimethylbenzene as swelling agent, proving that the additives greatly affected the particle size. It was also demonstrated that the stirring rate of the reaction mixture during the hydrolysis of tetraethyl orthosilicate (TEOS) had a critical role, altering either the size or the textural properties of the particles. When the reaction mixture was slowly stirred (600 rpm), the hydrophobic C12eSH molecules were able to insert into CTAB micelles, acting as a pore size expander, and after TEOS addition, the silica nanoparticles were formed through a self-assembly between the resulting micelles and the negatively charged inorganic species. If the stirring rate of the reaction mixture is high, C12eSH molecules may form hydrophobic cores through aggregation assisted by CTAB. In this case the self-assembly between CTAþ and anionic silicate species occurs at the micelle interface and hollow MSNs are formed. These MCM-41 nanoparticles exhibited a hierarchical pore network and high capacity to accommodate organic molecules. Monodisperse, spherical MCM-48 MSNs with a diameter of 70e500 nm and high porosity (994e1248 m2/g specific

2. Synthesis of Mesoporous Silica Nanoparticle Carriers

surface area and 0.96e1.11 cm3/g pore volume) were obtained using a binary surfactant system consisting of CTAB as structure-directing agent and the triblock copolymer Pluronic F-127 as grain-growth inhibitor. Their synthesis was carried out through the kinetic control of silica phase formation using a high stirring rate of the reaction mixture after TEOS addition and a low surfactant/silica precursor molar ratio of 0.16. The authors demonstrated the possibility of modulating the pore size by applying a hydrothermal treatment and decreasing the particle diameter through the enhancement of the nonionic surfactant Pluronic F-127 concentration, the smallest particles with an average diameter of 70 nm being obtained with an F-127 concentration of 0.094 M [26]. The synthesis of very small MSNs with a diameter of 20e50 nm and an ordered hexagonal pore array by using the triblock copolymer Pluronic F-127 as a graingrowth inhibitor in addition to cetyltrimethylammonium chloride as the template agent in acidic solution was also reported. The presence of nonionic surfactant micelles, which coated the inorganic species, suppressed the particles’ growth and favored the ordered mesophase formation [27]. Another dispersing agent that can be used is carboxymethyl cellulose (CMC). Thus, by controlling the viscosity of the reaction mixture through the addition of CMC, monodispersed mesoporous silica nanospheres (MCM-48) with a diameter less than 100 nm and an ordered 3D pore array with Pm3n symmetry were obtained [28]. Small MSNs with a narrow size distribution in the range of 20e100 nm could be obtained by a careful control of the synthesis parameters, including the use of different additives along with the structure-directing agent. Usually, the decrease in particle size leads to less ordered mesophases and a tendency of particles to aggregate. Similar to the synthesis of other nanoparticles, a highly dilute reaction mixture favors stable colloidal MSN suspensions. Urata et al. [29] reported the synthesis of spherical MCM-41-type MSNs with an average diameter of 30 nm and a 3-nm pore diameter. Larger spherical nanoparticles with a diameter in the rage of 200 nme3.5 mm and interparticle pore size of 15e20 nm were obtained through spray-drying, by self-assembling of initial small nanoparticles. A nonionic surfactant with hydrophilic poly(ethylene oxide) blocks (PEO) and hydrophobic poly(propylene oxide) chains (PPO), named Pluronic, forms either spherical or cylindrical micelles depending on the ratio of PEO to PPO parts, with lower PPO content promoting cylindrical micelles. These are also influenced by concentration and temperature. SBA-15 silica, with a structure similar to that of MCM-41 but with thicker pore walls, is prepared in acidic or high ionic strength solution using Pluronic P-123 as template agent. The presence of PEO chains in Pluronic copolymers explains the existence of micropores in the SBA-15 walls. This type of mesoporous silica has larger pore diameter (6e10 nm) and higher hydrothermal stability than MCM-41. Although the pore diameter of SBA-15 is enough large to host most biologically active molecules, there is the possibility of achieving even larger mesopores by using swelling agents, mainly aromatic or aliphatic hydrocarbons, such as trimethylbenzene, xylenes, hexane, etc. [30].

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A key step in the synthesis of good-quality MSNs for biomedical applications is their purification through the removal of the structure-directing agent, which can be done by calcination [31], solvent extraction [32], ozone treatment [33], supercritical CO2 extraction [34], or dialysis [35]. The last method preserves the dispersity of small particles, avoiding the drawback of particles agglomeration during their separation by centrifugation. The use of pristine MSNs suffers from limitations in many biomedical applications because of the weak interactions with APIs. Therefore, MSN surface grafting with different organic moieties or polymers is an important strategy in developing new DDSs, as the presence of functional groups can tailor the drugecarrier interactions and enhance their colloidal stability and biocompatibility. The functionalization procedures should not significantly decrease the MSN porosity, which is a key feature of its drug-delivery role. The organic groups can be grafted onto the silica network either during MSN synthesis via cocondensation of silica precursors with an organosilane or after their synthesis using the postgrafting approach, by chemical reaction between silanol groups present on both pore walls and the nanoparticles’ surface and an organosilane. The dilution of the functional groups is the simplest strategy to obtain their good dispersion on the inner pore and outer silica surface and therefore MSNs with high surface area are required. Many research efforts are focused on obtaining functionalized MSNs as vehicles for different APIs to control their adsorption and release [2,36e38]. Hence, by MSN surface modification it is possible to design multifunctional platforms for targeted delivery and diagnosis.

3. APPLICATIONS OF MESOPOROUS SILICA IN ANTIBIOTICDELIVERY SYSTEMS Based on the MSN versatility, a significant number of mesoporous silicaebased DDSs were proposed in the first decade and a half of the 21st century. Most of the research was aimed at obtaining efficient DDSs for anticancer agents. There are a number of comprehensive reviews on this topic for the interested readers [39e43]. In this section, we will look at MSN-based DDSs for less explored applications, namely, antibiotic-delivery systems. One of the great challenges facing medicine in the 21st century is the rise of antibiotic resistance. Thus, a two-pronged approach is being employed: searching for new antibiotics and at the same time improving the efficiency of existing therapeutic agents. It is the latter approach for which MSNs are investigated, with a focus on creating controlled DDSs that can release their therapeutic payload in such way as to achieve the desired therapeutic effect over a larger time frame. Controlled antibiotic-delivery systems thus improve patient compliance and reduce the risks of developing resistance. In the next pages, several classes of antibioticemesoporous silica DDSs will be presented.

3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems

3.1 MESOPOROUS SILICAeBASED TETRACYCLINE DRUG-DELIVERY SYSTEMS Tetracyclines are one of the oldest broad-spectrum antibiotics still in use (Fig. 11.3). Chlortetracycline was the first member of this class discovered in the late 1940s by Benjamin Minge Duggar. Both natural and semisynthetic tetracyclines have been introduced for human and veterinary use since then. Their mechanism of action relies on the inhibition of protein synthesis by disruption of translation, acting as an inhibitor of aminoacyl-tRNA binding to the mRNAeribosome complex. Tetracyclines can be administered either orally or topically. The tetracyclineemesoporous silica studies so far can be grouped based on the administration route, either oral or topical. For oral administration, the main goal is to improve the tetracycline release profile so that a sustained release formulation can be achieved. A study of doxycycline adsorption and controlled release by pristine SBA-15 or SBA-15 functionalized with propyl amino groups (SBA-15-APTES) has shown that drug loading of up to 50% could be obtained for the pristine carrier through incipient wetness impregnation [44]. The drug release at isoelectric pH (5.5), in phosphatebuffered saline (PBS), from the amino-functionalized SBA-15 carrier is slower than from the pristine matrix. This effect was explained by the presence of electrostatic interactions between the amphoteric drug molecule and the charged silica surface. Aluminum-doped SBA-15 carriers were also investigated for doxycycline DDS, as aluminum incorporation results in increased acidity and therefore higher electrostatic interactions between drug molecules and mesoporous carrier [45]. An AleSBA-15 carrier functionalized with aminopropyl groups was found to have the best release profile in terms of sustained doxycycline release. Interestingly, no difference in release profiles was noticed upon increasing doxycycline content from 25% to 50% wt for the pristine AleSBA-15 carrier [45]. Composites containing ceria and MCM-41-type mesoporous silica could also control the doxycycline release [46]. In particular, slower release rates were obtained for CeO2eMCM-41 composites in comparison with pristine MCM-41 carriers. In the case of tetracycline, a similar effect of lower drug release rates from aminopropyl-functionalized SBA-15 carriers than from pristine SBA-15 was noticed in PBS, at pH 7.4 [6]. The tetracycline release rates were higher in highly acidic

FIGURE 11.3 The chemical formulas of tetracycline and doxycycline. (A) Tetracycline. (B) Doxycycline.

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media (pH 1.2) and lowest at pH 4.8. This effect is linked with the speciation of tetracycline molecules at different pH values. For example, at acidic pH, both the drug and the amino groups of the mesoporous carrier are positively charged, leading to electrostatic repulsions and higher release rates. The optimization of tetracycline loading parameters achieved a 42.3% wt maximum drug fraction [6]. Tetracycline loaded into MCM-41-type silica of different particle sizes was shown to possess higher efficiency against Escherichia coli than the free drug under similar conditions [47]. A comparison of hollow-sphere periodic mesoporous organosilane (PMO) with solid PMO spheres or solid mesoporous silica was carried out by Lin et al. [48] Tetracycline shows the highest release rates from solid mesoporous silica, followed by solid PMO, while hollow-sphere PMO is the best carrier in terms of sustained drug release. The study also highlights the widely different tetracycline release behavior in PBS versus simulated body fluid (SBF), with the former being much more rapid. This apparent startling behavior is easily explained by the capacity of all tetracycline antibiotics to form stable, less-soluble complexes with the various metal cations present in SBF. This is especially true for Ca2þ and Fe3þ complexes. The Fe3þ complexation reaction was exploited to increase the adsorption capacity of amino-functionalized SBA-15 toward tetracyclines [49]. However, no data regarding the release rates from Fe3þeamino-functionalized mesoporous carriers are available. Oxytetracycline delivery systems containing either MCM-41 mesoporous silica or aluminosilicate have shown good antibacterial activity against Staphylococcus aureus [32]. As opposed to the hexagonally ordered MCM-41 carriers, MCM-48 matrices with interconnected cubic ordered pore arrays are not suited to controlled oxytetracycline delivery. The cubic matrices lead to fast drug release, since diffusion is faster in the interpenetrating cubic pore network [32]. Similarly, with doxycycline, the release from ceria-containing MCM-41 carriers is slower for oxytetracycline than from pristine mesoporous silica [50]. The potential of obtaining mesoporous silicaebased chlortetracycline delivery systems was also investigated [51]. Coreeshell nanoparticles containing a magnetic Gd2(OH)5NO3 core coated with mesoporous SiO2 could load up to 23% wt chlortetracycline and act as a controlled-release DDS for this therapeutic agent. CMC gels containing MCM-41 or MCM-41 and ZnO nanoparticles have been investigated for the topical delivery of tetracycline [52,53]. The addition of MCM-41 mesoporous silica improved the swelling and permeability of the gels. Tetracycline was released in a controlled manner from the gels for up to 1 week. Comparing the various reports on mesoporous silica carriers for tetracycline antibiotics, it can be concluded that drug release occurs as a two-step process, with an initial burst stage followed by gradual, sustained release. MSNs are suitable matrices for prolonging the therapeutic effects of tetracycline antibiotics. In particular, the introduction of positively charged amino groups or other inorganic cations, either as adatoms in the silica framework or as oxide nanoparticles, is a promising strategy to extend the therapeutic agent controlled release. It is worth

3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems

noting that tetracyclines have multiple functional groups and thus multiple pHdependent speciations in solution. The release profiles are greatly influenced by the pH, a point that must be remembered when designing MSN-based DDSs for various applications. Furthermore, MSNs can both act as a drug reservoir and improve the mechanical properties of topical gel applications.

3.2 AMINOGLYCOSIDEeMESOPOROUS SILICA DRUG-DELIVERY SYSTEMS Aminoglycosides are traditional antibiotics most effective against gram-negative bacteria. Their chemical structure contains an amino-modified sugar residue (glycoside) [54]. Their mechanism of action involves the disruption of bacterial protein synthesis through binding to ribosomes [55]. The first member of this class is streptomycin, introduced in 1944 (Fig. 11.4). Both naturally occurring and semisynthetic aminoglycosides have since been developed. Aminoglycosides are usually administered intramuscularly, intravenously, or topically. The vast majority of studies on aminoglycoside delivery using mesoporous carriers were focused on gentamicin. One of the earliest literature reports compares the gentamicin delivery rates from SBA-15-type silica, either in powder form or as disks [56]. The authors show that the delivery has a pronounced burst effect, with 60% of the drug released, while no important differences between powder and disks were noticed. Importantly, this first report shows that drug loading up to 20% wt can be achieved. The same pronounced burst effect was found for 2.9-nm MCM-41, 2.5-nm cubic MCM-48, and hollow mesoporous spheres with 2.8-nm pores [57]. The different pore arrangements do not significantly modify the drug-release profiles in this case. A strategy to alleviate the fast release of gentamicin from MSNs is to coat the drug-loaded particles with various polymer layers, which act to control the drug release rate. Such complex systems can yield drug release over days to months. Typical applications include antibacterial implants or coatings for medical equipment. An example in this case is coating 200-nm spherical porous silica particles with Nafion, a polysulfonic acid [58]. Increasing the number of Nafion coatings or the

FIGURE 11.4 The chemical formula of streptomycin.

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mass fraction of the polymer leads to a decreased gentamicin release rate. Interestingly, the slowest release rate is obtained at pH 7.4, compared with more basic pH. Similar MSNs with 2.8-nm pores were coated through layer-by-layer assembly with polystyrene sulfonate and poly(allylamine hydrochloride), yielding similarly slow gentamicin release kinetics [59]. These materials adsorbed only 3% drug, but they could sustainably release it over more than a week. Increasing the number of polymer layers did not significantly impact the drug release kinetics in this case. Scaffolds for bone repair are another type of application in which sustained antibiotic release over days to months is required. Shi et al. obtained a composite containing hollow mesoporous silica spheres with 3.3-nm pores and hydroxyapatite, which was used to load gentamicin [60]. The composites were then coated with poly(lactide-co-glycolide), PLGA. The uncoated particles showed a typical release curve with around 60% drug delivery in the first day, followed by slower sustained release, reaching 90% delivery after 7 days. Coated composites with 20% or 50% inorganic component show slightly slower release rates and a direct dependence of the polymer content to release rate. In the best case, 90% gentamicin cumulative release was obtained after 2 weeks, with only 50% on the first day. Chitosanemesoporous silica sphere composites were also investigated for gentamicin delivery [61]. The organiceinorganic composite hydrogel shows good delivery kinetics, with a small burst release of 40% over the first 2 days. Interestingly, removing the silica nanoparticles leads to the loss of sustained release behavior, as most of the drug is released in the first 10 h. SBA-15 particles loaded with gentamicin were coated with poly(methyl methacrylate) to create acrylic bone cements with antibacterial properties [62]. Sustained gentamicin release over 70 days and activity against S. aureus were obtained. Moreover, the mechanical properties of the bone cements were not negatively impacted by the presence of the mesoporous particles. A similar approach to control the drug release was employed by Kavruk et al. [63] MCM-41 nanoparticles were loaded with vancomycin and further grafted with aptamers to specifically target S. aureus (Fig. 11.5). The aptamer-functionalized

FIGURE 11.5 Aptamer-gated specific delivery of vancomycin. MSN, mesoporous silica nanoparticle.

3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems

MCM-41 showed a 15-fold increase in efficiency against S. aureus, as well as sustained release over 30 h. A refinement of the aforementioned polymer coating strategies was introduced by Molina et al. [64] in 2015. Instead of relying on a multistep synthesis of the mesoporous carrier, followed by drug loading and then polymer coating, the authors proposed a simpler approach, involving the direct synthesis of the DDSs. This approach is based on the formation of polymereaminoglycoside complexes in solution, which can act to direct both mesopores formation and drug loading upon addition of a silica precursor. Complex DDSs with both sensing and bacterial inhibition capabilities for X-ray dental imaging devices were reported in 2017, using kanamycin as the active payload [65]. This smart, dual-function material was obtained by capping kanamycin-loaded MSNs functionalized with aminopropyl groups with colloidal lysozyme-templated gold nanoclusters, dispersed in a polymer matrix of PEO/poly(butylene terephthalate). The gold nanoparticles act as gatekeepers for the drug-loaded mesoporous matrix and as a sensing agent. In the absence of bacteria, the gold nanoparticles exhibit strong fluorescence, while in the presence of E. coli, the fluorescence is quenched and kanamycin is released. An alternative strategy to control the drug release rate from mesoporous silica matrices is to change the surface properties of the silica to promote stronger forces between the carrier surface and the drug molecules, which in turn will decrease the release rate. The effect of various levels of Al doping of MCM-41-type silica was investigated using amikacin as the model aminoglycoside [66]. The effect of pore size was also investigated. The results show that slower release kinetics can be obtained for the Al-doped carriers, while lowering the pore size from 2.8 to 2.4 nm also results in a slight decrease in amikacin release rate (Fig. 11.6). Interestingly, the amount of drug that could be loaded in the mesoporous carriers is directly proportional to the carrier pore volume, while the acidity of the aluminosilicate carriers does not significantly increase the toxicity of the bare nanoparticles. A comparative study between kanamycin A and amikacin release profiles from various mesoporous silica and aluminosilicate matrices was also carried out [7]. The effects of Al doping on MCM-41 (2.9-nm pores) and SBA-15 (6.3-nm pores), as well as functionalization with hydrophilic aminopropyl or hydrophobic methyl groups, were investigated. DDSs with MCM-48 silica with cubic interconnected mesochannels were also obtained. The results of the study show a remarkable difference between the release kinetics of the two similar therapeutic agents, which differ only by a five-C-atom side chain. Complete recovery of amikacin was noticed from aminopropyl-functionalized SBA-15 and cubic MCM-48 carriers, while kanamycin was only partially released from all carriers. While the slowest release rates were obtained for AleMCM-41 and methyl-functionalized SBA-15 in the case of amikacin, AleMCM-41 showed the fastest kanamycin release. Slower kanamycin rates were obtained for the cubic MCM-48 silica, which showed fast and complete amikacin delivery. No cytotoxicity at concentrations up to 100 mg/mL was noticed for any reported carriers up to 72 h.

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FIGURE 11.6 Variation of amikacin release after 24 h with mesoporous silica pore size and Al content. From Nastase S, Bajenaru L, Matei C, Mitran RA, Berger D, Ordered mesoporous silica and aluminosilicate-type matrix for amikacin delivery systems. Microporous Mesoporous Mater 2013;182:32e9.

3.3 MESOPOROUS SILICA DRUG-DELIVERY SYSTEMS FOR PENICILLIN ANTIBIOTICS Penicillin is a group of b-lactam antibiotics still widely in use, even though many bacteria have developed resistance. Penicillin antibiotics are among the first medications effective against bacterial infections caused by streptococci and staphylococci. Penicillin G, the first member of this class, was discovered by Alexander Fleming in 1928. Penicillin antibiotics inhibit the formation of peptidoglycan bonds in the bacterial cell wall through binding to the enzyme DD-transpeptidase. Members of this class can be administered intravenously, intramuscularly, or orally. The most-used antibiotics from this class are ampicillin and amoxicillin (Fig. 11.7). Not surprisingly, these antibiotics have received the most attention as possible payloads for MSN-based DDSs. One of the earliest examples of MSN carriers for penicillin drugs was the study of amoxicillin release from hexagonally ordered SBA-15 silica [67]. A comparison of drug release from powder or compressed disk showed slower release kinetics from the amoxicillineSBA-15 disks. The profiles showed a significant burst release in the first minutes for the powder formulation, while a more gradual release rate was obtained for the disk. However, only 15%e20% of the adsorbed drug could be recovered by the authors.

3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems

FIGURE 11.7 The general chemical structure of penicillin antibiotics and those of penicillin G, ampicillin, and amoxicillin.

One of the most attractive strategies to control a drug’s release rate is the functionalization of mesoporous silica with various organic groups. Using MCM-41 with 3.3-nm pores, aminopropyl or chloropropyl groups were introduced and further reacted with the amino acid tryptophan [68]. Two sets of materials, obtained through either postsynthesis grafting or cocondensation, were investigated. Amoxicillin was adsorbed into these materials and the therapeutic agent release profiles were compared. The authors found that the functionalized DDSs had better release kinetics than the pristine MCM-41 for sustained delivery application. The slowest release rates were obtained for postsynthesis aminopropyl-functionalized MCM-41, while the chemical grafting of tryptophan was shown to slightly decrease the drug release kinetics in all cases. The same study also reports a kinetic investigation of amoxicillin adsorption from solution, establishing that 8e12 h is the optimum contact time to maximize drug loading. The effects of aminopropyl, mercaptopropyl, and methyl substituents and their concentration on amoxicillin adsorption and delivery were also investigated using SBA-15 hosts with 7.8-nm pores [69]. A 12-h contact time was again found optimal with respect to drug adsorption for all carriers. Methyl substitution resulted in the highest amount of adsorbed drug. All delivery profiles show the characteristic two-stage release with a burst and sustained release process. At similar adsorbed amoxicillin levels, the pristine and functionalized SBA-15 carriers show similar release kinetics, demonstrating that in this case the effect of organic groups on the drug release is small. Consecutive functionalization with 3-iodopropyl, diethyl iminodiacetate, and benzidine was reported for SBA-16 silica with 8-nm pores (Fig. 11.8) [70]. Unlike MCM-41 and SBA-15, which possess hexagonally ordered, parallel pores, SBA-16 has a cubic, interconnected mesopore arrangement, sometimes referred to as a 3D cagelike structure. This type of structure can facilitate the diffusion of small molecules. Amoxicillin adsorption up to 20% wt was evidenced, which was explained by the increase in hydrophobicity due to the presence of organic substituents and favorable supramolecular interactions between the silica pore wall and

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FIGURE 11.8 Functionalization strategy for SBA-16 carrier for amoxicillin-delivery systems.

the drug molecules. The release kinetics were found to depend on the type of release medium: simulated gastric or intestinal fluid. Tubular MSNs have been obtained by using sacrificial carbon nanotube templates and further functionalized with aminopropyl groups. These materials were employed as carriers for ampicillin [71]. Ampicillin release profiles showed a burst release during the first 12 h, followed by sustained release kinetics for up to 2 days. A comparative study of ampicillin adsorption and release from 2.2-nm MCM-41, 6.5-nm SBA-15, or aminopropyl-functionalized SBA-15 was also reported [72]. The adsorption study shows that aminopropyl-functionalized SBA-15 has the highest ampicillin loading, but lowest adsorption rate. The ampicillin release is both slower and less complete for the aminopropyl carrier. The total drug amount that could be recovered increased from aminopropyleSBA-15 to pristine SBA-15 and to MCM-41. Another strategy for controlling penicillin release from mesoporous silica carriers consists in coating the MSN particles with different agents that can limit diffusion, such as polymers. Layer-by-layer coating, which adds successive layers of materials with alternative positive and negative charges, was employed to create amoxicillin-delivery systems [73]. The therapeutic agent was first loaded into 110-nm spherical MCM-41-like silica, functionalized with negatively charged carboxylic acid groups. Positively charged lysozyme, negatively charged hyaluronic acid, and 1,2-ethanediamine-modified polyglycerol methacrylate were then successively coated (Fig. 11.9). The amoxicillin release was increased in the presence of the hyaluronase enzyme. The material showed excellent activity against both gram-negative and gram-positive strains, with no significant hemolytic activity against human blood even up to 1 mg/mL and no cytotoxicity against human cells

3. Applications of Mesoporous Silica in Antibiotic-Delivery Systems

FIGURE 11.9 Layer-by-layer assembly and proposed mechanism of action. HA, hyaluronic acid; Lys, lysozyme; MSN, mesoporous silica nanoparticle; PGMA, polyglycerol methacrylate.

at a concentration of 0.5 mg/mL. The good activity and biosafety of the proposed materials has prompted an in vivo investigation, showing good inhibition for pathogens in bacteria-infected wounds. Layer-by-layer assembly was also used to successively coat a carboxylic acide functionalized mesoporous silica with 1,2-ethanediamine-modified polyglycerol methacrylate, cucurbit[7]uril, and tetraphenylethylene tetracarboxylic acid to obtain an amoxicillin-delivery system with responsive behavior [74]. The drug release could be switched on by adamantaneamine addition owing to the disassembly of a modified polyglycerol methacrylate and cucurbituril supramolecular complex. This effect was also tested against E. coli and S. aureus, with minimum inhibitory concentrations of 250 and 125 mg/mL obtained, respectively. No significant cytotoxicity was found for the stimulus-responsive DDS. A simpler strategy to create coated MSN antibiotic-delivery systems consists in the addition of a dye (rose bengal) to a mesoporous silicaecarbon dot nanocomposite [75]. The nanoplatform was primarily developed for cancer treatment by combining chemotherapy through controlled release of doxorubicin with the photodynamic therapy effect of the carbon dots. However, because infections usually accompany cancer treatment, the delivery of ampicillin was also studied. The nanoplatform was able to almost completely inhibit E. coli at a concentration of 100 mg/mL. Similarly, spherical MSNs functionalized with 3-aminopropyl groups were loaded with sulbactam, a b-lactamase inhibitor [76]. Next, the particles were coated with an Fe3þecarbenicillin framework. The nanocomposite displays pH-dependent release of b-lactam carbenicillin antibiotic, with faster release rates obtained at pH 5.0 than at pH 7.4. The coreeshell codelivery system is nontoxic, stable at physiological pH, and effective against methicillin-resistant S. aureus. A different approach to obtain complex antibiotic-delivery systems involves the successive chemical grafting or functionalization of different organic species on the silica nanoparticle surface. Polymer-coated MSN delivery systems were obtained by the chemical attachment of poly(itaconic acidecopolymerized methacrylic acid)egraftechitosan copolymer through chemical bonds to

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carboxylic acidefunctionalized mesoporous silica [77]. In vitro release experiments showed slower release kinetics for the copolymer-modified silica than for the pure drug, and a complete release after one day. The release pH was also shown to influence the kinetics, which is faster at pH 1.2 than at pH 7.4 irrespective of the carrier. No significant toxicity against healthy cells was reported, while good antimicrobial activity against E. coli was noticed, with a minimum inhibitory concentration of 50 mg/mL. A self-adhesive antibacterial coating for stainless steel was developed by first growing vertically aligned MCM-41 mesoporous silica, followed by functionalization with 3-aminopropyl, succinic anhydride, propynol ethoxylate, and b-cyclodextrins [78]. The complex nanoplatform shows bacterial-triggered, pH and enzyme dualstimuli-responsive release, as well as dual ampicillin and cinnamaldehyde release. Decreasing the pH yielded cinnamaldehyde release due to structural transformations of the b-cyclodextrin nanovalves, while enzyme addition led to the simultaneous release of both antibiotic payloads. The coating also displayed excellent antibacterial properties against E. coli, S. aureus, and methicillin-resistant S. aureus.

4. PERSPECTIVES AND OUTLOOK FOR MESOPOROUS SILICAeBASED ANTIBIOTIC-DELIVERY SYSTEMS Mesoporous silica materials have excellent properties for drug-delivery applications. Even though most research efforts are devoted to improving cancer treatments using MSNs, antibiotic-delivery systems employing mesoporous silica carriers have also been investigated. The most attractive features of MSNs for antibiotic delivery consist in the possibility of creating long-acting sustained release formulations and of combining drug delivery with imaging and targeting capabilities, as mesoporous silica are very versatile platforms. The rise of antibiotic resistance is a major problem of the 21st century, and any treatment that can delay this phenomenon is highly desired. As shown in the previous sections, many studies are focused on improving the antibiotic release kinetics from MSNs. Antibiotic treatments are usually taken multiple times a day, so developing once-a-day formulations can greatly improve patient compliance. Together with multidrug treatments, such a goal can prevent bacterial resistance from developing. If the timescale of sustained antibiotic delivery is increased to weeks, then depot formulations become viable, offering the possibility of a one-time treatment for antibiotic infections. However, the drug release process from mesoporous carriers is complex, being influenced by both the chemical nature of the therapeutic agent and the silica surface, by supramolecular interactions between the two and diffusion through mesochannels, as well as by the aqueous release medium and the presence of interfering ions or counterions. As such, limited strides have been made in completely understanding and controlling this process with the goal of the rational design of DDSs. Part of the problem lies in the established models used to quantify the drug release process. These are empirical or semiempirical models (Higuchi, KorsmeyerePeppas, etc. [79]),

4. Perspectives and Outlook for Mesoporous Silica

which provide only limited information on the process. A theoretical kinetics model that could be used to explain drug release from mesoporous silica was introduced by Zeng et al. in 2012 [80]. In this model, the active therapeutic agent molecules are assumed to be either adsorbed on the carrier surface or dissociated from the surface as free molecules inside the mesopore volume. An equilibrium between adsorption and desorption exists. The drug release process is completed by the diffusion of desorbed molecules in the external release medium [81]. This model accurately predicts the two-stage release kinetics usually noticed for drug released from mesoporous silica carriers (Fig. 11.10). The fast-burst stage corresponds to the fast transport of initially desorbed molecules, while desorption from the mesopore surface is the main process during the sustained-release stage [82]. Thus the release rate during the burst release is proportional to the diffusion rate constant, while the sustainedrelease rate is proportional to the desorption rate constant. The fraction of drug released during the burst stage depends on the adsorptionedesorption equilibrium and it is proportional to its Gibbs free energy [83]. The drug-release profiles presented in the literature, as well as the strategies to control them, can be more easily understood with the help of the three-parameter kinetic model. In most cases, the amount of antibiotic released during the burst stage of the delivery should be minimized, Thus the adsorptionedesorption equilibrium should move toward desorption. This is achieved by increasing the supramolecular interactions between the drug molecules and the pore surface through grafting organic groups or doping the silica framework. These strategies work especially well if electrostatic interactions can be used. Since many antibiotic molecules

FIGURE 11.10 Kinetic model of drug release from mesoporous silica carriers.

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present various functional groups with acid/basic character, a pH-responsive release can be achieved through careful selection of the silica surface charge at different pH values. Increasing the mesocarrier’s surface area will also increase the number of possible adsorption sites for the drug molecules. However, if the attractive interactions are too strong, the drug molecules will not be desorbed, leading to incomplete recovery of the antibiotic and reduced sustained delivery rates, lowering the overall effectiveness of the DDSs. Another intervention point for the rational design of mesoporous silica antibiotic carriers is lowering the burst-release rate, which can be achieved through lowering the overall diffusion and transport through the mesochannels. Several strategies can be employed, ranging from the introduction of organic groups with different hydrophobicity compared with the therapeutic agent, to increasing the mesochannel length by enlarging the particle size or aspect ratio. In this context, the mesopore arrangement also plays a crucial role, since MSNs with cubic interconnected pores present faster diffusion rates than hexagonally ordered materials. Perhaps the most promising strategy to lower the overall diffusion rates consists in coating the external silica surface with other materials, such as polymers. Last, the release rate during the sustained-release stage should be high enough to permit the complete delivery of the antibiotic payload. Incomplete antibiotic delivery or very small sustained-release rates can be noticed in several studies. A possible strategy to increase the sustained-release rates through increasing the molecule desorption rate from the mesopore surface consists in using carriers with larger pore size and volume, thus minimizing steric hindrance effects inside the mesopores. As seen in the previous section, this effect could be achieved by exchanging MCM-41-type carriers with 2- to 3-nm pore sizes with SBA-15 materials, which typically have mesopores in the 6e8 nm range. The passive methods for controlling antibiotic release kinetics can also be combined with active, stimulus-responsive behavior. Examples of stimuli that can be employed in the fight against infections include changes in the pH environment, the presence of specific bacterial enzymes, decomplexation reactions, or conformational changes on DNA binding. As expected, such DDSs are more complex than simple antibiotic-loaded mesoporous silica carriers. These complex platforms can be obtained through successive addition of different layers using either electrostatic interactions or chemical bonding. Some reports of simplified procedures for simultaneous synthesis have been published. Complex delivery platforms can also be endowed with targeting and imaging behaviors. Targeting strategies range from electrostatic interactions with the bacteria cell wall to grafting specific aptamers able to bind to the bacterial surface. Perhaps one of the most important approaches to creating effective antibioticdelivery systems lies in the codelivery of synergetic agents together with the therapeutic agent. This approach is possible owing to the outstanding porosity of mesoporous silica materials. Especially important is the possibility of using this approach to decrease the chance of developing bacterial resistance, since resistance to one drug still leaves the bacteria susceptible to the other.

References

The progress in the field of mesoporous silica carriers for antibacterial treatments shows good promise in creating effective treatment options and stemming the rise of bacterial resistance. The high porosity and possibility of specifically tailoring the properties of mesoporous silica materials through both chemical synthesis and supramolecular interactions make this class of nanomaterials especially suited to the task at hand. A number of strategies have been developed to control the antibiotic release and to achieve stimulus-responsive delivery, targeting, and imaging for mesoporous silica-based antibiotic DDSs, which have been presented in the previous pages.

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