Mesoporous silica nanoparticles: synthesis, properties, and biomedical applications

Mesoporous silica nanoparticles: synthesis, properties, and biomedical applications

Chapter 16 Mesoporous silica nanoparticles: synthesis, properties, and biomedical applications Marco A. Downing and Piyush K. Jain Department of Chem...

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Chapter 16

Mesoporous silica nanoparticles: synthesis, properties, and biomedical applications Marco A. Downing and Piyush K. Jain Department of Chemical Engineering, Herbert Wertheim College of Engineering, University of Florida

16.1 What are silica nanoparticles? The Food and Drug Administration (FDA) defines nanoparticles as particles less than 1000 nm. In contrast to the FDA, the medical field commonly defines nanoparticles as less than 500 nm, as nanoparticles that are less than 500 nm can be endocytosed by cells. However, particles between 500 and 1000 nm can be used for medical applications, as they can possess useful bulk properties such as optical or magnetic properties despite not being able to enter cells. Nanoparticles’ role in medicine has mainly focused on drug delivery, as many types of nanoparticles can act as stable vectors in vivo while transporting less stable therapeutic drugs. Nanoparticles are chemical delivery vectors, opposed to the biological viral vectors, such as adenovirus, lentivirus, or adeno-associated virus. However, new research on modular nanoparticles that contain both biological components such as peptides or lipids and traditional chemical components such as silica or iron oxide show promise as a future sector of drug delivery. This chapter will focus on a type of nanoparticle that is particularly promising for medical applications: silica nanoparticles.

Silica nanoparticles, also known as nanosilica, make up a major section of nanoparticle research with an emphasis on biomedical applications due to their low toxicity and stability in the body. Silica nanoparticles are often referred to as mesoporous silica nanoparticles (MSNs) due to their unique property of being mesoporous or containing pores between 2 and 50 nm in diameter. MSNs have a structure of (SiO2)n and can be made in a variety of ways resulting in vastly different properties. MSN synthesis only requires four main components: a silica precursor such as silane, a catalyst, solvents, and a surfactant.1e3 However, even though synthesis only requires these four components, MSNs with different properties such as diameter, pore size, surface area, and shape can be achieved.4 There are three unique properties that make the mesoporous nature of MSNs ideal for biomedical application, see Fig. 16.1. First, their porosity makes MSNs effective carriers of small molecules and proteins for easy drug delivery. Second, their structure also provides MSNs with a half-life long enough to be stable in blood serum while also degrading by physiological systems at longer residence

FIGURE 16.1 Biomedical systems design and applications using silica. Credit: Original figure.

Nanoparticles for Biomedical Applications. Copyright © 2020 Elsevier Inc. All rights reserved.


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times. This is important, as any nanoparticle used in medical applications must not build up in the body. Finally, MSN formulation provides consistent and predictable particle sizes with tunable features such as diameter, shape, porosity, and both core and surface features. This tunability allows a wide variety of MSNs to exist and is a broad area of research, as different structures will be ideal for different medical applications, whether that is targeting different tissues or carrying different cargo. Recently, new areas of research in silica nanoparticles have arisen with developments in mesoporous organosilica nanoparticles (MONs) and periodic mesoporous organosilica (PMO) nanoparticles. Changing the silica precursor to include an organic R group has created these novel nanoparticles. This leads to a particle structure of (SiO1.5R-SiO1.5)n and can have significantly more complex internal chemistry, depending on the chosen functional R group.5e17 MONs and PMOs have potential for unique medical applications but will have a larger barrier to pass clinical trials. Toxicological studies on MSNs translate to other MSNs but do not translate over to MONs or PMOs. Additional toxicological testing would be required for each R group configuration of MON/PMO, adding an additional challenge to their medical use. For further reading on MONs and PMOs, refer to these excellent review articles1,18e21 which go into much more detail on these novel systems (Fig. 16.2).

FIGURE 16.2 Silica nanoparticles variants: silica nanoparticle (SNP), mesoporous silica nanoparticle (MSN), mesoporous organosilica nanoparticle (MON), periodic mesoporous organosilica (PMO). Credit: Original figure.

16.2 How are silica nanoparticles made? Silica nanoparticle production usually occurs under the solegel process, a soft chemistry process occurring at ambient temperature in either acidic or basic conditions. The process starts with a precursor, some type of silane such as tetraethyl orthosilicate (TEOS) Si(OEt)4 or tetramethyl orthosilicate (TMOS) Si(OMe)4 in an aqueous solution. The reaction occurs through a hydrolysis and condensation reaction in the presence of either an acid or base catalyst such as HCl or NH3.22e28 As the reaction occurs, the precursors form a crystalline nanostructure as shown in Fig. 16.3. The choice of an acid or a base as the catalyst determines whether the hydrolysis or the condensation step is faster. In the case of an acidcatalyzed reaction, hydrolysis is much faster than condensation, leading to many small silica particles forming. These smaller particles tend to form a gel-like structure. Conversely, the base-catalyzed reaction has a faster condensation step than the hydrolysis step, which forms larger silica nanoparticles. If only these three ingredients are used, the silica particles made are nonporous and tend to form either gel networks (acid-catalyzed) or solid spheres (base-catalyzed) (Fig. 16.4). MSN production is both simple and complicated; while requiring only four key components, the tuning of the process can give a wide variety of results. The addition of a surfactant to the solution allows the formation of MSNs. The generation of mesopores within the silica nanoparticles is due to the surfactant acting as a template for the growth of the silica structures. The choice of surfactant is important for determining the mesopore structure. A common surfactant used is cetyltrimethylammonium bromide, as it can form micelles in aqueous solutions when above a critical micellar concentration. A micelle is formed when the hydrophilic portion of the surfactant orients itself toward the aqueous solution, making the hydrophobic region orient inward. The hydrophobic regions then aggregate forming a sphere-like micelle (Fig. 16.5). As you increase the concentration of surfactant, these micelles change shape, going from spheres to cylinders to hexagonal channels. If larger pores are needed, the addition of a hydrophobic swelling agent as the fifth component can be used. By changing the quantity, type of surfactant, and by adding swelling agent,31 it is easy to repeatedly generate MSNs with defined porosity. Once the MSN structure is formed, the removal of the surfactant is critical for medical applications. As most surfactants are cytotoxic, complete removal of surfactants is vital for utilizing the generated MSNs. This is commonly done using two methods: calcination or solvent extraction. Calcination is done by heating the synthesized MSNs to temperatures as hot as 800 C. These extremely high

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FIGURE 16.3 Hydrolysis and condensation reactions of silanes. Credit: Ref. 29.

FIGURE 16.4 Silica synthesis pathways under acidic(gels) and basic conditions(sols). Credit: Original Figure.

temperatures are required to bring the solution above the decomposition point for the surfactant in solution. The downsides of calcination are the high temperature, energy requirement, and the surface modifications that occur. At high temperatures, the SieOH bonds on the surface of the MSNs react together to form SieOeSi bonds. This constricts the surface and pores, changing the pore size and making the particle more hydrophobic. Solvent extraction can also be used depending on the surfactant and whether the reaction occurred at acidic or basic conditions. An example of solvent extraction is using ammonium nitrate to extract the nanoparticles. The advantage of solvent extraction is the significantly lower temperature and energy requirement. The main downside to solvent extraction is the potential need for more costly separation processes

FIGURE 16.5 Variations in micelle shape formation which lead to an array of silica pore sizes. Credit: Ref. 30.

downstream due to additional solvents being used. Regardless of which method is used, complete removal of the surfactant must be confirmed before use of the MSN. Further modification of the MSNs can be done to functionalize the core, the surface, or both the core and the surface. Surface modifications can be through either chemical reactions or various coatings. Different surface chemistry reactions are possible on MSNs, depending on whether the surface groups are silanol (SieOH) or siloxane (SieOeSi). Adding functional groups to the surface of

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MSNs has been used for controlling the rate of drug release, determining the location of drug release, and reducing the toxicity of MSNs. Common coatings for MSNs have been different types of polymers such as polyethylene glycol (PEG),32 polyethyleneimine (PEI)-PEG copolymer,33 or poly (N-isopropylacrylamide).34 Core modifications are commonly used for hybrid nanoparticles. For example, MSN-coated iron oxide (Fe3O4) nanoparticles can be used to impart magnetic properties to MSN particles.35 Other metal cores such as gold-core MSNs36e41 and silver-core MSNs34 have been made, with more hybrids being published every year. The variety of MSNs leads to vastly different property ranges for size, pore shape, pore volume, surface area, etc. Common MSNs for biomedical applications can have diameters ranging from 300 nm to less than 10 nm.25 Particles can be made as a monopore (hollow silica nanoparticle with only one pore) with a diameter less than 10 nm42 allowing for very specific cargo sizes and pore diameters ranging from 30 nm to as small as 2 nm.43 Pores have been generated with a variety of shapes such as hexagonal,44 cubic,45 concentric,46 foam-like,46 radial wrinkle-like,47 worm-like,48,49 hierarchical dual,50 and triple porosity51 (Fig. 16.6). The hierarchical porosity structures can be formed through stepwise synthesis using different surfactant concentrations. The variation in the pore types allows for vastly different cargo-carrying capabilities. Most MSNs have a well-defined ability to carry cargo with a pore volume of 1 cm3/g; however, they can have a pronounced capacity for carrying cargo with the largest pore volume reported being as high as 4.5 cm3/g. Because of the large pore volume, MSNs also have large surface areas on the order of 1000 m2/g, making them much larger than nonporous silica which have a surface area on the order of 10 m2/g. The variability in the physical properties of MSNs leads them to have a wide variety of medical applications.

16.3 Why are silica nanoparticles appropriate for medicinal use? Silica nanoparticles have great potential for medicinal use due to their biocompatibility, lack of toxicity, and biodegradability. MSNs have well-understood biocompatibility in the human body with numerous studies having been performed. While some nanoparticles have issues with acute toxicity, MSNs have been found to have dosedependent toxicity.1 The therapeutic dose for MSN delivery is well below the toxic dose, making MSNs an excellent option for medical applications. A big part of MSNs’ biocompatibility comes from the generation of a protein corona on the surface of MSN particles.51,53e57 A protein corona is a dynamic coating of proteins that binds to

the outside of the MSN particles, masking it as it travels through the body. This protein corona can be utilized to improve MSN toxicity and stability by adjusting the surface chemistry of the MSNs. Finally, a key factor for medical use is whether a drug can effectively clear the body or whether there is toxic buildup over time. MSNs, as they are fundamentally just SiO2, are biodegradable for longer time spans in the body. This biodegradability is due to a hydrolysis reaction in the body that occurs on the surfaces of MSNs, breaking apart the silica nanoparticles into silicic acid. This reaction prevents the toxic buildup of MSNs in the body. MSNs are readily available for medical use as they have excellent compatibility with the human body compared with other potential nanoparticle vectors. Silica has been recognized as safe for use by the FDA due to their known biocompatibility, making them very attractive for pharmaceutical use. The FDA has recognized silica as “safe” for over 50 years, which makes the hurdle for deeming MSN-based drugs as “safe” mainly dependent on the modifications and cargo of choice. Silica nanoparticles, without modifications, have two primary mechanisms for toxicity in the human body.46 The first mechanism is due to surface silanol groups becoming reactive on losing their hydrogens. The reactive SieOgroup causes membranolysis by reacting with the tetraalkylammonium-containing phospholipids58 on the cell membrane. The second mechanism is due to siloxane groups on the surface, forming three-membered siloxane rings, which are unstable and, hence, reactive. These reactive siloxane rings, like the silanol groups, can also cause membranolysis.59 The presence of silanols and siloxane groups on the surface of the MSNs is dependent on whether the surfactant was removed through calcination or ion-exchange during MSN synthesis. This makes knowing the synthesis route of your MSNs important when understanding potential toxicity of your MSNs. It is important to note that both mechanisms are dependent on the surface chemistry of MSNs. Targeting surface modifications will have an acute effect on toxicity and is important when designing new MSNs for drug treatment. Regardless of whether the surface is primarily silanols or siloxanes, the potential for toxicity at higher dosages is present. Luckily, these mechanisms are not readily seen in MSNs at the dosages used for therapeutics.60 Therapeutic in vivo particle dosages have been shown to typically be anywhere from 1 to 50 mg/kg61 with 80 mg/kg being shown to be well tolerated.62 This is significantly less than the LD50 for MSNs which has been proposed to be around 1000 mg/kg.62 The high LD50 for MSNs suggests that regardless of what mechanisms there are for MSN toxicity, they do not pose major issues for biocompatibility at therapeutic dosages. Targeting the primary cause of toxicity, the surface of MSNs, should be the focus of increasing biocompatibility.

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FIGURE 16.6 Typical transmission electron microscopy images of pore types found in mesoporous silica nanoparticles. (A) Hexagonal, (B) cubic, (C) concentric, (DeF) radial wrinkle-like, (G) foam-like, (HeI) hierarchical dual, (JeO) triple porosity. Credit: Refs. 1,44e49,52.

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Surface chemistry and biology of MSNs gives pharmaceutical chemists unique ways to improve the medical applicability of MSNs. Surface groups are the primary reactive species that can cause toxicity due to MSNs. Through surface chemistry modifications, not only can the toxicity be changed but the medical applicability of MSNs can also be improved. Modification of the surface can change the biodistribution of MSNs in the body. Biodistribution is the understanding and quantification of where a target compound accumulates in the body. Targeting of tissues or cells of interest is key for an ideal biodistribution, which will be effective for medical treatment. Through improving the specificity of nanoparticle delivery to the cells of interest, the therapeutic dose is effectively reduced because less dosage is wasted. For MSNs, this has primarily been done with surface modifications allowing for targeting specific tissues or diseases. For example, treatment of MSN’s surface with PEI-PEG copolymer increased the percentage of MSNs that arrived in the target tumor cells from less than 1%e10%.33 This increase in specificity would allow for lower magnitude dosages to achieve the same results. MSNs are unique, in that their surface modifications can be done not just chemically but also biologically due to the presence of a protein corona. The protein corona is formed through proteins adsorbing onto the mesoporous surface, creating a shell around the nanoparticles.63,64 This is important because the nature of proteins that attach to the

surface of the MSN can change the way the body interacts with the MSN. Effectively, the presence of the protein corona reduces the hemolytic effect of the surface of the MSN65,66 and effects cellular internalization.67 This can potentially mask surface modifications, which is important to remember during MSN design. The protein corona can also allow for particles to pass through the bloodebrain barrier68 or to be taken up by monocytes or macrophages.69,70 Considering the protein corona while designing MSNs for drug delivery is key; if it is not considered, surface engineering modifications may not have the desired expectations.71 The protein corona can be controlled indirectly by changing surface charge, pore size, pore shape, and hydrophobicity/hydrophilicity. As the protein coronas are dynamic in vivo, it can be hard to pretreat MSNs with proteins before use. However, further research in binding proteins to the MSNs could allow that to be a useful option for improving specificity and reducing toxicity. Degradability of silica in the body promotes a fast track of MSNs into clinical trials. The largest barrier for clinical trials of nanoparticles is the requirement of particles to clear the body and not accumulate. Thus, proving that any particles delivered to the body will not have long-term effects due to accumulation is vital (Fig. 16.7). Silica nanoparticles have great promise for degrading in the body, as it is the third most abundant trace element in the body. Silica nanoparticles have one of highest potentials

FIGURE 16.7 Degradation pathways of nanoparticles in vivo. Credit: Refs. 18,72.

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for medical applications, being readily degraded in the body through a three-step reaction mechanism.73 The MSN’s surface first goes through a hydration step where water adsorbs onto the surface. Next, a hydrolysis reaction occurs as water reacts with the siloxane groups converting them to silanol groups. The silanol groups can then participate in an ion-exchange reaction, which causes the Si to leave the nanostructure in the form of silicic acid. Silicic acid is considered nontoxic18,74 and clears the body through the urine.75 This dissolution of Si from the nanostructure has been shown to follow this dissolution reaction rate, via Ehrlich, Demadis et al.76:  m p m Rdiss ¼ k1 SiOH2þ þ k2 ½SiOH þ k3 ½SiO  : [16.1] The dissolution rate and order of reaction is determined by which form of silanols are present on the surface of the nanoparticles, with m and p being the reaction orders. The pH of the system will determine whether the surface silanols are protonated, neutral or deprotonated effecting the overall rate of dissolution. Because the reactions occur primarily on surfaces, pore size and, by extension, surface area are important for degradation times. As the porosity increases, the rate at which the particle degrades in the body increases. Once silica degrades, it can be used in the body, and excess silicic acid or poly-silicic acid nanoparticles (less than 6 nm) can be excreted through the kidneys into the urine.77,78 The clearance time of MSNs can vary widely due to differences in surface coatings, morphology, thermal oxidation, and surface functionalization. This variance in clearance times mimics the variability in MSNs and is something that should be considered when designing new MSNs. Anything that limits or halts clearance of the MSNs will have the potential of introducing long-term toxicity and buildup.

16.4 What kinds of cargo can MSNs deliver? For any kind of medical use, silica nanoparticles are simply delivery vectors that can be tailored for a specific cargo of choice. Silica nanoparticles have the capability of carrying cargo in their mesoporous structure, ranging from small molecules to large proteins. This is primarily due to the tunability of the pore sizes and shape, allowing for accommodation of small (1 nm size pores)42 to large (50 nm size pores) molecules or proteins.79 Cargo can be loaded to MSNs without any kind of additional surface treatment. Specifically, MSNs can deliver two types of cargos: noncovalently loaded hydrophobic cargos and noncovalently loaded hydrophilic cargos. However, without surface treatment, MSNs have the issue of leaking cargo during delivery. One solution to this problem is the surface engineering of “pore-gates” or molecules that act as a way of


sealing the MSNs pores on the surface, preventing leakage. This is key for avoiding side effects and loss of efficiency, due to leakage, to nontarget tissues and cells. Scientists have created a myriad of “pore-gates” that can have a variety of drug-release “triggers.” Often the type of “pore-gates” used act as cleavable molecular bridges, or nanovalves, that perform conformational changes. These bridges can be activated in a variety of waysdsome under the control of the drug administrator, and some dependent on tissue/cell location. Many mechanisms have advantages and disadvantages due to their respective technologies. Thus, it is important to always consider the unique qualities of the disease or tissues of interest before selecting a drugrelease method (Fig. 16.8). One common release mechanism is pH-dependent drug release. This works as MSNs are brought into the cell through endocytosis. During this process, the endosome carrying the MSN will continually drop in pH. If the cleavable group reacts at a pH between physiological pH (<7.4), but higher than lysosomal pH (4.5 >), then drug release can be triggered during the endosome to lysosome transition. This drop in pH can either cleave the molecular bridges or change their orientation on the surface of the MSN, releasing the cargo from the MSN. However, it is important to consider the cargo, as many things can be degraded at such a low pH. Endosomal escape is imperative for release of cargo from the endosome/lysosome into the cell. One example of pH changing the surface conformation is rotaxane, which gradually changes its conformation as the pH drops below 5.81 Dissolvable coatings have also been used on MSNs such as a calcium phosphate.82 Like pH-based groups, redox-based groups have also been used. Targeting compounds upregulated in specific tissues or diseases that act as reducing agents allows for targeted delivery. For example, glutathione, a reducing agent, has a much higher intra- rather than extracellular concentration. One group took advantage of this property to trigger the redox reaction of disulfide groups of a nanocap formed from b-cyclodextrin with disulfide connecting groups. They showed that the extracellular concentration was not high enough to trigger the redox reaction and that leakage did not occur.83 Functional groups that are cleavable by specific enzymes have also been created. Specificity can be increased if the tissue of interest is the only tissue expressing a certain enzyme. For example, a group has used a molecular a-cyclodextrin with adamantane as “stoppers” to close the pores of silica nanoparticles, which can then be opened with the enzyme porcine liver esterase.84 A medical application of this has been performed with anticancer drug delivery, specifically targeting colon cancer. Drug delivery was limited to the colon by utilizing a polysaccharide coating, guar gum, which can only be cleaved by enzymes present in the colon. This is often very important as drugs

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FIGURE 16.8 Representation of pH control and the structures of mesoporous silica nanoparticle. Credit: Refs. 1, 46,80.

used in chemotherapy-based cancer treatment can cause significant negative side effects, which can be minimized by highly specific delivery mechanisms. Drug delivery mechanisms that are under the control of the person administering the treatment consist of lightactivatable,85 magnetically triggered,86 and ultrasoundtriggered groups.87 For example, light-activatable nanoparticles are controlled by exposing a light to the target tissue. This treatment is limited by the attenuation of light particles through the body, which limits applicability to targets close to the skin. Light-activatable groups can be photolysis-responsive, photoisomerization-responsive, photoredox-responsive, and photothermal responsive.85 Magnetically triggered groups can be triggered via an external magnetic field but are limited by the resolution of the applied magnetic field.87 These are often just nanovalves with thermally decomposable bonds that are broken when the magnetic particles are exposed to an oscillating

magnetic field, generating the heat required to break the bonds.86 Ultrasound-based groups are in the early stages of research and could be a potential option for future nanoparticles.

16.5 What applications are MSNs currently used for in medicine? MSNs currently have two main applications: imaging and drug delivery. Imaging applications have consisted of bioimaging through positron emission topography (PET) imaging, ultrasound imaging, time-gated fluorescence imaging,88 and magnetic resonance imaging. Drug delivery has been used to deliver a variety of cargos, such as genes or proteins, gaseous molecules, and multiple drug cocktails. These various drug delivery mechanisms can be used in a variety of medical applications, such as cancer therapy, Alzheimer’s disease therapy, and antibiotic treatment.

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Utilizing MSNs for bioimaging takes advantage of the large storage capacity of MSNs. A key issue with in vivo bioimaging is the stability and biodistribution of imaging particles in the body. Oftentimes, delivery vectors are the solution to these issues, as they provide protection from the various enzymes and molecules present in the body. One example of this technology being used in medical applications is bioimaging through PET; PET takes advantage of radionuclides which emit a positron during their decay. The positron then reacts with electrons nearby, annihilating into two distinct gamma rays in opposite directions, which can then be detected by a scanning device. PET traditionally has strong tissue signal penetration but has issues with low spatial resolution. This makes it useful for deep tissue imaging, though it often relies on other imaging techniques to improve its resolution. However, MSNs provide an alternative way to improve the resolution of PET directly. Through loading MSNs with radionuclides such as zirconium-89,89e92 arsenic-72,93 copper-64,94e102 technetium-99,103 titanium-45,103,104 fluorine-18,105e107 or carbon-11,108 it is possible to increase both the tissue selectivity and the resolution due to higher overall signals. The MSNs protect the radionucleotides from being lost during systemic circulation, which increases the quantity of molecules that make it to the target tissues. MSNs provide a novel way of improving the specificity and resolution of PET that were not previously possible. Another imaging technique utilizing MSNs is ultrasound imaging. This technology works by using high intensity focused ultrasound (HIFU) which uses mechanical vibrations on the order of 1e20 MHz frequency.87 This form of imaging is already an FDA-approved technology but has one key issue: poor resolution. One way to improve the resolution issue is to utilize enhancement agents (EAs),109 which can enlarge the tissue site and improve imaging. This tissue enlargement is often done through bubble formation; MSNs provide a unique way of adding “bubbles” due to their porosity. Delivery of hollow MSNs to the tissues of interest is a way of adding “bubbles” to improve HIFU imaging resolution. This has been performed in a coupled system, where the hollow MSNs also delivered additional EAs on their surface, further improving HIFU imaging resolution.109 The porosity of MSNs provides unique ways of carrying cargo that is useful for imaging, whether that is radionuclides, or just hollow “bubbles” for HIFU. MSNs are synonymous with drug delivery due to their diverse cargo-carrying capacity and medical applications. Originally, MSNs were mainly used for small drug delivery because pore size limited protein loading to only the surface of MSNs, but recently as MSN engineering has improved pore sizes, larger proteins are being delivered. Large molecules such as plasmid DNA have been successfully delivered with MSNs’ with pore sizes around


20 nm.110 MSNs have also been used to deliver siRNA with a concentration of 380-mg siRNA/mg MSN.111 Delivery of extremely small molecules such as nitric oxide (NO) and carbon monoxide (CO) via MSNs has also been shown.112 Small molecule drug delivery of CO and NO is done through carrying releaser molecules that can be externally triggered to release CO or NO. This is important because CO and NO, at a certain dose, can cause cell apoptosis, a trait that is utilized to kill cancer cells. Because of the ability for one MSN to have different pore sizes, it is possible to create a cocktail drug therapy within one MSN particle. This delivery mixture is important for medical applications as cancer and many other diseases often show improved treatment under multiple drugs. This process is known as combination therapy and is often used through the delivery of multiple drugs alongside siRNA for cancer treatment. While independently siRNA and cancer treatment drugs work, the combination has been shown to greatly increase efficiency. In one study, codelivery of siRNA and doxorubicin was shown to cause cell apoptosis in 37% of breast cancer cells versus 14% for just doxorubicin by itself.113 This combination therapy approach allows MSNs to be uniquely effective for complex drug delivery applications. MSNs’ drug delivery can also be used as a disease marker. For example, in Alzheimer’s disease, it is theorized that aggregation of amyloid-b (Ab) proteins leads to the progression of the disease. It is also known that during this aggregation process, cytotoxic reactive oxygen species are formed, such as H2O2. Scientists utilized this fact to design MSNs with an H2O2responsive trigger to deliver a drug known for reducing Alzheimer’s progression, clioquinol, to the brain.114 This controlled mechanism was important for reducing cytotoxicity through increased specificity. MSNs provide a great way for targeting brain-based diseases such as Alzheimer’s disease because of their ability to be designed small enough (<30 nm) to pass the bloodebrain barrier. MSNs can also be used to deliver antibiotics systematically through the body. Through loading MSNs with antimicrobial ionic liquids without a surface coating, passive drug delivery is possible.115 Similarly, one group delivered antimicrobial peptides via MSNs to combat lung infections.116,117 Another delivery mechanism is coating the surface of MSNs with antimicrobial lysosome enzymes that will become active once the MSNs are endocytosed into the bacterial cells.118 A combination of these two methods could prove useful for future antibiotic MSNs. The challenges remaining for utilizing MSNs in the clinic consist mainly of study-design issues such as quantifying biodistribution in humans. In addition, methods for determining MSN concentration in tissues can be challenging as most methods used on animal models are invasive and not applicable to humans.

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16.6 New types of silica NPs, MONs, and PMOs: what makes them different? While MSNs have historically been the major, if not the only, area of silica nanoparticle research, two additional types, MONs and PMOs, are budding sectors in current silica nanoparticle research. Despite the already highly customizable MSNs, the more complex MONs and PMOs provide exponentially more design possibilities. This order of magnitude increase in variability has everything to do with the structure of MONs and PMOs. The only difference from MSNs to PMOs is the replacement of one of the OMethyl or OEthyl groups in the silica precursors in TMOS or TEOS with an organic R group (Fig. 16.9). This additional organic group is only limited by the ability to allow the periodic structure of silica nanoparticles to be formed as shown in Fig. 16.10. This allows for a wide variety of additional silica nanoparticles to be formed with a variety of new chemistries due to the organic R group. To add additional complexity, MONs, that are silica nanoparticles, have regions of MSNs and PMOs that create a hybrid. These hybrids can have different proportions of the organic and nonorganic variants, creating unique porous structures. While PMOs and MONs are quite new, they already account for at least 10% of the papers currently being published on silica nanoparticles. MONs and PMOs have a lot of potential for making uniquely functional silica nanoparticles. This is due to the flexibility of the organic R group. The R group can have a drastic effect on what types of cargo the nanoparticle can carry, which is due to both the physical changes to the pore size and shape and the chemical changes affecting the

hydrophobicity/hydrophilicity and charge of the particle. For example, creating nanoparticles with an R group that has a triggerable group such as a light-activated photocleavable group can drastically change the control of drug delivery or degradability of the structure. It will also change the possibilities for surface modifications. In traditional MSNs, the surface groups will always be silanols or siloxanes. With MONs and PMOs, the options for surface groups open up the types of chemical modifications that can be made, allowing for unique triggerable groups to be used as “pore-gates.” PMOs and MONs have already been designed to do a variety of tasks such as traditional cargo delivery and release, imaging, cell adhesion, bacterial inhibition, and photodynamic therapy. There are many challenges to utilizing MONs and PMOs for medical applications. Most of these challenges are due to not being able to fall back on studies performed on MSNs. Although MSNs only have the safety considerations of the drugs being carried and the surface modifications, MONs and PMOs also have their baseline structure to consider. Despite the FDA’s consideration of silica as safe, MONs and PMOs do not receive benefit from this as they are considered a completely new compound. Furthermore, no two PMOs or MONs are the same, meaning each new R group or mix will have to be approved separately, adding additional complexity to medical use. Therefore, any clinical studies performed will require additional research on safety (toxicology, degradability, etc.) before being approved for every PMO or MON. Degradability of the PMO or MON structures is a source of concern, as the mechanism for degradation is not clearly defined and will differ from R group to R group. Understanding the effects of these changes is key for medical applications.

FIGURE 16.9 Mesoporous silica nanoparticle (MSN) versus periodic mesoporous organosilica (PMO) Structure. Credit: Original Work.

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FIGURE 16.10 Published mesoporous organosilica nanoparticle and periodic mesoporous organosilica precursors. Different functional R groups are represented in orange. Credit: Refs. 1,36,37,40,41,119e132.

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