Mesoporous silica nanoparticles (MSNs) have a total diameter below 1 µm and pores ranging from 2 to 50 nm in diameter. They are categorized as mesoporous (according to the IUPAC definition), making them ideally suited to catalysis, environmental chemical removal, and biomedicine.1
Fortis Life Sciences (FLS) provides synthetic expertise to adapt MSN design to target a planned application with maximum control.
Porosity and Surface Area
Along with biocompatibility, MSNs boast a high surface area and facile surface tunability.
The former has led to MSNs being described as "nanosponges", as their high surface area allows particles to adsorb vast quantities of molecules dissolved in solution. The surface area of MSNs is so great that 5 g of the material has the same surface area as an American football field.
The highly ordered porosity of MSNs can be closely controlled during synthesis.
Tunable Pore Size
MSNs can be designed with very narrow pore size distributions to ensure the nanoparticles selectively adsorb molecules of a specific size.
Only molecules within a specific size range (small green circles) can enter the cavities of the MSN, while larger molecules (large red circles) are excluded. This tunability is valuable for molecule separation by size exclusion.
Selective Adsorption
Due to the versatility of the silica, surface modification of MSNs with specific functional groups is possible. These functional groups interact selectively with specific categories of molecules.
For example, coating pores with a positive surface attracts negatively charged molecules, while a hydrophobic surface attracts more hydrophobic molecules.
MSN with pores are modified to absorb a specific surface functionality (green circles) and exclude others (red pentagons). This form of selective adsorption has numerous applications in fields, including hydrophobic drug encapsulation and environmental chemical removal.
Variable Pore Structures for Controlled Release
The organizational structure of the MSN pores can also be modulated (MCM-41, MCM-48, radial, cubic, wormlike). The structure choice depends on the intended application, as this characteristic determines the release or leakage of molecules loaded inside the pores.
For example, a hexagonal pore arrangement allows MSNs to release cargo from both ends of a specific channel, whereas the cubic arrangement allows molecules to travel freely inside the intricate network and be released from any pore outlet.
The radial pore arrangement restricts the molecule from accessing a single pore, meaning it must exit through the same pore it entered. This feature makes radial pore structures less prone to premature leaking (in the case of drug encapsulation).
Applications of MSNs
The unique structural properties of MSNs generally dictate how the materials are used. Below is a summary of valuable properties in biomedicine and catalysis.
Nanomedicine
Over the past two decades, the numerous advantages of MSNs have had a significant impact on the drug delivery field, evidenced by the increasing number of scientific articles centered on their use as drug carriers.2–4
High surface area, easy surface modification, and biocompatibility have established MSNs as the material of choice for the targeted delivery of active pharmaceutical ingredients for cancer therapy and other treatments.2
The high surface area allows MSNs to carry larger quantities of the desired drug than conventional methods such as polymers, liposomes, and vesicles. This is in addition to the size-selective capabilities discussed previously.
Easy surface modification and biocompatibility make MSNs valuable for targeted delivery of active pharmaceutical ingredients with different chemistries, such as molecules with hydrophilic and hydrophobic properties.
Surface functionalization allows specific tissues or cells to be targeted and the enhanced permeability and retention (EPR) effect to be increased by evading the reticuloendothelial system (RES).
While mesoporous silica is generally robust, MSNs can be engineered to degrade, facilitating the controlled release of their contents.5
Catalysis
Due to easily adjustable surface chemistry, MSNs possess a novel affinity for loading catalysts onto high surface areas.
MSNs (MCM41-type, in particular) have displayed shape-selective capabilities of the substrate due to a narrow pore size distribution. This effect has been observed in the epoxidation of bulky alkene substrates using titanocene-grafted-MSN structures.6
Grafting can be accomplished through surface silanol activation (or other surface chemistry) by displacing the ligands of the catalyst species and attaching them to the inorganic core.
Inorganic catalysts can also be incorporated into the structure of MSNs, increasing catalytic efficiency. For example, titanium can be integrated into an MCM41-structured zeolite for oxidation.7
MSNs can be used for catalysis. The analyte (green circles) penetrates the pores of the particles, where the catalysis reaction happens, and a new product is then formed and released (purple squares).
Surface-functionalized MSNs have been shown to exhibit catalytic capability using general acid/base chemistry without the use of transition metals.
For example, bi-functionalized MSNs with an acid and base group have activated carbonyl for Aldol, Henry, and cyanosilylation reactions. Examination of the reaction rates based on the varying ratios of acid/base functionalization suggested that MSNs participate in the reaction mechanism.8
The ease of centrifugation is a crucial benefit of MSNs, which do not require chemical separation to isolate products. This reduces the resources needed and makes the process greener.
Mechanical separation does not damage the catalysts or mesoporous framework, meaning the catalytic material can be easily regenerated or recycled.
Synthesis and Purification
Unlike regular silica nanoparticles, which are synthesized following the Stöber process, MSNs are formed in a water-based solution in the presence of a base catalyst and a pore-forming agent, more widely referred to as a surfactant.
Surfactants are molecules that present the particularity to have a hydrophobic tail (alkyl chain) and a hydrophilic head (charged group, such as a quaternary amine for example). In the introduction to the water-based solution, surfactants coordinate to form micelles with increasing concentration to stabilize the hydrophobic tails.
During the early stage of hydrolysis and condensation, oligomeric forms of silica appear in the precursor. Like the final material, these oligomers have silanol groups (Si-OH) that are deprotonated under the primary conditions of the reaction. These form negatively charged oligomers that condense on the surface of the positively charged micelles.
As the reaction proceeds, the oligomers grow larger around the micelles, ultimately forming a hybrid organic/inorganic silica network templated by surfactant molecules.
Following the reaction, the template is removed to create the porosity that defines MSNs.
Purification
After synthesis and for the practical use of MSNs, CTAB must be removed. This is essential for three primary reasons:
Pore Accessibility
The surfactant inside the pores will diminish the particles' ability to encapsulate any active pharmaceutical ingredient (API) by decreasing pore volume.
Cytotoxicity
Many of the common surfactants used in synthesizing MSNs harm the human body. The commonly used CTAB molecule interacts with phospholipids constituting the cell membrane and can lead to cell death at high concentrations.
It is vital to ensure the complete removal of these pore-forming agents before biomedical applications, particularly injections.
Pore Surface Modification
The removal of the surfactant molecules from the pores makes them available for further modification, such as amination, thiolation, and hydrophobization.
This makes having the same functionality throughout the entire silica surface (inside pores and outside particles) or having two distinct types of functionality (bringing different capabilities to each spatial region) possible.
An example is loading a negatively charged molecule inside the pores (after amine modification of the inner surface) while functionalizing the outside of the particle with thiol or any other functional group for targeted drug delivery.
Methods for the Removal of CTAB
Solvent Extraction
CTAB molecules can be removed from particles by solvent extraction using either a solvent mixture (concentrated hydrochloric acid and ethanol) or an ethanolic solution of ammonium nitrate.
Both extraction methods require heat, around 60 °C, for at least one hour. The methods are usually executed twice to ensure that all the CTAB molecules have been removed. Generally, the smaller and more tortuous the pores, the more extraction the sample will require.
Calcination
Calcination is another common technique for removing surfactants. It involves heating dried mesoporous silica samples in an oven at 500 °C for at least five hours.
The surfactants inside the pores will decompose at this temperature, leaving the desired mesoporous silica framework intact. This technique allows scientists to process a large amount of mesoporous silica but risks damaging pore structure.
Advantages and Disadvantages
Although the calcination technique can wholly free the pores from any organic molecules or surfactants, it cannot be used if the surface of the particle has already been modified (with amines, thiols, or carboxylic groups) for the same reason.
The calcination process can also stimulate irreversible aggregation due to crosslinking between particles and dehydration.
Ammonium nitrate and hydrochloric acid treatments are better matched with the presence of functionalities on the particles' surface, but such methods may lead to incomplete surfactant removal if the pores are too small.
Custom MSNs at FLS
At FLS, various-sized MSNs (from 50 up to several hundreds of nanometers in diameter) can be prepared with different pore arrangements, such as radial types of MSNs and the commonly used MCM-41 (hexagonal pore).
The 100 nm MCM-41 pore particles on the right are available from FLS as a standard product; the radial particles can be ordered customarily.
Modulating the porosity makes designing and synthesizing nanoparticles with various structures possible. These nanoparticles could have a hollow interior and a mesoporous silica shell or a more extensive hollow interior and a thin microporous silica shell; the possibilities are almost infinite.
Mesoporous Silica-Shelled Nanoparticles
The presence of surfactants (for example, CTAB) in the synthesis of MSNs appropriately enables the incorporation of a core of other material types at the center of the nanoparticle.
Cores made from other inorganic materials and other types of silica can be suspended in these aqueous surfactant solutions for shell deposition and growth.
For core and shell syntheses, the inorganic nanoparticles are generally stabilized directly by a surfactant. The surfactants provide the steric stability required for the inorganic nanoparticles to be dispersed in aqueous solutions.
The extra layer of CTAB on the surface of the inorganic particles behaves similarly to an anchor for the solubilized silicate species (obtained after hydrolysis of the silica precursor), leading to the growth of silica around the inorganic nanoparticles.
This technique has prepared core-shell nanoparticles composed of silver, gold, and iron oxide, or quantum dot cores surrounded by a mesoporous silica shell.
These materials unite the properties of mesoporous silica (biocompatibility, drug delivery platform) with the unique assets of the core (plasmonics, photothermal, magnetic, imaging, etc.). They are commonly used in the contemporary field of theranostics and can be applied to different particle morphologies to create a range of interesting heterostructures.
Large-Pore MSNs
Since 2010, there has been a rise in interest and research performed on synthesizing MSNs with large dendritic pores ranging from 5 to 30 nm in diameter.9 There are various pore-expanding agents in use today, ranging from ring (e.g. trimethyl benzene and cyclohexane) to chain structures (e.g. octadecene).10,11
There have also been effective syntheses using less abrasive agents, such as sodium salicylate and sodium trifluoroacetate, for an anion-enhanced expansion.12
References and Further Reading
Zhao, Q., Wu, B., Shang, Y, Huang, X., Dong, H., Liu, H., Chen, W., Gui, R. and Li, J. (2020). Development of a Nano-drug Delivery System Based on Mesoporous Silica and its Anti-lymphoma Activity. Appl. Nanosci. doi.org/10.1007/s13204-020-01465-0.
1 Rouquerol, J., Avnir, D., Fairbridge, C. W., Everett, D. H., Haynes, J. M., Pernicone, N.; Ramsay, J. D. F., Sing, K. S. W. and Unger, K. K. (2009). Recommendations for the Characterization of Porous Solids (Technical Report). Pure Appl. Chem., 66(8), pp.1739–1758. doi.org/10.1351/pac199466081739.
2 Li, Z., Barnes, J. C., Bosoy, A., Stoddart, J. F. and Zink, J. I. (2012). Mesoporous Silica Nanoparticles in Biomedical Applications. Chem. Soc. Rev, 41(7), pp.2590–2605. doi.org/10.1039/C1CS15246G.
3 Slowing, I. I., Vivero-Escoto, J. L., Wu, C.-W. and Lin, V. S.-Y. (2008). Mesoporous Silica Nanoparticles as Controlled Release Drug Delivery and Gene Transfection Carriers. Adv. Drug Deliv. Rev, 60(11), pp.1278–1288. doi.org/10.1016/j.addr.2008.03.012.
4 Argyo, C., Weiss, V., Bräuchle, C. and Bein, T. (2014). Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Chem. Mater, 26(1), pp.435–451. doi.org/10.1021/cm402592t.
5 Hao, X., et al. (2015). Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite. ACS Nano, 9(10), pp.9614–9625. doi.org/10.1021/nn507485j.
6 Maschmeyer, T., Rey, F., Sankar, G. and Thomas, J. M. (1995). Heterogeneous Catalysts Obtained by Grafting Metallocene Complexes onto Mesoporous Silica. Nature, 378(6553), pp.159–162. doi.org/10.1038/378159a0.
7 Corma, A., Navarro, M. T. and Pariente, J. P. (1994). Synthesis of an Ultralarge Pore Titanium Silicate Isomorphous to MCM-41 and Its Application as a Catalyst for Selective Oxidation of Hydrocarbons. J. Chem. Soc. Chem. Commun, 2, pp.147–148. doi.org/10.1039/C39940000147.
8 Huh, S., Chen, H.-T., Wiench, J. W., Pruski, M. and Lin, V. S.-Y. (2005). Cooperative Catalysis by General Acid and Base Bifunctionalized Mesoporous Silica Nanospheres. Angew. Chem. Int. Ed, 44(12), pp.1826–1830. doi.org/10.1002/anie.200462424.
9 Polshettiwar, V., Cha, D.; Zhang, X. and Basset, J. M. (2010). High-Surface-Area Silica Nanospheres (KCC-1) with a Fibrous Morphology. Angew. Chem. Int. Ed, 49(50), pp.9652–9656. doi.org/10.1002/anie.201003451.
10 Chen, F., Goel, S., Valdovinos, H. F., Luo, H., Hernandez, R., Barnhart, T. E. and Cai, W. (2015). In Vivo Integrity and Biological Fate of Chelator-Free Zirconium-89-Labeled Mesoporous Silica Nanoparticles. ACS Nano, 9(8), pp.7950–7959. doi.org/10.1021/acsnano.5b00526.
11 Shen, D., Yang, J., Li, X., Zhou, L., Zhang, R., Li, W., Chen, L., Wang, R., Zhang, F. and Zhao, D. (2014). Biphase Stratification Approach to Three-Dimensional Dendritic Biodegradable Mesoporous Silica Nanospheres. Nano Lett., 14(2), pp.923–932. doi.org/10.1021/nl404316v.
12 Wang, Y., Song, H., Yang, Y., Liu, Y., Tang, J. and Yu, C. (2018). Kinetically Controlled Dendritic Mesoporous Silica Nanoparticles: From Dahlia- to Pomegranate-like Structures by Micelle Filling. Chem. Mater., 30(16), pp.5770–5776. doi.org/10.1021/acs.chemmater.8b02712.
This information has been sourced, reviewed and adapted from materials provided by nanoComposix, Inc.
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