Talented Mesoporous Silica Nanoparticles - Chemistry of Materials

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Talented Mesoporous Silica Nanoparticles Karin Möller, and Thomas Bein Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.6b03629 • Publication Date (Web): 01 Nov 2016 Downloaded from http://pubs.acs.org on November 2, 2016

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Chemistry of Materials

Talented Mesoporous Silica Nanoparticles Karin Möller* and Thomas Bein* Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), Butenandtstrasse 5–13, 81377 Munich, Germany Fax: (+49) 89-2180-77622 Emails: [email protected], [email protected]

ABSTRACT The structure and functionality of mesoporous silica nanoparticles can be tuned by means of numerous and diverse synthetic strategies. Focusing on experimental methods, we describe how pore-size and pore topology of the mesopore system can be modified through templating and poreswelling agents, as well as different synthesis conditions. Moreover, we show how the mesoporous nanoparticles can be functionalized through cocondensation methods with silane coupling agents, with specific emphasis on the spatially selective anchoring of different molecular functionalities within the nanoparticles. We discuss methods for changing the composition of the pore walls of the mesoporous particles, for example by including redox-sensitive sulfide bonds or by creating autofluorescent curcumin-containing mesoporous organosilica. The efficiency of targeted drug delivery applications strongly depends on morphological parameters such as size and shape of the mesoporous nanoparticles. It is demonstrated how the particle size of the mesoporous nanoparticles can be modified over a wide range from about 30 nm to several hundred nm. Developing this context further, we consider several examples of triggered molecular mechanisms intended for the controlled intracellular release of bioactive substances from the pore system of mesoporous nanoparticles.

Introduction Motivated by decades of successful applications of crystalline microporous zeolites, the persistent desire for ever larger pores in order to accommodate sizable guest and reactant molecules culminated in the discovery of mesoporous silica in 1992.1 At that time, Kresge and coworkers revealed that pore sizes in ordered porous solids could be expanded into the mesopore range by using a new generation of templates. Instead of increasing the dimensions and complexity of individual template molecules, as generally pursued in zeolite synthesis, they relied on a micellar templating route. Silicate gels and quaternary ammonium surfactants of different chain lengths were used to obtain highly ordered materials with about three nanometer-sized pores. Depending upon the molar composition of the reaction medium, the pores were aligned in a hexagonal (MCM-41) or

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cubic (MCM-48) arrangement, however, in contrast to zeolites, they were surrounded by walls of amorphous silica. The mesopores were generated with dodecyl- or cetyltrimethylammonium (CTA) salts, the same as those used today in many base-catalyzed synthesis routes, e.g. CTAC or CTAB salts with chloride or bromide acting as counter ions, respectively. At that time, even the concept of pore expansion was already demonstrated by Kresge and coworkers, using auxiliary hydrocarbons such as trimethylbenzene to create pores of up to 10 nm diameter. It took about another decade until researchers were able to control the morphology of the mesoporous materials to create nanosized mesoporous particles that could be stabilized as colloidal solutions. Thus, “an MCM-41 type mesoporous silica nanosphere-based (MSN)” material was reported in 2003, describing a 200 nmsized, CdS-capped and controlled-release carrier system for pharmaceutical drug delivery.2 This work was pioneered by the late Victor S.-Y. Lin and his coworkers, and they have stimulated this field since then to a great extent. One of the most important and exciting applications of MSNs is in the field on nanomedicine, including theranostics and photodynamic therapy.3 They have attracted great interest as nanoscale carriers for drug delivery4-8, with cancer therapy being at the focus as documented in recent review articles.9-11 In this context, mesoporous silica nanoparticles are especially valued for being comparatively stable materials with large surface areas and pore volumes that offer a high loading capacity for guest molecules. They provide a general platform for drug delivery because they can be loaded with hydrophobic as well as hydrophilic drugs by adjusting the loading process and/or the properties of the host through surface functionalization. Surface functionalization also offers numerous possibilities for developing stimuli-responsive release concepts for the cargo12, as already demonstrated by Victor Lin et al.2, or for integrating theranostic capabilities by anchoring diagnostic dyes or by including magnetic particles. Additionally, site-specific functionalization allows for the attachment of targeting ligands to the particle periphery aimed at selective uptake of the MSNs in tumor tissue. Here, we describe a multi-parameter synthesis procedure for MSNs that allows us to control different key properties such as particle size, pore size, morphology, and spatially-selective chemical functionalization, thus creating multi-functional core-shell MSNs. Additionally, we present mesoporous organosilica nanoparticles (MONs) containing degradable or auto-fluorescent entities in the particle body, as well as a number of capping strategies for the pore systems. The intention is to provide detailed insights into synthesis procedures and to refer the reader to valuable references, without attempting to review the field of MSN synthesis and applications. For extensive fundamental insights into MSN synthesis including the tuning of morphology and particle size we direct the reader towards an excellent recent review by Kuroda et al..13 Finally, we wish to share our enthusiasm about the enormous versatility of multifunctional MSN particle design and hope to motivate the reader to engage in this exciting field and to explore additional novel applications of these intriguing materials. 1. Synthesis strategies for different pore morphologies Nanosized mesoporous silica particles have been made in recent years covering a broad range of morphologies and pore sizes. In the following we will describe selected synthesis strategies that were developed in our group or have been adapted from published procedures and were adjusted by cocondensation to function as drug delivery materials. The structural richness achieved so far is 2 ACS Paragon Plus Environment

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exemplified in Figure 1. In brief, small-pore MSNs with radially disposed disordered pores (SP-MSN, about 3 nm pore size) shown in Fig. 1a were made by our reaction procedure as described before.14 MSNs with ordered pores of about 4 nm with a helical arrangement (for a detailed description see Supplement, S1) and an amino-functionalized MSN derivative of our procedure with expanded stellate pores of about 5 nm in Fig 1b and c, were all synthesized from basic reaction solutions. MSNs with bottleneck pores of about 10 nm (large pore MSN or LP-MSN) and single pore MSNs with even larger pore diameters in Fig. 1 d and e were based on an adapted acidic synthesis strategy.15 An overview over strategies for controlling the MSN particle morphology can also be found elsewhere.16 In the following we will describe in detail our ‘standard procedure’ in basic medium including a number of variations used to change the pore size and particle size as well as the surface chemistry. Additional newly developed procedures for curcumin-containing MONs as well as acidic synthesis strategies for creating functionalized mesoporous particles with larger pores will be discussed at appropriate places later in the text.

Figure 1: MSNs with different morphologies and pore-sizes 2. From small-pore (SP) to medium-pore (MP) to large-pore (LP)-MSNs using synthesis procedures in basic medium a) Changing the template (samples A) The following approach describes our standard MSN procedure, which is further used to create several variations with larger pore sizes and/or to create functionalized as well as core-shell particles. We developed this synthesis strategy for mesoporous silica nanoparticles almost a decade ago by replacing the commonly used base catalyst NaOH with the polyalcohol triethanolamine (TEA).14 TEA is a weak base that allows us to control the hydrolysis and condensation rates of the molecular silica precursors in a favorable manner, aimed at preparing stable colloidal solutions of individual mesoporous nanoparticles even in highly concentrated solutions. In addition it may serve as a chelating substance for silica thus influencing the growth mechanism of the MSN particles. As we showed before, we can use the molar ratio between the silica precursor tetraethoxysilane TEOS and TEA to tune the average particle size between 100 and 50 nm. Our updated standard recipe for completely siliceous small-pore MSNs is described below: Two reaction solutions have to be prepared. Solution A: A combination of 100 mg NH4F (2.7 mmol), 21.7 g H2O (1.12 mol) and 2.41 mL of a 25% aqueous CTAC solution (1.83 mmol) was stirred at 750 rpm in a 50 mL round bottom flask equipped with a stir bar and heated to 60°C. 3 ACS Paragon Plus Environment


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Solution B: 14.35 g TEA (97 mmol) and 2.06 mL TEOS (9.3 mmol) were statically heated in a 20 mL capped polypropylene vial at 90°C for 30 minutes. Both components remain unmixed after heating. Solution B was then added to solution A at once while stirring vigorously, followed by removal of the oil bath, leaving the reaction solution to slowly cool down to room temperature while continuing to stir overnight. After adding solution B to solution A, we observed a transition of the initially clear solution to a progressively more whitish suspension starting after about 5 minutes. This time may vary depending on variations in the composition of the reaction mixture. On the next day after 12 hours, 50 mL ethanol was added to the solution, which was then transferred into two 50 mL centrifuge tubes and spun down at a speed of 20 000 rpm (47 800 rfc) for 20 minutes at room temperature. This time might have to be extended when very small particles are produced. The supernatant of the solutions was decanted, and the samples were refilled with 30 mL ethanol each, redispersed mechanically with a spatula and by sonication for 10 minutes, and centrifuged again. The molar ratios of the above ‘standard recipe’ are as follows: TEOS 1.0 : TEA 10 : CTAC 0.196 : NH4F 0.29 : H2O 140, resulting in a pH of about 11.8. The silica precursor is easily hydrolyzed and the resulting silica species are highly charged at this pH, thus associating themselves with the cationic template micellar aggregates in a cooperative self-assembly process. Silica condensation finally results in template-containing individual silica nanoparticles. Template removal (to open the pore system) can be performed by calcination or extraction. Calcination is typically done in air with the dried powder by ramping the temperature at 2°C/min to 550 °C, where the sample is kept for 5 hours. However, we generally prefer to remove the template by extraction, since calcination usually leads to agglomeration of the MSN particles thus preventing complete redispersion into a colloidal solution. Moreover, extraction is the method of choice for all organosilane-functionalized materials described later, because calcination would destroy the organic moieties. The extraction solution used here consisted of a 90:10 mL solution of ethanol: concentrated HCl (37%), using 50 ml for each extraction cycle for the whole batch of sample performed at 90° under reflux for 45 minutes in a 100 mL round bottom flask. After cooling, the sample was collected by centrifugation (as described above) and a second extraction was performed following the same procedure. After a threefold washing cycle in i) ethanol, ii) water and iii) ethanol again performed in the centrifuge tubes for at least 1 h each under stirring the sample was kept in about 15 mL absolute ethanol. For obtaining a good redispersion of the sample after each centrifugation cycle, we use mechanical stirring with a spatula followed by exposing the sample to an ultrasound bath for 30 minutes. Standard analytical methods were used to characterize the samples after each synthesis. The specific surface area, pore-size distribution as well as the pore volume were obtained from nitrogen sorption experiments. Here, 10 to 15 mg of dried powder was heated to 120 °C 12 h under 10-6 torr vacuum prior to nitrogen adsorption, which was carried out at -196 °C with a Quantachrome Nova 4000e analyzer. Specific surface areas were obtained by Brunauer Emmett Teller (BET) analysis over similar pressure ranges for all samples, usually between 0.05 and 0.2 relative pressure (p/p0). Pore size analysis was performed using the non-local-density functional theory NLDFT module in the instrument software with the cylindrical pore equilibrium model and the adsorption branch model as described in the text. The pore volume was usually determined at a relative pressure p/p0 = 0.8 in 4 ACS Paragon Plus Environment

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order to evaluate only the mesopore volume and to exclude textural pores > 10 nm generated by particle packing. This value has to be extended to 0.98 p/p0 for large-pore particles. FTIR measurements were taken from dried powders in KBr pressed into pellets in a commercial KBr pellet holder after slight grinding. Raman spectroscopy was performed on pure powders in backscattering mode with an IR-laser having a wavelength of 1064 nm. For FT-IR and Raman measurements we used a Bruker Equinox 55 combined IR/Raman Instrument. To determine particle size distributions in colloidal solution, dynamic light scattering (DLS) was usually performed with 0.1 mg sample in 1 mL ethanol with a Malvern Zetasizer instrument, used as well for Zeta potential measurements with the MPT-2 accessory. Zeta potential measurements were performed with 1 mg samples dispersed in 10 mL aqueous solution between pH 2 to 8. For transmission electron microscopy (TEM) samples were dispersed in ethanolic solution; one drop of this solution was placed on a Cu-grid covered with holey carbon and dried for several hours before taking images on a Jeol JEM2011 instrument at 200 kV. SEM measurements were performed on the identical grids used in TEM measurements using a dual beam FEI Helios NanoLab G3 UC at 20 kV without prior sputtering. Following the above recipe and using cetyltrimethylammonium chloride (CTAC) as the poregenerating template, we obtained nanoparticles with a wormhole arrangement as seen in the TEM images in Figure 2, column a. Roundish, isolated particles with a diameter of mostly 70-80 nm are predominantly observed, while a few larger particles of about 170 nm consist of condensed doublets. The samples were template-extracted as described above. The extraction process can be evaluated by FTIR, where the C-H stretching and bending frequencies of the template molecules are observed at 2925, 2854 and 1473 cm-1 respectively before extraction. The zeta-potential of MSN samples prepared by this synthesis route showed a slightly positive surface potential up to the isoelectric point at about 4.7, and became highly negatively charged with increasing pH as shown with zeta potential measurements (see supporting information for FTIR and zeta-potential measurements, S2).



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Figure 2: MSNs synthesized using different templating agents. Figure 2 top: TEM pictures, Figure 2 bottom: BET isotherms and corresponding pore-size distributions obtained from NLDFT adsorption and equilibrium branches, as well as dynamic light scattering derived particle-size distributions. Column a) sample A1 with the chloride salt of cetyltrimethylammonium (CTAC), column b) sample A2 with the tosylated form (CTATOS), column c) sample A3 with octadecyl trimethylammonium bromide (OTAB). A Type IV isotherm was obtained from nitrogen sorption showing a pore-condensation step around the relative pressure range p/p0 = 0.3-0.4 and a hysteresis at higher pressure, the latter indicating textural pores that result from packing of the small particles. We indicate the specific surface area and the pore volumes in the isotherm plot. Corresponding values are also compiled in Table 1 (see Supplement), listed together with specific synthesis parameters. These ‘standard’ MSN particles exhibit a large specific surface area of 960 m2/g as derived from BET analysis in the pressure range between 0.05 and 0.2 p/p0. The corresponding pore-size distribution retrieved using either the NLDFT adsorption or the equilibrium kernel is very narrow with a maximum at 3.9 nm. Both pore size distribution functions coincide, indicating an unrestricted cylindrical pore architecture. When these particles were investigated with dynamic light scattering in an ethanolic solution, we retrieved a particle size distribution with a maximum around 185 nm if the autocorrelation function is weighted either related to number, volume or intensity, with a polydispersity index PDI of 0.23. The apparent discrepancy between TEM and DLS particle size data is mostly attributed to weak association in solution. We also investigated the influence of the templating agent on the above MSN synthesis by using cetyltrimethylammonium with different counter ions, i.e. the much larger tosylate ion (CTATOS, sample A2) when compared to the chloride ion. This seemingly small change was found to markedly 6 ACS Paragon Plus Environment

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increase the pore radius and to change the pore morphology from wormlike into a stellate appearance when used either at basic or near neutral conditions in a related published procedure.17 Compared to CTAC we do obtain particles nearly identical in structural appearance (TEM) or surface properties. Slightly larger particles of 120-130 nm diameter are seen, however, the surface area, pore size and pore volume show no differences compared to sample A1. Under the basic conditions used here, creating strongly negatively charged polysilicates, there is no visible size-effect of the cation that could change the micellar radius and thus the pore size. In contrast, when we used a surfactant with a longer hydrocarbon chain, such as octylammonium bromide (OTAB) for sample A3, both particle size and pore size changed. When a 25 wt% aqueous OTAB solution was prepared in order to perform a similar synthesis as with CTAC, only a stiff gel was obtained. We therefore reduced the template concentration by half, using a 0.9 mmolar solution under conditions otherwise comparable to sample A1. Under these conditions we obtained slightly smaller, very evenly shaped particles of 60-70 nm (by TEM and SEM, for SEM see Supplement S3), which now showed a marked increase in pore diameter to 4.3 nm. A similar pore extension had already been observed by Kresge et al. in bulk MCM-41 under basic conditions.1 b) Pore enlargement to SP-MSN using swelling agents (samples B) Pores ranging between 3 - 4 nm in diameter are sufficient for the uptake and delivery of numerous small molecules used for biomedical applications and conventional cancer therapy, e.g. doxorubicin or cis-platin. However, for packaging larger drug molecules, proteins or oligonucleotides inside the pores of mesoporous particles, a pore expansion exceeding 4 nm is necessary. To achieve this, besides extending the chain length of the surfactant templates it is possible to use the hydrophobic interior of the micellar aggregates to accommodate auxiliary organic molecules. We used this approach and prepared samples following the recipe as described above, but added 12 mmol of different swelling agents to solution A (molar ratio TEOS : swelling agent: 1 : 1.3). The swelling agents include triisopropyl benzene (TIPB), trioctylamine (TOA), decane and N,N-dimethylhexadecylamine (DMHA) or even mixtures thereof. In all instances we obtained isolated MSN particles with high surface areas around 1000 m2/g (see Supplement, Table 1) similar to our standard recipe, but with enlarged pores ranging from 4.5 nm (with TOA) up to 5.7 nm (with DMHA). As an example, we show electron micrographs of our sample B1 containing CTAC with TIPB in Figure 3. The pore morphology has evolved from the wormhole structure without TIPB to a more stellate architecture as seen in the TEM image below, while the particle size remains around 100 nm. SEM micrographs give an impression of the pore mouths of the 4.7 nm mesopores being evenly distributed all over the spherical nanoparticles. The pore-size distribution is very narrow, as seen in the corresponding graphs for the different swelling agents at the bottom of Figure 3.



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Figure 3: Pore-size expansion by using swelling agents as additives in the standard recipe in basic medium. Top: TEM and SEM micrographs of sample B1 prepared with CTAC and TIPB as swelling agents. Bottom: Pore-size distributions of samples prepared with CTAC and TIPB (sample B1), DMHA (sample B2), decane (sample B3) and TOA (sample B4). We note that in some instances we do obtain some ‘doublet’ particles or larger particles of slightly different morphology within the majority of homogeneously shaped MSNs (see Supplement for sample B1, Fig. S4) Nevertheless, this is a minority of particles and the DLS signature is similar to samples without any such features. The pore widening using different swelling agents in the different particles can also be observed by a shift of the main feature of the X-ray scattering curve to smaller 2 theta values (see Supplement Fig. S5). c) Shape-controlled MP-MSN at near neutral pH (samples C) 8 ACS Paragon Plus Environment

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MSNs similar to sample B1 can also be prepared at near neutral conditions by using a very similar approach as our standard synthesis, but by drastically decreasing the amounts of TEA. Wu et al. have recently shown that under these conditions very small and evenly sized siliceous MSN particles can be obtained.18 They used this approach for the inclusion of sulfide-containing bis-organosilanes for generating hybrid MSN particles. We will discuss this topic later. We have adapted similar conditions for the inclusion of TIPB and have used the following reaction procedure: The amount of 2.0 g of a 25% aqueous solution of CTAC was added to 20 mL water and mixed with 2.97 mL TIPB and only 0.1 g of TEA, resulting in a pH of 8.0. The molar ratio is TEOS 1.0 : TEA 0.07 : CTAC 0.163 : TIPB 1.25 : H2O 187. This solution was stirred in a 100 mL round bottom flask at 95 °C for 20 minutes before 2 mL TEOS was added dropwise. The low pH required a higher reaction temperature and a longer reaction time since condensation rates were markedly slowed down. Thus, the solution was kept at this temperature for 4 h before being retrieved and template-extracted as described before. Under these circumstances we obtained well-defined, 60-65 nm sized spherical MSN particles showing a similar pore architecture as sample B1 as shown in Figure 4. The DLS particle size distribution around 70 nm was now very similar to the size obtained from TEM images. However, the difference compared to B1 is reflected in reduced surface area and pore volume, which are nearly cut in halve down to 540 m2/g and 0.55 mL/g, respectively. The pore diameter remained similar at 4.6 nm, showing a slight offset between the adsorption and equilibrium distribution.

Figure 4: Sample C1 synthesized with CTAC and TIPB and reduced TEA content at pH = 8.0. Top: TEM and SEM micrographs, bottom: nitrogen sorption and NLDFT pore-size distribution.



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We attribute the reduced surface area to an enlarged wall thickness, a phenomenon known from the synthesis of bulk mesoporous silica under acidic conditions.19 In our samples the thicker pore walls can be appreciated by comparing TEM images of sample B1 and C1 (see Supplement Figure S6). d) Pore extension to LP-MSN at neutral pH (samples D) In some instances even a pore size of 4.8 nm might not enable an unhindered diffusion of larger guest molecules into the particle interior. Members of our group20 have adopted another recent procedure aimed at producing larger-pore MSNs published by Zhang et al.17 for reversibly anchoring extremely small antibodies (chromobodies) to the particle walls. This procedure involves TEA as base catalyst again, however, the amount is reduced to the point that the final synthesis solution has a neutral pH. To further increase the pore size, a small amount of CTATOS was used. The final molar ratio was as follows: TEOS 1.0 : TEA 0.033 : CTATOS 0.06 : H2O 80. In the synthesis, 0.263 g (0.58 mmol) CTATOS was mixed with 13.7 g (0.77 mol) of water and 47 mg (0.32 mmol) of TEA and heated at 80 °C for 20 minutes. This was followed by adding 2.013 g (9.6 mmol) of TEOS under heavy stirring at 1250 rpm. The reaction was performed for 2 h at this temperature and the sample was retrieved by centrifugation/washing as described before. Following the above procedure, 80-100 nm particles were obtained as shown in the SEM in Figure 5a. It is immediately obvious that the pore morphology is drastically different in that very wide, seemingly folded wall structures are observed. Even when a cocondensation reaction is performed (for more details see later) where 10 mol% of the total silica content is replaced by mercaptopropyl triethoxysilane (MPTES, sample D1), a similar structure was obtained as seen in the TEM image in Figure 5b. The resulting colloidal solutions were very stable and the DLS measurements showed a particle size distribution around 160 nm. When nitrogen sorption data were evaluated, a surface area of 670 m2/g was obtained for the functionalized sample (nearly identical to the unfunctionalized silica sample) and an apparent pore volume of over 3 mL/g was measured at a relative pressure of 0.99. This value as well as the pore size distribution have to be considered with care: since the sample consists of very small particles there will be a textural pore volume that cannot be distinguished from the intra-particle pore volume in this case. Accordingly, the pore-size distribution obtained from the equilibrium kernel displaying values between 4 and about 80 nm is not realistic since the particle size is just as large. Some indication can be taken from the adsorption branch, where a maximum in the pore size distribution is seen at about 14 nm. This corresponds rather well with the maximum measured in the X-ray scattering curve between 0.6 and 0.8° 2 theta (not shown).


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Figure 5: a) SEM micrograph of 100% siliceous sample D1, b) TEM micrograph and c, d) nitrogen sorption results with NLDFT pore-size distribution of sample D2 functionalized with 10 mol% MPTES. Contrasting these results with sample B1, it may be speculated that the condition of a neutral pH leaves the oligosilicates less charged such that the CTA+ cation is mostly associated with the tosylate anion and can thus function as an enlarged template. At basic pH highly condensed and negatively charged silicates may compete more efficiently against the tosylate ion resulting in conventional pore sizes around 4 nm. There are several possibilities to vary the pore architecture of stellate MSN particles, and a helpful overview can be found in the review by Du et al..21 Increasing the pore size clearly opens the possibility to adsorb larger guest molecules, and it may further ease the biodegradation of the particles. Concerns regarding the possible accumulation of silica in the human body have been raised with a view on the use of silica nanoparticles for drug delivery.22 However, the group of Zhao recently created hierarchical MSNs with pore sizes ranging from 2.8 to 13 nm and showed that particles with larger pores degraded faster in simulated body fluid (SBF).23 3) Functionalization of MSNs (samples E) The surface chemistry of mesoporous nanoparticles can be altered by including functional groups into the particle body, principally following two different routes. The first approach is to synthesize the siliceous MSN particles, remove the template and perform functionalization via a grafting procedure. Usually, a certain amount of pre-prepared MSN sample is suspended in a dry solvent like toluene and is reacted under refluxing conditions with carefully added silanes under exclusion of air to avoid premature hydrolysis and self-condensation of the silanes. This method is advantageous 11 ACS Paragon Plus Environment


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when a stock solution of MSN samples with defined properties should be compared when treated with different silanes. It can also be the method of choice when the desired silylating agents disturb the initial MSN condensation reactions; examples will be discussed later in this article. However, we usually do prefer the second method, where functional silanes are added directly into the MSN synthesis solution. This way, it is straightforward to control the amount of surface functionalization and a homogeneous distribution of the functional groups is usually obtained even when a high loading of about 10 mol% silanes is used. A number of popular silane coupling reagents are shown in Figure 6.

Figure 6: Selected organo-silane reagents for surface functionalization. We have already shown in earlier publications that this method is straightforward for creating MSNs with different surface characteristics, by including organic residues such as vinyl-, benzyl- or phenyltriethoxysilanes24, or by creating surface charges by introducing chargeable groups like amines or mercapto groups. Especially in the latter cases, reaction conditions can influence the sample morphology to a great extent, as we will describe in chapter 5. Our standard procedure proved stable with respect to the functionalization with 10 mol% MPTES, which could then be oxidized to sulfonic acid residues.25 The procedure to introduce the silane coupling reagents is very simple. The desired amount is used for partially replacing TEOS in solution B (see chapter 2), thus TEOS and the silane are premixed and added to TEA which is then used as described in the standard procedure. This method of cocondensation was further developed in our group in order to spatially control the surface chemistry in restricted areas of the MSN particle body.26 We have shown that by a multistep addition of TEOS/silane mixtures with certain time delays it is possible to create core-shell particles, that is, the interior of the MSN particle carries different functional groups than its exterior. This procedure is sketched in Figure 7.


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Figure 7: Overview over synthesis procedures for obtaining unfunctionalized MSNs, homogenously functionalized MSNs or site-specific functionalized core-shell MSNs via cocondensation. Three possible synthesis outcomes are depicted in Figure 7. First, we show the simple MSN preparation, where the mixture of TEOS and TEA is added to solution A containing the template, a swelling agent if so desired, NH4F and water resulting in MSNs covered only by hydroxyl groups on their surface. The second possibility is to premix TEOS with the desired silane coupling agent R1, which is then added together with TEA to solution A, resulting in a homogeneously functionalized sample with the R1 residue. The last possibility describes a multistep approach, where the first coupling agent R1 together with TEOS is added to solution A resulting in the functionalized core of the particle, while a mixture of 1 or 2 mol% TEOS (of the entire silica content) together with 1 or 2 mol% R2 silane (of the entire silica content) is added dropwise after a delay time of 30 minutes, forming the selectively functionalized shell around the particle. The sum of the silica contents should always stay the same. Following this, the reaction solution is treated as described for the standard procedure. The latter approach offers the possibility of introducing chemically orthogonal functional groups thus allowing subsequent, site-specific chemical reactions, for instance to functionalize the MSNs just at their external surface. We have used this method extensively for creating a whole family of diverse mesoporous drug delivery carriers, especially for attaching targeting ligands or pore-closing entities to the outer surface (see later). Some selected examples of core-shell particles are shown in Figure 8, where we introduced different amounts of amine functional groups into the internal part of the particles while decorating the particle exterior with mercapto groups. The TEM micrographs show that the different functionalizations do not cause obvious changes in the particle morphology, even when the amount of the amino groups is increased from 4 to 9 mol% (of all silica) in the reaction medium. In the first 13 ACS Paragon Plus Environment


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situation (sample E1, 4 mol% NH2) a large surface area of 937 m2/g is obtained, which is reduced to about 700 m2/g when the aminopropyl content increases to 9 mol% (sample E2). The pore volume and pore size is concomitantly reduced, which is consistent with the internal localization of the amino groups. The external mercapto groups are easily visible in the Raman spectrum of this sample (see Supplement Figure S7).

Figure 8: Core-shell particles made with CTAC and TIPB including 4 (sample E1) or 9 (sample E2) mol% APTES in the particle core and 2 or 1 mol% MPTES in the shell defining the particle exterior. 4) Changing the particle size (samples F) The ability to tune the size of MSN-based drug carriers is crucial for studying parameters such as cell uptake, toxicity, retention time and clearance as well as biodegradation. Several parameters are known to strongly affect the size of silica nanoparticles. Chiang et al. systematically studied the influence of reaction time and TEOS concentration but concluded that changing the pH had the strongest impact on particle size.27 Hydrolysis and condensation rates are also dependent on the size of the silicon-bound alkoxy groups, and larger particles were generated with butoxysilanes as shown by Yamada et. al.28 Our synthesis relies on triethanol amine acting as base as well as chelating agent, thus influencing the pH and the reaction kinetics. We have shown above that even with a substantial degree of molecular functionalization it is possible to obtain nanoparticles with large pore volumes and surface areas. These samples are stable as colloidal solutions showing a size distribution maximum in the DLS of 220 nm, while size distributions obtained from TEM micrographs center around 150 nm. These particles are synthesized with a molar ratio of TEOS and TEA of 1 : 10 as described in our standard synthesis procedure, resulting in a pH of the synthesis solution of about 11.8. In our earlier publication we have already shown that tuning of the particle size of pure mesoporous silica particles is possible by varying the TEOS : TEA ratio.14 Here we show that the size of highly functionalized core-shell particles can also be changed (9 mol% NH2 core and 1 mol% SH shell). A reduction of the original TEA amount from 14.3 g (TEOS : TEA = 1: 10) stepwise down to 10 g (TEOS : TEA = 1 : 7), 7.1 g (TEOS : TEA = 1 : 5) or even 4.3 g (TEOS : TEA = 1 : 3) drastically reduces the particle 14 ACS Paragon Plus Environment

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size while an increase to 21.4 g (TEOS : TEA = 1 : 15) increases the size as shown in Figure 9. The pH still remains in the range between 11 – 11.8.

Figure 9: Core-shell functionalized MSN particles with 9 mol% APTES in the core and 1 mol% MPTES in the shell synthesized with varying TEOS : TEA ratios ranging from 1:3 up to 1:15. TEM micrographs (top) and corresponding particle size distributions as obtained from DLS (bottom; samples F1 to F4 from left to right). All of these samples stay in colloidal suspension for at least several days, after which settlement occurs at least to some degree. The DLS data of all samples show the increasing particle size ranging from about 80 nm with the lowest amount to 270 nm with the highest TEA amount used here. When the particle size is obtained by measuring about 100 particles in TEM images of each sample we usually find a smaller size distribution, ranging from 50 nm (sample F1, 1:3) over 115 (sample F2, 1:5) to a broad distribution between 100 to 300 nm in the sample made with a ratio of 1:15 TEOS : TEA (sample F4). All of these samples retain a very high surface area from over 700 (1:3) to around 600 m2/g (1:15) and pore sizes between 4-4.7 nm, even with the high content of functional groups lining the pore walls. Similar particle size effects are described by He et al. who used propane triol as a cosolvent under buffered conditions at neutral pH for the synthesis of purely siliceous, small-pore MSNs.29 Very homogeneous particles are obtained under their conditions, however, as common at lower pH, surface areas are strongly reduced in these unfunctionalized particles, ranging between 200 m2/g for small particle sizes and 500 m2/g for particles of over 300 nm. Control of particle size is highly desirable for applications of MSNs in drug delivery, where biological particle clearance from organisms is often observed at sizes below 50 nm and where retention times can be strongly influenced by the particle size. A size preference for 50 nm MSN particles was found with HeLa cells.30 Without attempting to be comprehensive, we refer the reader to additional literature concerning this topic.31-34



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5) Changing the MSN composition a) Incorporation of reducible di- and tetra-sulfide bonds (samples G) Besides functionalizing the pore walls of siliceous mesoporous nanoparticles, it is also possible to introduce other properties into the MSN body by replacing TEOS with varying amounts of bridged organosilane precursors. In the last decade, a rich knowledge has accumulated concerning mesoporous organosilica bulk materials (also called periodic mesoporous organosilica, PMO35). The first mesoporous organosilica nanoparticles (MONs) sized 20 nm with ethylene-bridges were reported by Urata et al. 201136 and a number of corresponding nanomaterials have been reported recently, reviewed by Chen at al.37 and by Du and coworkers with view on their biomedical applications.38 Inspired by reports of the groups of Durand39, de Cola40 and Shi18 we have used our standard synthesis and replaced TEOS with certain amounts of potentially biodegradable di- and tetrasulfide-containing bis-silanes. Disulfide-containing residues are frequently used in biomedical applications since the high intracellular content of the thiol-containing tripeptide glutathione (GSH), especially in cancer cells, can induce the reduction and cleavage of disulfide bridges, thus disrupting targeted bonds. When included into MSN particles, this may lead to enhanced intracellular particle degradation. We have used our core-shell particles as displayed in Figure 8 containing 9% amino groups and 1 % mercapto-groups, and have substituted 10, 30 and 50 mol% of TEOS with bis(3triethoxysilylpropyl)disulfide (BTDS or S2). The reaction was performed as usual, now by mixing TEOS with BTDS and APTES and adding it to TEA to result in solution B. Figure 10 displays the analytical data obtained after template extraction.

Figure 10: Core-shell samples with 9% amino groups in the particle core and 1 % mercapto groups in the external shell with 10, 30 and 50 mol% of the silica content replaced with BTDS (Samples G1, G2, G3). a) nitrogen sorption isotherms, b) pore-size distributions, c) thermogravimetric results with the first differential displayed for increasing organosilane contents and d) FT-Raman spectroscopy. 16 ACS Paragon Plus Environment

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Starting with a very high surface area of nearly 900 m2/g in sample G1 with 10% BTDS, the nitrogen sorption data show that increasing the organic content in the sample results in a successive loss of surface area down to 290 m2/g accompanied by a reduction in pore size. However, when preparing a 50% BTDS sample without surface functionalization (sample G4, see also Supplement, Table 2) we still obtain over 800 m2/g surface area. A high content of tridentate silica precursors as in the form of bis-silanes and functionalized silanes (such as APTES used here) seems to interfere with a sufficient cooperative self-assembly and condensation around the CTAC/TIPB micelles. Nevertheless, the increase of BTDS in the particle body is easily seen in the growing weight loss in the TGA as well as in the growth of characteristic CH-stretching vibrations of the propylene groups at 2916 and 2890 cm-1 in the Raman spectrum. Correspondingly growing bands at 1456 and 1271 cm-1 can be attributed to CH2-SH deformation bonds while a band at 650 cm-1 indicates the C-S stretching band. The S-H vibration of the functionalized shell is seen at 2576 cm-1. The TEM image of the 10% BTDS sample G1 is seen in Figure 11, showing the typical stellate pore morphology and particle sizes of around 150 nm. When we decreased the TEOS : TEA ratio in this sample from 1:10 to 1:3, we observed again a drastic reduction of the particle size, down to only 35 nm, showing evenly shaped MSNs with 4.8 nm pores.

Figure 11: TEM micrographs of a) the 10% S2 containing core-shell sample G1 shown in Fig. 10 with TEOS : TEA = 1:10, and b, c) 10% S2 containing core-shell sample G5 with TEOS : TEA = 1:3. Similar small-sized mesoporous particles can be made with tetrasulfide-bridged bis[3-(triethoxysilyl) propyl]tetrasulfide (BTTS or S4). We substituted up to 50 mol% of TEOS with S4 and used a TEOS : TEA ratio of 1:5 to obtain 30-40 nm particles (Sample G6, see Figure 12). Wu et al. have reported on S4-bridged MSNs under near neutral conditions.18, 41



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Figure 12: Tetrasulfide-containing MSNs: Sample G6 made with 50% S4.a) TEM, b) SEM c) TEM of the sample G6 after 7 d treatment in 10 mM GSH, d) BET and d) NLDFT pore-size distribution of sample G6 and e) FT-Raman spectroscopy before and after GSH treatment. These unfunctionalized tetrasulfide samples show a high surface area of over 500 m2/g. However, when samples with 10% or 30% S4 in the particle body were prepared with cocondensation of 10% amino groups we could again observe that the surface area is drastically reduced upon cocondensation (see Supplement, Figure S8 Table 2). Degradation experiments were performed on a number of these samples by exposing small amounts to near physiological conditions of a 10 mM buffered aqueous solutions of GSH or 5 mM dithiothreitol (DTT) for up to a week at 37°C. After this time we could still retrieve solid remains of these samples, as shown for sample G6 in the TEM micrograph in Figure 12c. The morphology has changed by being seemingly less rough and less dense, indicating at least a partial decomposition of the particles. This is supported by the Raman spectrum shown in Figure 12. Before GSH conditioning the triplet of S-S stretching frequencies at 490, 460 and 437 cm-1 is clearly seen, while after this process some of these bands have vanished, a band near 506 cm-1 emerges but most importantly, the reduction of the disulfide bond is visible in the occurrence of the S-H mercapto vibration at 2576 cm1 . Finally we should mention that all of the di-or tetrasulfide-containing MSN samples became increasingly aggregated with higher organic content. b) Autofluorescent MSNs with curcumin bridges (samples H) Very recently our group has developed a completely new kind of mesoporous organosilica nanoparticles consisting solely of bis(triethoxysilyl)ethane (BTSE) and a curcumin-bridged bis-silane, the latter being obtained by reacting curcumin and 3-isocyanatopropyl(triethoxysilane).42 Templated by CTAB under basic conditions, 0.32 mmol curcumin and 0.51 mmol BTSE were condensed into microporous MONs of about 200 nm size with very large surface areas of around 1000 m2/g, see Figure 13. 18 ACS Paragon Plus Environment

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Figure 13: Autofluorescent mesoporous organosilica nanoparticles consisting of curcumin and ethane bridged bis-silanes. Top: TEM micrographs, bottom: nitrogen sorption and NLDFT pore size distribution. These particles show the typical wormhole pore characteristics as usually observed when CTAC or CTAB templates are used without an additional swelling agent. Due to their autofluorescence, they can serve as analytical markers and can be easily observed in cellular environments. Combined with their low silica content, they present a new class of biocompatible drug carrier systems. 6) LP-MSN synthesis under acidic conditions (samples I) When aiming at protecting large guest molecules such as (small) proteins or oligonucleotides from premature degradation during drug delivery, it is necessary to enable their adsorption into the interior of the carriers by offering pores of suitable sizes. We have seen above that most of the MSN particles described so far can have pore-sizes between 3 to 6 nm, except when using CTATOS at reduced pH that produced wide stellate pores of at least 14 nm. However, a very different pore morphology with bottleneck pores sized between 6 to 15 nm is obtained following a synthesis procedure under acidic conditions. This synthesis of mesoporous nanoparticles with ordered pores in the 10 nm range is derived from a recipe published by the group of Corma.15 They used the cationic fluorocarbon surfactant FC-4 (C3F7O(CFCF3CF2O)2CFCF3CONH(CH2)3N+(C2H5)2CH3I-) that had been introduced before by Han et al.43 and which is believed to function as growth inhibitor, enabling the formation of isolated mesoporous particles at low pH. In combination with the well-known Pluronic 127 triblock copolymer acting as 19 ACS Paragon Plus Environment


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pore forming template, the pore swelling agent TiPB and a multistep synthesis procedure they created highly ordered silica nanoparticles with ultra-large pores. We have adapted this strategy by incorporating functionalization via cocondensation with organosilanes to produce samples such as those shown in Fig. 1d and e). The standard recipe for purely siliceous samples is described below. Standard recipe in acidic conditions: a) 0.5 g Pluronic F127 and 1.4 g FC-4 are combined with 60 mL 0.02 M HCl in a 100 mL plastic vial equipped with a stirrer set to 600 rpm and are dissolved in a thermostat at 60 °C for 2.5 h: the solution turns from turbid to a milky solution. b) This solution is then cooled down to 15°C, 0.4 g TiPB is added and the solution is stirred for 2 h. c) 3 g TEOS (0.0144 mol) is added dropwise under stirring and is further stirred at 15 °C for 24 h resulting in a white suspension. d) This suspension is transferred into a 100 mL Teflon-lined autoclave and is heated at 150 °C for 24 h, then quenched and centrifuged 20.000 rpm for 30 minutes. The supernatant is decanted and e) refilled with 30 g of a 2 M HCl solution which is additionally heated at 140 °C for 24 h. A sketched overview over this procedure is seen in Figure S10 in the Supplement. For the cocondensation reactions we added dropwise 1-5 mol% of the desired silane coupling agent mixed with the same amount of TEOS to the reaction in step 3, with a 5 minute delay after the amount of 3 g TEOS had been administered. All other reaction steps were the same. In some instances we have changed the temperature of the first and second autoclaving step, which is noted in Table 3 in the Supplement. Figure 14 shows selected results that were obtained with and without amine cocondensation.

Figure 14: LP-MSN made under acidic conditions. TEM micrographs of a) purely siliceous LP-MSN I1, b) cocondensation with 1 mol% APTES, sample I2, c) cocondensation with 2.5 mol% Ph and 0.5 mol% APTES, sample I3, d, e) nitrogen sorption isotherm and pore size distribution of sample I3. 20 ACS Paragon Plus Environment

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The TEM micrographs indicate the very different pore morphology of apparently spherical pores with dimensions of at least 10 nm. When the pore size is evaluated with the NLDFT kernel for cylindrical/spherical pores from the adsorption branch, we see a wide size distribution with a small maximum at 16 nm and smaller peaks evolving at 8 and 5 nm. When we use the kernel for cylindrical pores we do obtain size distributions similar to those depicted in Figure 14 e). Under these conditions, the unfunctionalized sample displays a size distribution maximum at 11 nm (ads. branch), while if analyzed with the cylindrical pore equilibrium kernel, we obtain a wide distribution with a maximum at 8 nm reaching up to 16 nm. Since the fitting errors between the spherical and cylindrical approach are very similar, we decided to display the pore-size distributions resulting from the cylindrical pore kernel as we did for all other presented samples. This uncertainty in the pore size determination is attributed to the unusual pore morphology, which we interpret as bottleneck pores. The BET surface area of sample I1) is very small with only 220 m2/g and a pore volume of 0.6 mL/g (at now 0.98 p/p0 due to the large pores). A cocondensation with amine groups was challenging under these reaction conditions. Even including only 1 mol% of APTES resulted in completely different structures as shown in Figure 14 b, sample I2). In contrast to 50-150 nm sized particles in the pure silica sample we obtained single-shell structures of about 30 nm. Here, the pore size is centered around 18 nm. Surface area and pore volume are much higher with 413 m2/g and 1.57 mL/g, respectively. A functionalization with amines by cocondensation was only possible with a low content of 0.5 mol% APTES (sample I3); this sample was additionally treated with 2.5 mol% phenyltriethoxysilane (PHTES). The corresponding isotherm and pore-size distributions are shown in Figure 14 d and e. To increase the amine content in this sample, we had to return to classical grafting procedures in order to introduce a strongly positive surface charge in these particles; this is necessary for the adsorption of negatively charged guest molecules like siRNA.44 Similar challenges were encountered when mercapto groups were co-reacted in these LP-MSN syntheses. We could achieve a functionalization with 1 mol% MPTES as shown in Figure 15 a, sample I4 with the corresponding isotherm and pore-size distribution shown below. However, the particles became nearly dense when 5 mol% MPTES were added during the synthesis (Figure 15 b, sample I5). In contrast, a core-shell synthesis with 1 mol% SH in the core and 1 mol% NH2 in the shell was successful, the product is shown in Figure 15 c, sample I6.



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Figure 15: Mercapto-functionalized LP-MSNs: TEM micrographs of samples made by a) cocondensation with 1 mol% MPTES, sample I4 b) cocondesation with 5 mol% MPTES, sample I5 c) core-shell particles with 1 mol% MPTES in the core and 1 mol% APTES in the shell, sample I6 d,e) nitrogen sorption isotherm and pore size distribution of sample I4). When other less chargeable functional groups were used for creating hybrid LP-MSNs we did not encounter these morphological changes. Additional examples with glycidoxy- and cyanopropyltriethoxysilane residues are shown in the Supplement, Figure S10. We should mention that the particle size distribution obtained with this acidic pathway is very broad and the colloidal stability is limited. To remove larger particles, we typically performed a size-discriminating centrifugation at 5000 rpm for 1 minute. Best results were obtained with a sample functionalized on its shell with polyethylene-glycol (MeO)3-Si-PEG(10)-OH), however, even here we used centrifugation to obtain samples that could be evaluated in the DLS. We can conclude that today a number of reaction pathways are at hand to create mesoporous silica nanoparticles with a wide spectrum of surface properties and morphologies. For our purposes we have mainly relied on the basic synthesis strategy to produce a series of different MSN-based nanoscale host systems. To transform the particles into efficient drug delivery agents we have also developed appropriate pore-closing and release functions, which we briefly present in the last chapter. 7) Pore-closing and release strategies for drug-delivery applications of MSNs Functionalization of the particle outer shell has allowed us to selectively anchor molecular entities externally while leaving the inner particle surface and volume open for the adsorption of guest molecules. An overview over the following examples is given in Scheme 1 below. For example, in order to study pore closing mechanisms, we have used mercaptofunctionalized MSN particles that were covalently coupled to maleimide-carrying residues (MAL-R, see Scheme 1). The thiol-reactive 22 ACS Paragon Plus Environment

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MAL-group was, for instance, coupled to biotin which itself has a high affinity towards the protein avidin. Avidin can bind up to four biotin entities and due to its size it can act as a pore closing molecule. This mechanism proved to form a tight closure with SP-MSNs that were loaded with the dye fluorescein. Pore opening was achieved via protolytic enzyme degradation of avidin using trypsin.45 Similarly, biotin-labeled double stranded short DNA oligonucleotides were attached to the MSN surface and reacted with avidin, which could then function as a thermosensitive molecular valve by heating the system above the DNA melting temperature.46 In another example, we attached a PEGylated porphyrin to the particle surface and sealed the pores with a lipid bilayer. The latter could then be opened with light by taking advantage of the photoinduced generation of singlet oxygen.47 The combination of a red light-responsive photosensitizer bound to the MSN surface that was enclosed with a lipid bilayer shell could further be used for site-specific particle delivery by attaching targeting ligands into the lipid membrane.48 An enzyme-based capping system was developed by linking a pH-responsive arylsulfonamide moiety to the MSN particle exterior that specifically binds to and is closed by the carbonic anhydrase enzyme.49 Endosomal acidification then served to release the enzyme from the surface-bound arylsulfonamide inhibitor, thus serving as a biological pH-sensitive capping and release agent. A very different approach was taken for the direct delivery of chromobodies (small dye-labeled antibody fragments from camelids) into cellular nuclei. Here, overall mercapto-functionalized LPMSNs as described in Chapter 2d were used to generate metal ion-chelating nitrilotriacetic acid complexes in the pores that are able to bind histamine-tagged chromobodies. The intracellular release of the chromobodies was achieved through acidification within the cell and acid-induced decomplexation of the His-tags of the chromobodies.20 In a different approach, a unique core-shell particle was created by internally functionalizing MSNs with mercapto groups that were used to couple dyes via a reducible disulfide bond while the exterior of the particles was functionalized with a dendrimer-like polyamidoamine-polymer silane (PAMAM). The latter served as pore-closure mechanism and additionally as endosomal release agent, presumably via a process called protonsponge effect.50 Polymer coupling on the outer shell of multifunctional MSNs was also used in combination with amine-functionalized MSN particles, where poly(vinylpyridine)-poly(ethyleneglycol) block copolymers (PVP-PEG) were stepwise attached to the outer particle surface, while the interior could be used for the adsorption of the anticancer drug colchicine.51 Loading and release of the drug was achieved by a pH-sensitive opening and closure mechanism of the block-copolymer. Finally, core-shell particles with amino groups inside and mercapto groups outside were used to adsorb large quantities of negatively charged gene-silencing RNA (siRNA) into MP-sized MSNs.44 The negatively charged particle exterior was exploited for the association of positively charged block copolymers consisting of artificial amino acids that served as pore closure mechanism and simultaneously as endosomal escape agents. This is an example where the pore-size adjustment was of key importance for achieving optimized drug release. In this context, medium-sized pores showed a higher efficiency than LP-MSNs made by the acidic pathway. Conclusions and outlook In this article we provide a sampling of the many possibilities available for tuning structure and functionality of mesoporous silica nanoparticles by means of synthetic strategies. We offer examples 23 ACS Paragon Plus Environment


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for the adjustment of pore size and pore topology of the mesopore system through templating and pore-swelling agents as well as different synthesis strategies. Functionalization through cocondensation strategies is discussed, highlighting the spatially selective anchoring of silanecoupling reagents within the mesoporous nanoparticles. Moreover, we show how the composition of the mesoporous walls can be modified with organic moieties by including redox-sensitive sulfide bonds or by creating autofluorescent curcumin-containing mesoporous organosilica. We also show how the particle size of mesoporous nanoparticles can be tuned over a wide range from several hundred nm down to 30 nm simply by changing the stoichiometry of the reaction solution. Structural parameters such as particle size are of great importance for targeted drug delivery applications. In view of the above, mesoporous silica nanoparticles can be regarded as the most versatile existing platform for drug delivery purposes. However, for MSNs to serve as benign and reliable shuttles for potentially toxic guest molecules, requires not only effective ‘mechanics’ for safe guest-enclosure, efficient cell uptake, and site-specific (triggered) release. Competent nanocarriers also need to be constructed for appropriate retention times in the body, thus allowing for sufficient accumulation in targeted tumors. In addition to controlled particle size, this may also require stealth properties against recognition by the immune system or other biological effects. Such features can be generated by appropriate surface decorations, which also need to ensure colloidal stability in body fluids. Hemolytic effects and toxicity towards healthy cells need to be minimized. Ultimately, particles should decompose into non-toxic and removable residues. If possible, all these requirements should be fulfilled by simple, easy-to-handle and even cost-effective particles. Several of the above requirements, especially concerning particle morphology, have been mastered during the last decade of research on mesoporous silica nanoparticles. Nevertheless, the final drug carriers need to be carefully tested for toxicity, particle aggregation and timely degradation and dissolution. Provided that these important issues can be addressed for the application at hand, MSNs and related hybrid materials can be envisioned as promising multipurpose drug carriers. The examples discussed in this article serve to illustrate the enormous versatility of mesoporous silica nanoparticles as a general platform for compartmentalizing matter at the nanoscale, both in the biological and non-biological context. For example, (reactive) interior spaces can be generated, separated and protected from exterior phases, cargo can be transported and delivered, as well as released depending on internal and external triggering stimuli. With this exposition we hope to convey the excitement and intellectual richness associated with the field of multifunctional mesoporous nanoparticles.


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Scheme 1: Overview over pore closing and release mechanisms with functionalized MSN particles.

Acknowledgements We thank the Deutsche Forschungsgemeinschaft (DFG) for financial support (SFB 1032). Additional support is gratefully acknowledged from the Excellence Cluster Nanosystem Initiative Munich (NIM) and from the Center for NanoScience Munich (CeNS). We thank Kathrin Grieger and Carola Lampe for preparing selected samples during their internships with K.M..

Supporting information TEM, SEM, nitrogen sorption, FTIR spectroscopy, Zeta-potential measurements, Dynamic Light Scattering, X-ray diffraction, Raman spectroscopy, Synthesis Scheme, Tables with sample listings.

REFERENCES (1) Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.; Beck, J. S., Ordered mesoporous molecular sieves synthesized by a liquid-crystal template mechanism. Nature 1992, 359, 710-712. (2) Lai, C.-Y.; Trewyn, B. G.; Jeftinija, D. M.; Jeftinija, K.; Xu, S.; Jeftinija, S.; Lin, V. S. Y., A Mesoporous Silica Nanosphere-Based Carrier System with Chemically Removable CdS Nanoparticle Caps for Stimuli-Responsive Controlled Release of Neurotransmitters and Drug Molecules. J. Am. Chem. Soc. 2003, 125, 4451-4459. (3) Chen, N.-T.; Cheng, S.-H.; Souris, J. S.; Chen, C.-T.; Mou, C.-Y.; Lo, L.-W., Theranostic applications of mesoporous silica nanoparticles and their organic/inorganic hybrids. J. Mater. Chem. B 2013, 1, 3128-3135. (4) Knezevic, N. Z.; Durand, J.-O., Large pore mesoporous silica nanomaterials for application in delivery of biomolecules. Nanoscale 2015, 7, 2199-2209. (5) Chen, Y.; Chen, H.; Shi, J., Inorganic Nanoparticle-Based Drug Codelivery Nanosystems To Overcome the Multidrug Resistance of Cancer Cells. Mol. Pharmaceutics 2014, 11, 2495-2510. (6) Argyo, C.; Weiss, V.; Bräuchle, C.; Bein, T., Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Chem. Mater. 2014, 26, 435-451. (7) Colilla, M.; Gonzalez, B.; Vallet-Regi, M., Mesoporous silica nanoparticles for the design of smart delivery nanodevices. Biomater. Sci. 2013, 1, 114-134. (8) Giret, S.; Man, M. W. C.; Carcel, C., Mesoporous-Silica-Functionalized Nanoparticles for Drug Delivery. Chem. - Eur. J. 2015, 21, 13850-13865. (9) Mekaru, H.; Lu, J.; Tamanoi, F., Development of mesoporous silica-based nanoparticles with controlled release capability for cancer therapy. Adv. Drug Delivery Rev. 2015, 95, 40-49. (10) Martinez-Carmona, M.; Colilla, M.; Vallet-Regi, M., Smart mesoporous nanomaterials for antitumor therapy. Nanomaterials 2015, 5, 1906-1937. (11) Baek, S.; Singh, R. K.; Khanal, D.; Patel, K. D.; Lee, E.-J.; Leong, K. W.; Chrzanowski, W.; Kim, H.-W., Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles. Nanoscale 2015, 7, 14191-14216. 26 ACS Paragon Plus Environment

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Talented Mesoporous Silica Nanoparticles - Chemistry of Materials

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