Multifunctional Mesoporous Silica Nanoparticles as a Universal

Perspective pubs.acs.org/cm

Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery Christian Argyo,# Veronika Weiss,# Christoph Braü chle,* and Thomas Bein* Department of Chemistry and Center for NanoScience (CeNS), University of Munich (LMU), Butenandtstr. 5-13 (E), Munich, 81377 Germany ABSTRACT: Nanosized mesoporous silica particles with high colloidal stability attract growing attention as drug delivery systems for targeted cancer treatment and as bioimaging devices. This Perspective describes recent breakthroughs in mesoporous silica nanoparticle design to demonstrate their high potential as multifunctional drug delivery nanocarriers. These types of nanoparticles can feature a well-defined and tunable porosity at the nanometer scale, high loading capacity, and multiple functionality for targeting and entering different types of cells. We focus on the requirements for an efficient stimuli-responsive and thus controllable release of cargo into cancer cells and discuss design principles for smart and autonomous nanocarrier systems. Mesoporous silica nanoparticles are viewed as a promising and flexible platform for numerous biomedical applications. KEYWORDS: mesoporous silica nanoparticles, stimuli-responsive drug delivery, targeted drug delivery, endosomal escape, controlled release, bioimaging

1. INTRODUCTION Multifunctional mesoporous silica nanoparticles (MSNs, size typically 15 nm) (Adapted from ref 53. Copyright 2011 American Chemical Society.).

molecules, such as enzymes or oligonucleotides, leads to a growing research activity in the synthesis of MSNs with large pores (10−20 nm, Figure 1d).53,54 In order to gain access to the pores, the templating surfactant molecules have to be removed. This can be achieved either by calcination or with extraction methods. To overcome impediments such as reduction in pore size, particle agglomeration, removal of organic moieties, or low degree of condensation of the silica network, Cauda et al. established a new approach that combines the advantages of both aforementioned methods for template removal.57 Here, a liquid-phase high temperature “calcination” of MSNs is performed in a high-boiling organic solvent leading to a higher degree of silica condensation while maintaining the colloidal nature of the nanoparticles. 436

dx.doi.org/10.1021/cm402592t | Chem. Mater. 2014, 26, 435−451

Chemistry of Materials

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Functionalization. In order to exploit the whole potential of MSNs for drug delivery applications, it is desirable to add functionality to the silica scaffold. Molecular functionality attached to the surfaces of inorganic silica can dramatically change the properties of the obtained material, which is important in host−guest interactions with the cargo. The incorporation of organic moieties at specific locations is intended to fine-tune surface and materials properties and is a subject of current research.58,59 The spatially selective modification of the internal pore system and the external particle surface with organic and inorganic moieties is often an essential requirement for these materials to operate as multifunctional drug carriers exhibiting the required features. External surface functionalization is particularly important for colloidal and chemical stability as well as for interactions with the environment, such as modifying the particles for specific cell targeting or attaching large molecules for pore gating and improving biocompatibility (cf. Section 2.2).60−64 On the other hand, internal organic moieties can supply enhanced interaction or covalent binding sites for cargo molecules, such as drugs or proteins, which allows for control over diffusional transport, delivery kinetics, and stability of the therapeutic molecules.65−67 In general, there are several approaches to achieve functionalization of silica materials. The most important functionalization strategies are via postsynthetic grafting and via co-condensation, besides the synthesis of periodic mesoporous organosilicas (PMO) and employment of metal organic reagents.35,68−70 In order to gain control over the location of the functional groups in silica nanoparticles, Bein and co-workers established a site-selective delayed co-condensation approach.22,71 Here, bifunctional MSNs with a selective functionalization of the interior and an orthogonal functionality at the external particle surface in different onion-like shells can thus be prepared (Figure 2).This strategy opens new possibilities for the design of numerous highly functionalized porous nanoparticles with applications in controlled drug delivery.

can create multifunctional drug carriers, making the delivery process highly controllable. Gating. One of the important functionalities in this context is triggered release of the cargo through specially designed gating concepts. In general, gatekeepers can be classified into three different types (cf. Figure 3). Pore gating systems can consist of either bulky molecular groups or nanoparticles, such as proteins, superparamagnetic iron oxide nanoparticles (SPIONs), or gold nanoparticles (Au-NPs) which block the pore entrances for efficient sealing of the interior mesoporous environment.25,73,74 These macromolecular structures are either degradable or attached to the silica particle surface via linkers that are cleavable upon exposure to certain stimuli.75,76 Very good pore sealing can also be achieved by a complete coating of the MSNs. For instance, polymers, oligonucleotides, or supported lipid bilayers (SLB) have been shown to prevent premature cargo release.24,27,77−84 Often, phase transitions or competitive displacement reactions lead to opening of the pores and efficient cargo delivery.85,86 The third strategy for controlled cargo release involves attachment of the cargo molecules in the porous system of the silica nanocarriers. Coordinative or covalent bonds can be cleaved by certain stimuli such as competitively binding molecules or reducing agents to activate cargo release.87−89 Zink and co-workers have presented different nanocarriers with on-demand controllable release mechanisms, including nanoimpellers consisting of azobenzene groups that have been described to trigger UV-light-activated release of a cell membrane-impermeable dye.90 Biocompatibility and Stability. For applications of MSNs as nanocarriers, biocompatibility and low toxicity are required. A modification of the nanoparticle surface with functional shells, such as polymer coatings, charged groups, or a supported lipid bilayer was found to decrease particle aggregation and improve stability in biological media. For instance, functionalization of the particle surface with phosphonate groups was shown to improve the stability and dispersibility of MSNs in aqueous media.95,96 This modification helped to prevent interparticle aggregation, and redispersion after a drying process was highly improved.1 In general, MSNs provide good biocompatibility, but the high surface area and a low degree of condensation of the silica framework can promote a high rate of dissolution.97,98 Bare, nonfunctionalized MSNs featuring silanol groups at their surface dissolve fairly rapidly in simulated body fluid under physiological conditions and produce soluble silicic acid species (which are found to be nontoxic).99 The rate of silica dissolution is dependent on particle size, functionalization, degree of silica condensation, and pore morphology. A surface functionalization can prevent fast degradation and provide prolonged stability of MSNs in biological media. For example, a hydrophilic polymer shell such as poly(ethylene glycol) (PEG) or an SLB on colloidal MSNs improves stability in water, maintains monodispersity, and can minimize nonspecific adsorption of proteins on the nanoparticle surface.79,20,96 Such a polymer coating provides a protective shell for the silica surface, which is important when prolonged circulation time in an organism is required for effective drug delivery. PEGylation can hinder capture by organs of the reticuloendothelial system (RES) and consequently slow down biodegradation.100 Hemocompatibility is another important attribute of MSNs. Surface functionalization of bare MSNs can reduce or even completely prevent thrombogenic effects and nonspecific protein adsorption on MSN surfaces.101 For example, heparincoated core−shell MSNs have recently been described.102

Figure 2. Site-selective delayed co-condensation approach for creating bifunctional MSNs. In a first step, a mixture of organosilane (green) and tetraethylorthosilicate (TEOS) in an aqueous solution containing template and base catalyst creates a functionalized nanoparticle core. Subsequently, the nanoparticle growth is completed by addition of pure TEOS (blue) resulting in an unfunctionalized silica shell around the core. Finally, the addition of another organotriethoxysilane (RTES, R represents an organic moiety, red) and TEOS forms an external skin with different functionality.

2.2. Modification of MSNs with a Functional Shell. Surface modification with organic and inorganic species can introduce a large variety of functionalities for controlling diffusion and release of cargo molecules and cell surface recognition, among others. The potential to design biocompatible external surfaces of nanoparticles providing tunable interactions with the biological environment by attachment of molecular or macromolecular moieties for biomedical applications has been recently demonstrated.25,26,72 The combination of the properties of such an external functional shell and the advantageous structural properties of the mesoporous silica core 437



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Figure 3. Strategies for controlled release can be classified into three different types, molecular/particle pore gating (a,b), surface coating (c,d), and internal pore modification (e,f). (a) Mesoporous silica nanorods capped with superparamagnetic iron oxide nanoparticles (SPIONs) containing redoxresponsive cleavable disulfide linkers (Reprinted from ref 73 with permission by Wiley-VCH, Copyright 2005.); (b) temperature-dependent programmable molecular valve system consisting of avidin caps being opened by melting the DNA linkers (Reprinted from ref 91 with permission by Wiley-VCH, Copyright 2010.); (c) temperature-dependent phase transition of PNIPAM-coating on MSNs (Adapted from ref 92. Copyright 2008 American Chemical Society.); (d) disulfide-linked polymeric network at the outlet of mesoporous silica allowing redox-responsive controlled release of the cargo (Adapted from ref 93. Copyright 2008 American Chemical Society); (e) schematic release mechanism for a pH-responsive system based on coordination bonding in mesopores (Reprinted from ref 94. Copyright 2010 American Chemical Society.); and (f) light-activated cis/trans isomerization of azobenzene groups inside mesopores expels the cargo (Adapted from ref 90 with permission by Wiley-VCH, Copyright 2008.).

necessary to eradicate malignant cells.103,104 Extensive studies showed that passive targeting of nanocarriers in tumor tissue could be observed.105,106 Well-stabilized nanoparticles with optimal size and appropriate antifouling surface can remain in blood vessels long enough to accumulate at the tumor site. Passive targeting relies on the enhanced permeability and retention (EPR) effect. This effect is described as the tendency of particles of certain sizes, such as liposomes, nanoparticles, and macromolecular drugs, to preferentially accumulate in tumor tissue. Tumor vasculature typically exhibits an increased permeability and is lacking effective lymphatic drainage.107 Enhanced passive bioaccumulation via the EPR effect could be achieved by modifying the MSN surface with positively charged groups.108 However, the EPR effect is not universal for all types of tumor cells, and a lack of cell-specific interactions might decrease therapeutic efficacy and induce multiple drug resistance (MDR).84,107,109 In contrast, employing targeting ligands like folic acid or macromolecules like the epidermal growth factor (EGF) in order

Heparin is a highly sulfated, anionic polysaccharide, known for its anticoagulant properties. This novel nanoscale system combines the efficiency of heparin in preventing blood-clotting with multifunctional core−shell MSNs featuring excellent structural properties and colloidal stability. In general, MSNs with organic shells offer multifunctionality and improved biocompatibility and hemocompatibility and are expected to have potential as bloodstream-injectable drug-delivery systems offering new options for cancer therapy.

3. DRUG DELIVERY AND BIOIMAGING APPLICATIONS 3.1. Targeting and Cellular Uptake. Targeting. Insufficient target selectivity of drugs can cause unwanted side effects and reduce therapeutic efficacy. Especially in anticancer chemotherapy, limited selectivity of cytostatins and cytotoxins toward tumor cells is responsible for many undesired side effects. The efficacy of the treatment can be affected when nonspecific toxicity to normal cells prevents an effective dose that is 438



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to antigens overexpressed on different cancer cell lines.110,111 MSN bioconjugates with DNA-aptamers were also investigated and showed specific binding to nucleolin, a cell membrane protein overexpressed on breast cancer cells.112 However, concerns may arise about the stability of these systems in body fluids due to potential degradation of the targeting ligands by extracellular nucleases or proteases, which may reduce targeting efficiency of antibody- and aptamer-aided delivery concepts. Endocytosis. In general MSNs are internalized into the cells via endocytosis.12 For illustration, a typical sequence of cytosolic delivery of therapeutics to cancer cells with mesoporous silica nanocarriers is depicted in Scheme 2. The endocytic pathway is

to exploit the overexpression of certain receptors on tumor cell surfaces can promote specific and active nanocarrier binding and cellular uptake. Active targeting can be achieved by covalent attachment of targeting molecules (ligands) to the particle surface. The main challenge for targeted nanocarriers is to achieve high targeting specificity and drug delivery efficiency simultaneously, while avoiding nonspecific binding and activation of immunogenic effects. A recent advance has been reported by Brinker and co-workers, who combined a porous, inorganic MCM-41-type silica core coated with a supported lipid bilayer to prevent cargo leakage with a short targeting peptide (SP94).84 This small peptide was identified by phage display to bind efficiently to hepatocellular carcinoma cells. The complementary receptor is still unknown. In this study, a ligand recruitment procedure was described leading to efficient receptor-mediated endocytosis of the nanocarriers. The small molecule folic acid (FA) has been widely investigated as targeting ligand and has shown a notable enhancement in uptake efficiency of MSN nanocarriers (for citations, see Table 1). Often, long spacers, e.g., PEG chains, are

Scheme 2. Schematic Representation of Different Stages of a Targeted Cellular Uptake of a Multifunctional MSN and Controlled Release of the Cargo into the Cytoplasm of Cancer Cellsa

Table 1. Diverse Targeting Ligands Used for Active and Specific Cell Recognition of Nanocarriers Based on MSNs targeting ligand

cell membrane receptor

folic acid (FA) RGD motifs

folate receptor (FR-α)

HeLa, KB

integrins

antibody ME1 antibody ab2428 antibody Herceptin aptamer AS 1411 mannose galactose

mesothelin

HeLa, MCF-7, U87MG, HT-29, SCC-7 MM

ErbB 2

MCF-7

111

HER2/neu

BT-474

125

nucleolin

MCF-7, MDA-MB-231

112

mannose receptor galactose receptor

126 127

hyaluronic acid anisamide EGF SP94 FA, TEM-7, CD31

CD44 (RHAMM, CD168, HARE) Sigma-receptor EGF-R unknown FR-α, TEM-7 antibody, CD31 antibody

MDA-MB-231 HCT-116, Capan-1, MDA-MB-231 MDA-MB-231 ASPC-1 HuH-7 Hep3B MCF-7, HUVEC

129 27 84 130

targeted cell line

ref. 27, 79, 113−121 122−124 110

a

(1) Active docking to cell surface receptor of a nanocarrier via targeting ligands; (2) process of ligand/receptor-mediated endocytosis; (3) MSN entrapped in endosome; (4) intracellular transport and acidification of endosome; (5) triggered endosomal escape of nanocarrier, thus obtaining access to the cytoplasm; (6) controlled delivery of the cargo inside the cell.

128

the most common uptake mechanism of cells for many different nanoparticles and macromolecules. Endocytosis is a very complex process by which cells absorb such particles by engulfing them with lipid bilayer forming vesicles. For this purpose, a part of the cell membrane is used for creating an endosome.131 Size and morphology of the silica nanoparticles and functional groups on the external particle surface influence the ability of MSNs to be internalized via endocytosis.132−137 Utilizing such modifications of the MSNs can aid in specific cellular uptake in a precisely controlled manner. In a study of Slowing et al.,63 endocytosis of aminopropyl-functionalized MSNs was shown to be affected by caveolar inhibition suggesting a cellular uptake via a caveolae-mediated mechanism. Endocytosis of MSNs can be investigated via flow cytometry, transmission electron microscopy, confocal microscopy, and other techniques.138 3.2. Endosomal Escape. Recent studies have demonstrated that MSNs are able to undergo smooth cell internalization, but endosomal escape has been identified as a bottleneck for the efficient delivery of macromolecular substances or nano-

used for the covalent attachment of the targeting ligands to the external surface of the MSNs. This linkage provides high flexibility to obtain efficient binding of the targeting ligands to the cell membrane receptors. Ligands such as FA, mannose, hyaluronic acid, and EGF (among others) used as targeting devices are abundantly present in organisms. Moreover, the associated receptors are widely present on many eukaryotic cells. This implies concerns about the achievable targeting specificity. In those cases, the significant overexpression of receptors on cancer cells has been exploited. Extensive efforts have been made to create actively targeted nanocarrier vehicles using ligands for specific recognition of the cell-surface receptors as well as antibodies and DNA aptamers. Important examples are summarized in Table 1. Studies on antibodies attached to the nanoparticle surface via either electrostatic interactions or covalent linkage showed highly specific binding with high affinity 439



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particles.72 The entrapment in the endosomes could lead to degradation of the nanocarriers and their cargo molecules by specific digestive enzymes when fusion with a lysosome occurs. Thus, an important step in achieving an appropriate therapeutic effect is to facilitate the endosomal escape and to ensure cytosolic delivery of the therapeutics. Many anticancer therapeutics such as doxorubicin (DOX) feature cell membrane permeability, and consequently, a trigger for endosomal escape is not required. These permeable drugs only require a means of preventing premature release from the nanocarrier to avoid global distribution in the organism and targeted transport into cancer tissue to achieve a sufficiently high local drug concentration. Nevertheless, a large number of molecular and macromolecular therapeutics are either hydrophobic or membrane impermeable. Therefore, the multifunctional nanocarrier vehicles should provide an efficient endosomal escape mechanism for the local delivery of the drug molecules into the cytoplasm, thus gaining access to the targeted cell compartments or to the nucleus. Excellent strategies for achieving endosomal escape are provided by nature. Evolution created bacteria and viruses, which are able to penetrate membranes via different mechanisms to escape the endosomal pathway and to reach their target sites. Thus, it would be desirable to transfer these very efficient natural mechanisms to the drug delivery vehicles. Different mechanisms such as pore formation in the endosomal membrane, pH-buffering effects of protonable groups (“proton sponge”), or fusion into the lipid bilayer of endosomes have been proposed to facilitate the endosomal escape.139 In addition, photochemical methods to rupture the endosomal membrane have been introduced to MSNs.27,72,140 In a study by Sauer et al.,72 MSNs were taken up into cells and transported within endosomes, but no release of the cargo into the cytoplasm could be detected during incubation. In order to overcome the barrier of endosomal entrapment, photoinduced endosomal release via excitation of a photosensitizer (PS) was employed. Photochemical internalization (PCI) using PS that generate reactive oxygen species upon photoactivation is a powerful tool to overcome trapping by the endosomal membrane.141 Initial approaches of combining PS with mesoporous silica as a drug carrier did not provide a covalent bond of the PS to the particles. This could lead to uncontrolled spreading of the compounds and toxic effects on the cells. To achieve a more spatially controlled activity of nanodevices operating with PS, it is desirable to bind the PS directly to the surface of the mesoporous particles. Thus, a mesoporous core− shell system with covalently surface-linked PS was designed that provides an on-board trigger for light-activated endosomal membrane rupture.140 The nanocarriers can be loaded with model drugs in a broad size-range and are encapsulated by a SLB. The controlled release mechanism in living cells operates in a two-step cascaded manner, where the SLB is disintegrated by singlet oxygen in a first step and, second, the endosomal membrane is ruptured causing efficient cytosolic drug release. This nanodevice for drug delivery is capable of stimuli-responsive and localized endosomal escape and drug release without the systemic cell toxicity exhibited by common (dissolved) PS. In order to create a general photoactivatable drug delivery platform being applicable in biological environments, such as cancer tissue, further improvements have to be accomplished. Strategies for red-light activation have already been investigated.27,127 The activation of the photosensitizer with light of low energy reduces the phototoxicity and significantly increases the depth of tissue

penetration, which will be crucial when activation in vivo is required. Another promising endosomal release strategy is based on the proton sponge ef fect, in which osmotic swelling and membrane rupture of endosomes is initiated by macromolecules with high buffering capacities.142 This mechanism does not require an external stimulus, and custom-made nanocarriers can activate an “automatic” pathway for endosomal escape. Several cationic lipids and polymers, such as poly(ethylene imine) (PEI), possess substantial buffering capacity below the physiological pH which is a potential trigger to escape the endosomal entrapment.143,144 The cationic polymers or particles enter the cell via endocytosis, subsequently being entrapped in the endosome. Upon intracellular trafficking to late endosomes or lysosomes, the compartment is acidified from an initial physiological pH value of 7.4 to 5.5.145 Thus, the overall protonation level for PEI increases drastically.146 The accumulation of positive charge inside the endosome is coupled with a passive influx of chloride anions through ion channels to maintain electroneutrality. The large increase of ion concentration within the endosome in turn results in an inflow of water molecules, which causes osmotic swelling and subsequent membrane rupture. Employment of the proton sponge ef fect would provide an elegant solution for the problem of endosomal entrapment of MSNs. However, the exact mechanism is not fully understood. It is still an open question whether there has to be a high-capacity buffering agent present that is subsequently protonated and highly charged or if an already highly charged surface of particles is also sufficient to cause counterion influx, endosome swelling, and rupture. Lin and co-workers reported on MSNs with negatively charged surface functionalization achieving endosomal escape via the proton sponge ef fect.63 More negatively charged nanoparticles would escape more easily from endosomes of cancer cells owing to their high buffering capacity. The zeta potential of the silica nanoparticles seems to have a great impact on the ability of particles to escape the endolysosomal pathway. However, such highly negatively charged nanoparticles exhibit unfavorable cellular uptake behavior due to electrostatic repulsion with the negatively charged cell membrane. Nanocarriers providing protonable groups at mildly acidic conditions should result in much more efficient cellular uptake and subsequent drug release to the cytosol. In general, the proton sponge ef fect is a promising intrinsic endosomal escape pathway that should be further investigated. As an alternative mechanism, endosomolytic peptides can be utilized to achieve endosomal release.147 The lipid bilayerenclosed MSNs established by Brinker and co-workers were decorated with such an endosomolytic peptide (H5WYG) (Figure 4).77 This peptide sequence is a subunit of the

Figure 4. “Protocell” consisting of MSN-supported lipid bilayers with targeting peptides (SP94) and endosomolytic peptides (H5WYG) attached to the outer periphery of the nanoconstructs (Reprinted from ref 83. Copyright 2012 American Chemical Society.). 440



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Table 2. Controlled Cargo Release Mechanisms Triggered by External Stimuli external stimulus

gating system

opening mechanism

cargo

release experiments

ref.

Molecular Pore Gating UV−vis light (λ = 240− 639 nm)

thymidine dimers

cleavage

dye

in vial

151

cylcodextrin (CD) cucurbit[6]uril nitroveratryl carbamate

dethreading photothermal dethreading cleavage Coating photolysis, dethreading photolysis

dye dye anticancer drug

in vial in vial in vial

152 153 154

dye dye, therapeutic

in vial, in vitro in vitro

155, 156 27, 140, 157

dye

in vial

87

anticancer drug

in vitro

78

anticancer drug

in vitro

89

dye dye

in vial in vitro

158 73

dye

in vial

159

dye, enzyme

in vial

160

dye dye

in vial in vial

91 161

dye, anticancer drug dye, antibiotic, anticancer drug

in vitro in vial, in vitro

162 85, 92, 163

dye dye, antifungal drug anti-inflammatory drug dye, colchicine

in vial, in vitro in vitro in vial in vitro

86, 164, 165 166 167 24

polymer shell supported lipid bilayer (SLB)

paraffin polymer

Internal Pore Modification cleavage Coating photothermal dehybridization Pore Modification photothermal cleavage Molecular/Particle Pore Gating thermal cleavage heat-shock induced cleavage of disulfide linker cleavage of boroester linker Coating thermal phase transition Molecular/Particle Pore Gating cleavage of DNA linker cleavage of DNA linker Coating melting phase transition

DNA glycoprotein 18-crown-6 SLB

Molecular Pore Gating competitive displacement cleavage of boroester linker competitive displacement lysis

coordinative bonds IR-light (λ = 808 nm)

aptamer DNA shell coordinative bonds

magnetic field + absorber

DNA SPIONs Au-NPs PEI/NIPAM

temperature

molecules

biotin−avidin Au-NPs

MSNs serving as drug delivery vehicles can be functionalized on the external particle surface with stimuli-responsive molecules, nanoparticles, polymers, and proteins acting as caps and gatekeepers for such a controlled release of various cargos. Delivery of antitumor drugs and other pharmaceutical cargos such as enzymes or oligonucleotides requires effective protection from undesired degradation in harsh environments, such as the stomach and intestines. On the other hand, when injected into the bloodstream, such a drug delivery device should offer perfect enclosure of the cargo to prevent undesired premature release and systemic distribution before reaching the targeted tissue or cells. The most common pore sealing strategies can be classified into three different types of gatekeepers, i.e. molecular/particle pore gating, coating of the external particle surface, and internal pore binding (as already described in Section 2.2). Reported in vial and in vitro studies and the diverse opening mechanisms based on external or internal stimuli are presented in Tables 2 and 3, respectively. A broad spectrum of triggers for specific cargo release has been described. External triggers such as light, external magnetic fields and temperature require activation of the release mechanism from the outside.152,160,162 These systems provide perfect control over temporal and spatial release of the drugs into the targeted tissue or cells, but tissue penetration in in vivo studies can limit

glycoprotein hemagglutinin of the influenza virus A and undergoes a conformational change upon protonation. H5WYG peptides were often employed in combination with nanocarriers, but experimental evidence for the exact molecular mechanism was not provided so far.148−150 Different endosomal escape pathways were believed to take place, such as the proton sponge effect (protonation of the histidin residues of the peptide) or fusion of the endosomal membrane with the SLB. Further investigations are needed to evaluate the exact mechanism, which could lead to full exploitation of this endosomal escape pathway. In general, endosomal entrapment was found to be a bottleneck in efficient cytosolic delivery of nonpermeable drug molecules and further efforts have to be made to overcome this entrapment. Complete understanding of the diverse escape mechanisms is highly desirable. Internalized multifunctional MSNs with an integrated trigger could rapidly escape from endolysosomal vesicles into the cytoplasm and resist the lysosomal degradation and thus protect the loaded drugs from bioerosion. 3.3. Controlled Release of Cargo. Extensive in vitro studies have been performed to gain insights regarding the feasibility of MSNs as drug nanocarriers. Cargo release in a controlled manner is highly desirable, since side effects can be drastically reduced by locating delivery to single cells or target tissue and since the optimal amount of drug can be liberated. As discussed above, 441



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Table 3. Controlled Cargo Release Mechanisms Triggered by Internal Stimuli internal stimulus pH (acidic)

gating system SPIONs Au-NPs CD [2]pseudorotaxane curcubit[6]uril saccharides layered double hydroxides (LDH) polymer coordination polymer chitosan

coordinative bonds acetal linkage electrostatic interactions template hydrazone linkage pH (basic)

β-lactoglobulin lysozyme sulfophenyl isothiocyanate

enzymes

azopyridine derivatives cucurbit[7]uril [2]pseudorotaxane biotin−avidin hyaluronic acid ethylene glycol ester peptides starch derivatives lactose derivatives

reducing agent

CD ssDNA collagen polymer disulfide linkage

molecules

ATP aptamer insulin derivatives Au-NPs

enzyme multilayers

opening mechanism

release experiments

cargo

Molecular/Particle Pore Gating cleavage of boroester linker anti-inflammatory drug cleavage of boroester linker dye dethreading dye, anticancer drug dethreading dye dethreading dye Coating cleavage of boroester linker dye dissolution dye phase transition

anticancer drug, insulin, dye

cleavage phase transition

anticancer drug anti-inflammatory drug, anticancer drug Internal Pore Modification cleavage anticancer drug cleavage peptide cleavage anticancer drug extraction anticancer drug cleavage anti-inflammatory drug Molecular Pore Gating phase transition dye, anti-inflammatory drug detaching dye cleavage anti-inflammatory drug Molecular Pore Gating cleavage dye, anticancer drug competitive displacement dye cleavage of ester linker dye enzymatic digestion dye Coating cleavage dye, anticancer drug cleavage dye, anticancer drug cleavage dye enzymatic digestion dye, anticancer drug enzymatic digestion dye Molecular Pore Gating cleavage of disulfide linker dye cleavage of disulfide linker anticancer drug, ssDNA Coating cleavage of disulfide linker dye cleavage of disulfide linker dye Internal Pore Modification cleavage enzyme, cysteine Molecular Pore Gating competitive displacement dye competitive displacement insulin, cAMP dehybridization of DNA dye linker Coating phase transition insulin

ref.

in vitro in vial in vial, in vitro in vial in vial

76 159, 168 169−172 173 174, 175

in vial in vial

176 177

in vial, in vitro in vitro in vial, in vitro

67, 77, 85, 154, 178−181 182 48, 111, 183

in vial, in vitro in vitro in vitro in vitro, in vivo in vitro

89, 94 184 185 186 187

in vial in vitro in vial

188 189 26

in vitro in vial in vial in vial

190 191 192 25

in vitro in vitro in vial in vitro in vial

128 193 194 75 195

in vial in vitro

172 196

in vial in vial, in vitro

197 93, 156, 181

in vial, in vitro

72, 88

in vial, in vitro in vial in vial

198−200 201 74

in vial

202

initiated cargo release due to rupture of the SLB. Photosensitizers are promising components of nanocarrier systems for efficient drug delivery because they can simultaneously serve as a means for endosomal escape and for triggering controlled release in combination with SLB-coated MSNs. Changes in pH, enzymatic reactions, and reducing agents are internal triggers that can provide intrinsic and autonomous release of the loaded cargo molecules from the mesoporous host system. Many mechanisms for controlled closure and release

performance. Temperature changes have been investigated to release encapsulated molecules.162,163 Light can also be used to activate various opening mechanisms.151,153 Recently, Bein, Bräuchle and co-workers could demonstrate an improved system consisting of MSNs coated with an SLB and equipped with a covalently attached PS.27 The SLB was shown to seal the pores and to prevent premature release of the loaded cargo. Upon photoactivation of the PS with red light, generation of reactive oxygen species 442



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mesoporous silica-coated gold nanorods,78 and to MSNs including targeting functionalities like aptamers.112 In Figure 5, we show the release behavior of calcein in HeLa cells over time driven by photoactivation of an on-board PS (AlPcS2a).

have been developed in recent years, often with a view on utilizing such biologically relevant changes in the cell environment encountered by the particles upon endocytosis. Thus, pH changes have been used to open gates at the pores of the mesoporous nanoparticles, and changes in redox potential could be used to cleave disulfide bridges. pH-responsive nanocarriers have been designed to achieve a site-selective controlled release, because tumor and inflammatory tissues are more acidic than normal tissue and blood. Importantly, the acidification of endosomes inside targeted cells can be utilized to trigger pHresponsive intracellular release of the cargo molecules.111,182,187 Zink and co-workers have described a pH-responsive dethreading of bulky β-cycodextrin molecules upon protonation of a complementary stalk located at the pore entrances and the resulting efficient DOX release in vitro. In the context of oral administration, nanocarrier systems have been designed with acid-stable gatekeepers to be able to pass the stomach without premature release. After passing the acidic environment, pH-responsive caps can be cleaved in the basic milieu of the intestines to efficiently release the loaded pharmaceuticals.26,188,189 Enzyme-responsive controlled release can be highly efficient once the nanocarriers have entered the cancer tissue or the cytosol of targeted cells. Many intracellular and extracellular enzymes are overexpressed in cancer tissue and exhibit increased activity, resulting in preferential cargo release at those locations.190,194 Summarizing, molecular and particlebased pore gating or coatings, removable by either intracellular or external triggers, can provide exquisite control over the location and time of cargo release during drug delivery. 3.4. Biological and Pharmaceutical Activity. On-demand cargo release from the mesopores of silica nanoparticles has been proven to be feasible. To understand the biological and pharmaceutical activity of the MSN drug delivery systems in vitro and in vivo, it is useful to investigate the response of cells, such as knock-down of certain genes, stimuli-responsive labeling of cell compartments, destruction of the microtubule network, or apoptosis of cancer cells.24,140,203,204 Dependent on the charge of the cargo, the surface of the nanocarriers has to be tuned and the release systems need to be adjusted to the scope of the application. Diverse model systems have been devised to learn more about the complex processes during cellular uptake of MSNs and subsequent drug release. Here, the focus is not to discuss the challenges of preclinical studies but to provide information about the mode of operation of multifunctional MSNs in the biological environment. For instance, attaching fluorescent dyes to the MSNs provides the possibility to directly observe the behavior of the nanocarriers and the cells. Common dyes include rhodamine or fluorescein derivatives, as well as ATTO or ALEXA dyes.72,118,135,205 Fluorescent cargo and/or labeling of cell compartments also aids in the examination of the intracellular processes. Drug loading of small anticancer therapeutics can be achieved by simple immersion of the particles into a concentrated solution of the desired drug, followed by sealing with the gating mechanism under study. Efficient loading was shown by Bein and co-workers upon adsorbing colchicine, propidium iodide, phalloidin, chromobodies, calcein, or a rhodamine derivative into MSNs, which were subsequently sealed by an SLB.24,27,140 Doxorubicin (DOX) is a commonly used anticancer therapeutic due to its efficient induction of apoptosis in cancer cells, and it is fluorescent, thus enabling direct microscopic observation.206 Several DOX-containing systems have been investigated, ranging from Fe3O4@mSiO2 nanocapsules207 to hollow MSNs,208−210 to

Figure 5. Fluorescence microscopy of MSN-AlPcS2a-SLB-FA loaded with calcein inside HeLa cells, after incubation time of 16 h. (a−c) Calcein (green) and AlPcS2a (red) are colocalized (yellow) prior to photoactivation. (d) Intensity profile along the white line in the merged image for both. (e−h) 1 min, (i−l) 5 min, and (m−p) 10 min after photoactivation. The scale bar is 10 μm (Reprinted from ref 27. Copyright 2013 American Chemical Society.).

In vitro methods can verify the encapsulation of a large amount of drug molecules in MSN carriers, which increases their efficiency. This was proven in a study of Tian and co-workers.203 They demonstrated a significant increase of early and late apoptosis of paclitaxel-loaded MSNs on MCF-7 cells compared to free drug molecules. Gene transfection or oligonucleotide delivery with MSNs has not been studied to a large extent yet, and in most reported cases, the oligonucleotides are only adsorbed on the external surface of the MSNs or incorporated in a polymer shell of coated MSNs.211 Milligan and co-workers used so-called “protocells” for GFP and IL-10 gene delivery in vitro and in vivo, but no proof of gene adsorption inside the pores was provided.82,211 Tamanoi and coworkers attached siRNA to the external surface of coated MSNs with the aid of PEI and observed gene silencing of EGFP.212 Attachment of the oligonucleotides exclusively on the external particle surface could cause concerns about premature degradation via abundantly available ribonucleases. Therefore, controlled loading of siRNA into large pores of MSNs is a highly desirable approach that is expected to provide efficient protection from bioerosion. In addition to extensive in vitro investigations, the first in vivo application of MSNs was reported in 2008.213 Recently, Nel and co-workers presented a successful proof of principle aimed to overcome DOX resistance in a mouse xenograft model with PEIPEG functionalized MSNs.214 Unfortunately, heterogeneity in the tumor microenvironment, such as differences in the vascularity, possibly influences the efficacy of drug delivery in 443



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Figure 6. Knockdown of GFP genes with siRNA-loaded, PEGylated (P), and carboxytetramethylrhodamine-labeled (T) MSN with a pore diameter of 23 nm (P-T-MSN23) in vivo. In vivo optical images before (a) and after (b, top) removal of tumors and quantitative analysis of GFP-expressing tumors (b, bottom). (c) Optical microscopic images of a tissue section after 4′,6-diamidino-2-phenylindole (DAPI) staining show considerable reduction in GFP expression in the siGFP−P-T-MSN23-treated tumor, compared with tissue treated with P-T-MSN23 (Adapted from ref 204 with permission by Wiley-VCH, Copyright 2012.).

molecules221−223 as well as the anticancer agent DOX224 moving inside mesoporous channels of silica materials. Such studies are crucial for understanding diffusion processes and confirm the need for defined surface modifications for controlling adsorption and desorption processes of the cargo molecules in the mesoporous system. Functionalization of the mesoporous interior with amino-groups in order to achieve positively charged surfaces resulted in preferential and increased uptake of negatively charged siRNA constructs.225 Issues of cargo loading efficacy may arise due to electrostatic repulsion when negatively charged molecules like double stranded DNA should be absorbed into nanocontainers featuring negative surface charge.226 On the other hand, electrostatic interactions may not be too strong; otherwise, they can cause entrapment in the porous system, and consequently, cargo release is inhibited. The stability of the cargo to be transported is a key factor in particle design, especially if the goal is to efficiently deliver sensitive cargos like siRNA. Fluorescent donor−acceptor pairs offer the possibility to investigate the stability of oligonucleotides inside the pores by measuring the Förster resonance energy transfer (FRET).225,226 Thus, the stability of oligonucleotides in specifically functionalized mesopores after adsorption was demonstrated. Since nanocarriers provide protection against diverse biological attacks, incorporation of oligonucleotides into the mesopores of silica materials is very promising for future experiments in gene delivery, especially because previous efforts in delivery so far have focused on oligonucleotides attached to the external particle surface, as already discussed in Section 3.4.211,212 FRET is also a useful method to monitor the release of payload from the pores of MSNs in real-time. For that purpose, Lee and co-workers attached a FRET donor−acceptor pair of coumarin and fluorescein isothiocyanate (FITC) to the cap system β-cyclodextrin located at the pore entrances of MSNs. After light activation, cleavage of the gatekeepers occurred and subsequently the FRET-signal vanished due to great distance of the donor−acceptor pair.227 Optical imaging is also the most widely used technique to study the feasibility of custom-made drug nanocarriers based on MSNs. The direct release and distribution of cargo inside cells can be monitored via fluorescence microscopy. Furthermore, precise investigations of uptake behavior and cellular internalization mechanisms of MSNs in single cells can be realized. Methods that were developed to evaluate the uptake behavior of viruses and single polymeric gene carriers (polyplexes) were extensively exploited by Bräuchle and co-workers.228−231 Subsequently, the internalization of epidermal growth factor receptor (EGFR) targeted MSNs into living cells was also

vivo. Further research is necessary to evaluate the MSN distribution in tumor models, particularly with targeting ligands to ensure the capability of the delivery systems to efficiently reach all cells within the tumor tissue. Nevertheless, these early experiments provide strong evidence that MSNs are promising candidates for improved cancer therapy and that they are able to reduce side effects for healthy tissues.47,215 Furthermore, very promising results for siRNA delivery were obtained by Min and co-workers.204 They showed successful delivery of GFP downregulating siRNA in a tumor xenograft mouse model (Figure 6). The reduction of GFP fluorescence could be observed with optical imaging in vivo (Figure 6a,b) and more clearly in tissue sections (Figure 6c). Although the results demonstrate the feasibility of this approach, the system is still lacking control over pore sealing and a release mechanism. In addition to possible cancer therapeutics and gene delivery, there are also studies for inhibitor delivery and delivery of cytokines.118,216 A detailed overview on in vivo biosafety evaluations and diagnostic/therapeutic applications of MSNs has recently been provided by Shi and co-workers.217 3.5. Imaging. The imaging possibilities for MSNs and their combinations with other materials range from optical microscopy to magnetic resonance imaging and to ultrasonic imaging, near-infrared imaging, and other techniques. Here, we will focus on optical microscopy and its applicability to gain real-time observation of MSNs in cell cultures and tissues. Other imaging techniques and the preparation methods for functionalized hybrid nanoparticles, such as silica nanoparticles containing magnetic cores, have been extensively discussed elsewhere.2,217−219 In this context, MSNs are being developed as a platform for incorporation of nanocrystals or for doping with active species including iron oxide nanocrystals, quantum dots, gold nanoparticles, and manganese or gadolinium ions. These types of multifunctional nanocarriers attract great interest with a view on theranostic applications. There are different possibilities to fluorescently label MSNs. Depending on the desired type of labeling (removable or not), fluorescent dye molecules can be attached to the inner and outer particle surface by covalent linkage via postsynthetic grafting, incorporation into the silica framework, or pH-/redox-sensitive linkage. Diffusion of dye molecules or nanoparticles like quantum dots inside the pores has been investigated as well.220 In that case, efficient enclosure of the fluorescent cargo in the mesopores can be achieved by an SLB or other bulky molecules used as valves. Diffusion dynamics of fluorescent molecules in porous silica materials were intensively studied with fluorescence microscopy. Bräuchle and co-workers could image single dye 444



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Figure 7. Internalization of epidermal growth factor receptor (EGFR)-MSNs with supported lipid bilayer.27 (a) Trajectory of an MSN during uptake into HuH7 cells. The particle was tracked 4 min after addition of the particles on top of the cells, for 5 min and 50 s at a temporal resolution of 150 ms/ frame. Three phases are typically observed during the internalization process.229 The starting point of the trajectory is indicated with an arrow. The overlying color boxes indicate the three phases. Yellow: phase I, slow active transport; green: phase II, anomalous and confined diffusion; red: phase III, active transport with back and forth movement. (b) Instantaneous velocities of the trajectory shown in (a) and (c−e) the mean square displacement (MSD) plots of the three phases obtained from several trajectories. The corresponding plots from the trajectory are indicated in blue. The analysis of the trajectories was performed with the help of the viro-tracker developed by Godinez et al.232 to localize the xy-coordinates and with the help of the transport-program developed by Arcizet et al.233 to calculate MSD plots.

Figure 8. (I) Comparison of FITC-tagged MSN with ICG-tagged MSN (50−100 nm). (a, b) Biodistribution of MSN-NH2-FITC in an anesthetized rat before and after (90 min) i.v. injection. The experimental conditions were set at 492 nm (excitation) and 518 nm (emission) and (a) a longer shutter time (60 s) for a visible imaging and (b) 30 s shutter time. (c) Biodistribution of MSN-TA-ICG in an anesthetized rat before and after i.v. injection for 90 min. MSN-TA-ICG sample showed less interference of autofluorescence in a shorter shutter period (30 s). (d) MSN-TA-ICG in nude mice after i.v. injection for 3 h. (II) Dissected organs from a rat sacrificed after i.v. injection of MSN-TA-ICG for 3 h. (a) representative white-light and (b) fluorescent images. (III) In vivo biodistribution of silicon percentage in various organs of rat after i.v. injection of MSN-TA-ICG for 6 h (Adapted and newly arranged from ref 234 with permission by Wiley-VCH, Copyright 2009.).

investigated. Detailed information on the internalization pathway, the behavior of the MSNs inside the cells, and information on unexpected interactions between the particles and the cell can be gathered by life-cell imaging, and consequently, possible challenges can be monitored. Similar to the behavior of polyplexes, it was observed that porous silica nanoparticles exhibit three phases of motion during their internalization (Figure 7). The particle motion was measured on a sensitive fluorescence wide field microscope and analyzed with single particle tracking methods. In the first phase, the particles attach to the cell membrane and consequently show a slow directed movement, provoked by movement of the subjacent actin

cytoskeleton mediated by the EGF receptor and linker proteins. With the transition to phase II, the particles are internalized into the cells. Phase II consists of either normal, anomalous, or confined diffusion or a combination of all three. Normal diffusion is often hindered in the cytoplasm by the local microenvironment (cytoskeleton, organelles, large molecules, etc.). Phase III shows much faster, active transport of the particles entrapped inside endosomes along the microtubule network via motor proteins with velocities up to 2 μm/s. Optical microscopy also provides the capability to image in vivo. However, attenuation of photon propagation and a poor signal-to-noise ratio due to autofluorescence of the tissue can 445



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intracellular uptake, trafficking, and the fate of multifunctional MSNs in the body would be highly desirable. Up to now, only a few in vivo studies of the pharmacokinetics of multifunctional MSNs including biodistribution, biodegradation, and excretion and clearance have been performed, and additional work in this area is clearly needed.99,238−241 Additional functional groups such as PEG chains on the external surface of MSNs seem to be important for achieving the EPR effect; they were shown to decrease the clearance through the RES.99,105 Selected strategies and model systems are needed to gain insights into such complex processes before reaching the stage of clinical trials. Comprehensive reviews address the state of the art regarding preclinical studies.217,237 Model systems for investigations on the way to clinical trials are being discussed, including chorioallantoic membrane, zebrafish embryo, and mouse, among others.242−244 The pharmacokinetics of nanomaterials are closely related to in vivo toxicity, biocompatibility, and retention. The issue of potential toxicity to cells or organisms caused by nanocarriers seems to be strongly influenced by several particle properties including size, morphology, and surface functionality.64 Studies on the dissolution of silica nanoparticles concerning retention and clearance in the body showed that the silica was adsorbed or excreted in the urine in the form of silicic acid or organic silica species.99 For future applications of multifunctional MSNs as drug delivery devices and to pave the way to clinical trials, these nanocarriers could be designed with two very different operating modes in mind. One approach would pursue the design of autonomous drug delivery vehicles, which can perform their tasks as a response to stimuli already present in the organism, including receptors on cell and tissue surfaces, changes of pH and redox potential in endosomes (for opening gate functions), the presence of enzymes, and autonomous endosomal escape. Reversible opening and closing methods should also be developed further, because it was shown that MSNs can also be exocytosed from cells.245 Successful resealing of the MSNs could efficiently hinder further drug release after leaving the cell or tissue to prevent unintended distribution of the drug. The other approach would rely on the use of external triggers (in combination with internal stimuli) to spatially control the drug release behavior, for example, to focus the release to a certain area of tissue or a certain time period. Light activation with red or near-infrared light, two-photon activation (to enhance tissue penetration), ultrasound, and local heating by different means such as RF absorption all present intriguing opportunities for future research. External stimuli for endosomal escape and controlled cargo release are also excellent tools for mechanistic studies in cell cultures, because they allow control over time and location of the initial release. Finally, recent studies focus on the ultimate combination of diagnostic and therapeutic capabilities in the multifunctional mesoporous nanoparticles, such that the nanocarrier uses diagnostic information to control or tune its therapeutic actions. One such approach could be the detection of the presence of multiple receptors indicating specific target tissue, where the logical combination of this information leads to release of drug only at this location, and another one could be the detection of several enzymes that together constitute the signature of a target tissue. The future is bright for multifunctional mesoporous nanoparticles in diagnostics and therapy.

cause difficulties and should be considered in the selection of the type of dye and its concentration. Nevertheless, the high loading capability of MSNs makes them promising candidates to overcome this problem. Thus, Lo and co-workers could study the spatial distribution of MSNs with positive surface charge and loaded with indocyanine green (ICG) via near-infrared microscopy inside anesthetized rats.234 In that case, the biodistribution of the optical MSN probe was evaluated in comparison to FITC-labeled MSNs. FITC seems to be not appropriate for in vivo optical imaging, since tissue penetration depth of the fluorescent signal of this dye is too small and consequently not detectable. NIR fluorescent dyes can be clearly detected after intravenous injection for evaluating particle accumulation inside the liver and kidney and partially in lungs, spleen, and heart. Further verification of the biodistribution in the dissected organs can be seen in Figure 8. Optical microscopy utilizing NIR fluorescent dyes offers the possibility to investigate long-term biodistribution of nanocarrier systems, since it is a noninvasive method and animal models do not need to be sacrificed. As observed in such experiments, bare MSNs seem to face the problem of being cleared through the reticuloendothelial system (RES), such as spleen or liver, and the EPR effect is decreased.99,105,234 Further modifications of the particle surface including PEGylation of the MSNs are needed to avoid the activation of the immune system.235

4. FUTURE PERSPECTIVES Colloidal MSNs have attracted great attention as potential drug delivery systems for cancer cell targeting and as bioimaging devices. In addition to their biocompatibility and biodegradability, they can be selectively modified at their inner and outer surface. Guest molecules can be efficiently encapsulated in their tunable pore system. Furthermore, it is possible to functionalize their outer surface with targeting ligands, biomimetic and other pore gating molecules, fluorescent dyes, and biocompatible polymers. Compared to most other prominent organic carriers, such as liposomes and polyplexes, MSNs offer several advantages including high loading capacity, high stability, and the ability to protect the guest molecules from various biochemical attacks causing degradation of the bioactive cargo molecules. Extensive in vitro studies on the controlled release of therapeutics and the evaluation of cytotoxicity have proven the feasibility of multifunctional MSNs for a sustainable and efficient drug delivery to cancer cells. Today’s challenge is the investigation of pharmacokinetics and pharmacodynamics of mesoporous silica nanoconstructs for in vivo diagnostic and therapeutic applications. Issues and opportunities have been recently reviewed by several groups.32,217,236,237 The biological effects of MSNs at different levels ranging from molecules, cells, and blood to tissue and organs, involving cytotoxicity, biodegradability, blood compatibility, biodistribution, and excretion, are currently under investigation. Oral administration and injection into the bloodstream of such nanocarriers require specific properties for long-term stability during circulation in the organism, specific targeting of the desired location, and controllable release of the loaded drugs to obtain the desired therapeutic outcome. Controlling all these requirements is important to avoid side effects harming healthy tissue. Researchers are still faced with many challenges, especially in vivo applicable stimuli-responsive release mechanisms, targeting specificity, and biosafety issues, which need to be fully understood to achieve efficient and safe drug delivery. A complete understanding of the mechanisms for 446



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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions #

C.A. and V.W. contributed equally.

Notes

The authors declare no competing financial interest. Biographies Prof. Thomas Bein obtained his PhD in Chemistry from the University of Hamburg (Germany) and the Catholic University of Leuven (Belgium). He continued his studies as Visiting Scientist at DuPont in Wilmington (DE, USA) and was appointed Assistant Professor of Chemistry at the University of New Mexico in Albuquerque. In 1991, he accepted a position of Associate Professor at Purdue University in Indiana, where he was later promoted to Full Professor of Chemistry. In 1999, he was appointed Chair of Physical Chemistry at the University of Munich (LMU). His current research interests focus on the synthesis and physical properties of functional nanostructures, with an emphasis on energy conversion and porous systems such as mesoporous silica for drug delivery. Christoph Bräuchle studied Physics and Chemistry at the Technical University Berlin and the University Tübingen. He received his PhD at the University of Munich (LMU), was a postdoctoral fellow at IBM San Jose, California, USA, and after several calls from different Universities accepted a Chair of Physical Chemistry at the University of Munich (LMU). His current research focuses on imaging, spectroscopy, and manipulation of single molecules and nanoparticles in the bio- and nanosciences. Having authored and coauthored more than 300 publications, Prof. Bräuchle has also won several honors, including the Philip Morris Research award and the Karl Heinz Beckurts Prize. He is also a member of the Bavarian Academy of Sciences and the Academia Europaea. Christian Argyo studied chemistry at the University of Munich (LMU). He received his Diploma in Chemistry in 2010. He is presently pursuing his PhD under the supervision of Prof. Thomas Bein. He is an associate of the Center for Nano Science (CeNS). His research focuses on the synthesis and characterization of multifunctional mesoporous silica nanoparticles used for biomedical applications such as drug delivery. Veronika Weiss studied chemistry at the University of Munich (LMU) and received her M. Sc. in Chemistry in 2011. She is currently pursuing her doctorate degree in chemistry under the supervision of Prof. Christoph Bräuchle. Her current research focuses on fluorescence lifecell imaging of novel drug delivery systems based on mesoporous silica nanoparticles.

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ACKNOWLEDGMENTS The authors wish to acknowledge the important contributions of their coworkers and collaborators in this field. Financial support from Deutsche Forschungsgemeinschaft (DFG) through the SFB 749 and the Excellence Clusters CiPSM and NIM is gratefully acknowledged.

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REFERENCES

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