Journal of Materials Science

, Volume 49, Issue 2, pp 481–495

Stimulus-responsive mesoporous silica particles


DOI: 10.1007/s10853-013-7726-6

Cite this article as:
Nadrah, P., Planinšek, O. & Gaberšček, M. J Mater Sci (2014) 49: 481. doi:10.1007/s10853-013-7726-6


The field of stimulus-responsive mesoporous silica nanoparticles has expanded greatly over the last decade. Novel advanced drug delivery systems (DDSs) that are using interesting techniques to achieve stimulus responsiveness were developed, advancing the knowledge in both the pharmaceutical and material science fields. In this review, we focus on the stimulus-responsive mesoporous silica systems with gate-like assemblies on pore openings. These assemblies are sensitive to a particular stimulus and allow precise control over the release of cargo. An overview of a variety of gating assemblies in connection with respective stimuli will provide the reader with an insight in the field with the emphasis on the construction of complete drug carrier systems. Systems are presented based on the structure of the nano-gates on pore openings in combination with the release stimuli. New achievements such as co-delivery of drugs, combining multiple stimuli with AND logic and coupling DDSs with targeting moieties and reporting systems are also highlighted.



Drug delivery system


Mesoporous silica






Capping agent




Deoxyribonucleic acid


Poly(ethylene glycol)




Cyclic adenosine monophosphate


During previous decades great progress in combating illnesses, such as cancer, has been made thanks to newly discovered chemotherapeutics. The battle with disease, however, is still difficult and with pronounced side effects. Contrary to bacteria, cancer cells are much more similar to healthy human cells, since they are in fact human cells. To eradicate cancer, diseased cells have to be killed and in this process, finding differences between healthy and cancer cells is of paramount importance. These differences can be minimal and that makes the distinguishing process more complicated, something delivery system with a drug molecule alone can hardly address. Developing new advanced drug delivery systems (DDSs) with passive or active targeting of target cells, stimulus-induced release of the drug, or diagnostic abilities can help in the battle with the disease.

Traditionally, drugs are administered via a passive vehicle. Such vehicle releases the drug with little respect to the environment. In the case of orally administered drugs pH has been widely used to limit the release of drug to a certain part of the gastro-intestinal tract. With the advancement of the nanotechnology new challenges are appearing. An advanced nano-sized DDS can be not only a passive reservoir for the drug, but rather an active part of the medicine. Such active DDS will transport the drug to the disease site, avoiding premature release, enter the target cell, if necessary, and finally release the payload upon a specific stimulus.

One of the materials used in advanced DDS is mesoporous silica (MS). MS has emerged as an important and widely used basis for DDSs. Following IUPAC nomenclature, mesopores are defined as pores with a diameter between 2 and 50 nm [1]. MS features a highly ordered rigid mesoporous structure featuring excellent biocompatibility, chemical stability, high surface area, and ease of functionalization. MS can be tailored to encapsulate a large payload of the drug. To achieve stimulus-responsiveness of the MS, gate-like assemblies can be constructed on the pore openings, capping the pore in its “closed” state, thus holding the drug molecules inside the pores. Upon stimulus, these gates are opened, allowing the release of the molecules from within the pores. In last 10 years, MS-based stimulus-responsive systems have emerged from complicated systems functioning in an organic solvent to modern biocompatible systems with numerous encouraging in vitro cell culture experiments and few in vivo animal experiments as well.

In this review, we will focus on the construction of recent gated stimulus-responsive systems from initial step of silica synthesis to cargo loading and subsequent closing of the pores. Comparison of a variety of gating assemblies in connection with respective stimuli will provide the reader with an overview of the field with the emphasis on the construction of complete systems. New achievements such as co-delivery of drugs, combining multiple stimuli with AND logic, and coupling DDS with targeting moieties are also highlighted. For other aspects of MS for drug delivery, the reader is referred to the excellent recent reviews of biocompatibility of MS [2, 3], application of MS in biomedicine [4], review of stimuli used by MS systems [5], and magnetic MS [6].

Mesoporous silica

At the beginning of 1990s MS was synthesized by two different research groups [7, 8]. One type of this material, synthesized by Mobil Corporation scientists, was termed MCM-41 (Mobil Composition of Material 41). The materials synthesized according to these first procedures are mostly MS sheets [8]. Submicrometer MCM-41 particles were later synthesized by Grün et al. [9]. MCM-41 boasts with large internal surface area and with tunable pore size up to 8 nm [10]. Another widely used and studied type of MS is SBA-15 (Santa Barbara Amorphous 15), which is synthesized in acidic medium and offers a pore size in the range from 2 to 30 nm [10]. MS possesses unique characteristics, such as large surface area, uniform and tunable pore size, high pore volume, low toxicity with good biocompatibility, and ease of functionalization [5].

Like Stöber-type silica [11] MS is synthesized via sol–gel process [12] in aqueous solution in either basic or acidic conditions. Hydrolysis and subsequent condensation of organosilane precursors form a new phase (sol). In a Stöber-type synthesis, nucleation of silica particles takes place first, after which particles of a few nm in diameter bond to form larger particles. In synthesis of MS, the presence of a surfactant, which forms micelles, is the basis for mesoporous structure. The silica matrix is built around rods of these micelles which, up to post-synthetic removal, occupy the inner space of the mesopores. The pore size depends on the type of surfactant used and reaction conditions, such as temperature and pH. MS particles can be prepared from various silica precursors, the most widely used being tetraethoxysilane (TEOS). In the presence of water TEOS is partially hydrolyzed (Eq. 1), followed by condensation (Eqs. 2 and 3) with nearby TEOS molecules to form a silica network (R = C2H5 for TEOS).
$$ {\text{Si}}\left( {\text{OR}} \right)_{ 4} + {\text{ H}}_{ 2} {\text{O }} \to {\text{ HO}} {-} {\text{Si}}\left( {\text{OR}} \right)_{ 3} + {\text{ ROH }}\left( {\text{hydrolysis}} \right) $$
$$ 2 {\text{ HO}} {-} {\text{Si}}\left( {\text{OR}} \right)_{ 3} \to_{{}} \left( {\text{RO}} \right)_{ 3} {\text{Si}} {-} {\text{O}} {-} {\text{Si}}\left( {\text{OR}} \right)_{ 3} + {\text{ H}}_{ 2} {\text{O }}\left( {\text{condensation}} \right) $$
$$ {\text{HO}} {-} {\text{Si}}\left( {\text{OR}} \right)_{ 3} + {\text{ Si}}\left( {\text{OR}} \right)_{ 4} \to_{{}} \left( {\text{RO}} \right)_{ 3} {\text{Si}} {-} {\text{O}} {-} {\text{Si}}\left( {\text{OR}} \right)_{ 3} + {\text{ROH}}\left( {\text{condensation}} \right) $$

The ease of functionalization allows introduction of a variety of organic functional groups onto MS’s surface or its pore walls. This can be done either during the condensation process or after the synthesis in a separate post-synthetic grafting. Functionalization is usually carried out with organosilane molecules with three alkoxy groups per silicon atom and one alkyl chain with a functional group at the other end. A large variety of functional groups can be attached to silica in this manner, such as amines, thiols, carboxylic acids, alkyl groups, etc. providing MS with novel characteristic and/or serving as anchoring points for further attachment of molecules.

Drugs and mesoporous silica particles

An important advantage of MS is its ability to encapsulate drug molecules into the pores, thereby protecting the drug from enzymatic degradation as well as protecting the body from some of the side effects of the drug. The use of MS as a DDS was first reported by Vallet-Regi et al. [13] in 2001, whereas the first MS modification to incorporate stimuli-induced release of guest molecules was reported by Mal et al. [14] in 2003. Development of a DDS that will safely deliver drugs to the target tissue, and subsequently release them in a controllable manner, is an important research area in biomedical nanotechnology and material science [5]. MS possesses many attributes needed for such DDSs. Besides being loaded into the mesopores, the drugs can also be adsorbed onto the outer surface. Surfaces containing silanol groups can be easily functionalized to control drug release. Additionally, luminescent dyes, such as organic dyes, quantum dots and rare-earth nanophosphors, and magnetic nanoparticles (NPs) allow tracking of the DDS [5]. Much attention has been given lately to the safety and biocompatibility of MS NPs with reports on in vitro and in vivo studies of toxicity [15, 16]. However, the biocompatibility and possible toxic effects of MS particles cannot be given only in relation to the inorganic material that builds the particles. Effects in the organism are dependent upon many structural and other aspects, among them particle size, surface charge, porosity, aspect ratio, and type of administration [2].

Pore and outer surface functionalization, pore diameter, and pore structure affect the amount of loaded cargo molecules and their release profile [5]. Drugs are usually adsorbed onto silica with non-covalent interaction, such as hydrogen bonding, electrostatic interaction, physical adsorption, and π–π stacking [17]. While drugs can be incorporated into the silica matrix without any functionalization, the release of drug molecules from such a system cannot be effectively controlled using an external stimulus. For example, highly water soluble drugs would be released as soon as the particles are placed in an aqueous medium [4]. A certain degree of control over the release can, however, be achieved using hydrophobic drugs with low aqueous solubility. In vitro studies have shown that interaction of MS particles and cellular membrane during endocytosis can release hydrophobic drugs [18]. Aznar et al. [19] showed dependence of drug release rate on the alkyl chain length anchored at the pore outlets. These chains are flexible, thus they cannot prevent the diffusion process of drug but can slow it down. Some of us recently showed that the drug release rate is significantly affected by the nature and intensity of drug–matrix interactions [20].

Functionalization of silica surface with organic molecules or NPs can also control drug release. This includes either tuning the release kinetics with different organic molecules attached to the surface [21] or completely preventing drug release until certain condition is met—a procedure known as stimulus-responsive drug release [22]. The majority of these systems include cargo molecules loaded in the mesopore voids and pores closed by gate-like assemblies, usually termed capping agents (CAs) as schematically depicted in see Fig. 1. These are discussed in detail below. In addition to drug incorporation, other functionalities can be added to improve DDS. Bioimaging moieties such as fluorophores, quantum dots, or magnetic NPs can be incorporated to enable tracking of the particles. Protecting polymers such as poly(ethylene glycol) increases blood circulation time of particles, whereas ligands such as antibodies or aptamers provide active targeting of cells.
Fig. 1

Schematics of advanced drug delivery and release system based on MS particles: drug molecules (A) are kept in mesoporous voids by CAs (B), which is attached to silica through stimulus-responsive bond (C). Bioimaging agents (D) such as fluorophores, quantum dots, or magnetic NPs can be incorporated. Shielding can be provided by polymers (E), such as poly(ethylene glycol). Active targeting is possible by attachment of ligands (F), such as antibodies or aptamers

Stimulus-induced drug release

Therapy of cancer usually consists of multiple drugs being administered in high enough doses to eradicate cancerous tissue. Being cytotoxic, these drugs have significant side effects on the immune system, reproduction, hair growth, etc. [5]. Providing a DDS that can guide the drug inside human body without releasing it before it reaches target tissues is of great importance. The system would exhibit a “zero release” of drug after administration and safely transport the payload through the healthy tissue. Upon reaching the target area the stimulus-responsive property comes into action. The structure of the CA is altered, most often by cleaving the corresponding covalent or non-covalent bonds. The drug is then allowed to diffuse out of the pores. MS particles with a high porosity are ideal candidates for this application. Pore voids offer a storage space for drug molecules, while drug release can be tuned by blocking the pore openings by various gatekeepers.

While covalent attachment of drugs to the carrier provides means of control over the release, chemical derivatization of drugs is a cumbersome process, compared in its complexity to the drug synthesis itself. In addition, such derivatization can change the efficiency of the released drug and is not likely to be applicable to more than small subsets of drugs. Physical or chemical adsorption, on the other hand, is unlikely to change the characteristics of the drug once it is released. Loading drug molecules into pores and then closing the pores with molecules big enough to prevent drug release is a method to achieve stimulus-induced release without derivatization of the drug. Pore closing agents are connected to the silica by covalent or non-covalent interactions, such that stimulus induces their detachment and dissociation from the surface, followed by diffusion of the drug from the now-opened pores. These closing molecules will be referred to as CAs, although not all of them strictly cap mesopores, but they do prevent leakage of molecules from inside the mesopores via various system-specific mechanisms. Although CAs are usually schematically depicted as capping the pores from the outside, as seen in Fig. 1, we cannot confirm such specific attachment of CAs to MS particles. Small enough CAs could very well diffuse into the mesopores and sterically prevent diffusion of the drug molecules inside the pores. References discussed in following chapters are grouped in Table 1 by stimulus and CA.
Table 1

References ordered by the type of release stimulus and the type of capping agent used


Capping agents





Small functional groups

Crosslinking of functional groups


45, 58, 60

25, 26, 65, 72, 73, 74, 75, 80

88, 91, 93, 96, 97



Disulfide reducing compounds

30, 57

32, 52, 65, 66, 67, 79

81, 95





64, 77, 78

37, 40, 41, 82, 103






21, 62, 98, 104



45, 56, 61

43, 44, 76

61, 89, 90, 94


14, 101

Magnetic field






53, 59

51, 69, 70, 71

83, 84, 85, 87, 92, 102


Based on their origin, stimuli can be divided into two groups: endogenous (pH, concentration of reducing agents, presence of enzymes, etc.) and exogenous (light, temperature, magnetic field, etc.). DDSs based on MS have been developed for each of these stimuli. Some of the systems also feature a response to more than one stimulus—either via AND or OR logic.

The majority of systems with pore closing agents use MCM-41 as the mesoporous support, although reports using SBA-15, hollow silica particles, and rattle-type silica particles also exist. MCM-41 features pores small enough to be efficiently capped with macrocycles and polymers. However, while smaller pores are easier to close, their dimensions prevent incorporation of larger molecules such as proteins and nucleic acids, both of which are important therapeutic agents. SBA-15 offers larger pores than MCM-41. The latter can be synthesized in sub 100 nm region, whereas reducing the size of SBA-15 particles to submicrometer level is difficult due to acidic synthesis conditions. Pores in MCM-41 and SBA-15 particles are parallel, and therefore not connected to each other. In such a case, there will be no leakage of molecules from successfully capped due to certain degree of unsuccessfully capped or even completely uncapped pores.


The value of pH varies greatly inside a human body, from 1 to 2 in the stomach to ~8 in the intestine. On the cellular level, pH of the extracellular fluid is around 7.4, but drops to 4–5 in lysosomes [6]. In addition, the variation of pH can also be associated with a disease such as cancer; pH of extracellular fluid in tumor tissue and inflammatory tissue is lower, around 6.8 [6]. This difference in pH makes selective release of drug from the DDS possible, thus increasing efficacy, while simultaneously decreasing side effects. The pH of lysosomes is important for DDS as endocytosis is the primary route of entry of nanosized DDS into the cell [23]. First pH-responsive gated MS particles featured construction of complexes on the surface, which responded to changes of pH by dissociation of a macromolecule from a ligand, thus allowing release of the cargo [24]. In recent years, complex systems emerged incorporating either ionic interactions or pH sensitive covalent bonds [25, 26].

Disulfide reducing compounds

In a human body disulfide bonds can be reduced or mercapto groups oxidized by small redox molecules, such as glutathione alone or in the presence of redox enzymes [27]. Although certain enzymes can catalyze reduction of disulfide as well as oxidation of mercapto group, in the cell cytosol reduction prevails over oxidation due to the presence of tripeptide glutathione, which cleaves the disulfide while it is oxidized to its dimer. The ratio of glutathione to its dimer is over 100 in most cells [27] and it is maintained by glutathione reductase and nicotineamide adenine dinucleotide phosphate, which catalyze the reduction of the glutathione dimer. Intracellular concentration of glutathione is 1–10 mM, while its extracellular concentration is significantly lower (0.002 mM in plasma) [28]. This difference allows the design of DDSs which protect the drug in extracellular fluid, while releasing the drug upon DDS entry into the cell [29]. One of the first MS responsive DDS was reported by Lin’s group [30]. The CAs were CdS NPs, which were covalently attached to silica through disulfide bonds. The same group also reported a system in which dendrimers were used instead of CdS [31]. In the following years more systems were presented by Zink, Stoddart [32], and Feng [33] and the respective coauthors.


Overexpression of certain enzymes can be associated with various diseases, such as cancer [34] and neurodegenerative developments [35]. Responsiveness of DDS to elevated level of enzymes could provide a route to release the drug only in enzyme-overexpressing (i.e., diseased) cells. Various enzyme-responsive MS systems were developed, including senescence associated β-galactosidase [36], pancreatin mixture [37], reductase [38], amidase [39], urease [39], deoxyribonuclease I [40], and hyaluronidase-1 [41].


Disease states such as inflammation can lead to increased temperature of the inflamed tissue. Apart from taking advantage of this fact, the increase of temperature can serve as stimulus, also based on sources from outside of the body. An example is hyperthermia therapy for treatment of certain types of cancers (e.g., melanoma, esophagus, and gastrointestinal tumors) [42]. An interesting concept is to use plasmonic heating of metal NP to increase temperature locally, which then leads to guest molecule release through temperature–labile complex [43].


While relying on an endogenous stimulus has its advantages, exogenous stimulus offers drug delivery control from outside the patient. With a good enough system drugs can be delivered and released in a precise location in the body. Light, for example, offers a noninvasive stimulus for drug release. The popular o-nitrobenzyl group in which the covalent bond is cleaved under irradiation of ultraviolet (UV) light has been used in a variety of MS systems [44]. A disadvantage is the use of UV light, which does not reach deep into the tissue, so it is more appropriate for under the skin application. Systems responsive to visible light and two-photon sensitive functional groups seem to promise an improvement in this area [15]. Use of near infrared light (1064 nm) with plasmon resonance excitation of Au NP to control payload release was also reported [45].

Magnetic field

Another promising exogenous stimulus is a magnetic field. Systems incorporating this route of drug release usually include magnetic NPs inside MS particles or on the surface of particles [46, 47]. Release can be triggered by motion of magnetic NP in alternating magnetic field or by local temperature increase, both due to external magnetic field.

Dual stimulus release

While the therapeutic systems with responsiveness to one stimulus indeed show improved efficiency with fewer side effects, the systems that release the payload in response to two stimuli in an AND logic, could improve the efficiency and diminish side effects to even greater extent. However, only a few such systems have been reported. A system reported by Aznar et al. [48] uses light-induced isomerization of spiropyran photochrome to achieve a dual stimuli-responsive release. A spirocyclic derivative was immobilized on silica surface to act as an anchoring point for poly(amidoamine) dendrimers. Upon irradiation with UV light or when kept in dark, the spirocyclic form isomerizes to the merocyanine form. The latter is either positively charged at neutral pH, or behaves as zwitterion at a higher pH. Negatively charged dendrimers bind to this form with greater affinity than to the spiropyran form, however, only at neutral pH. The transition back to spiropyran form is achieved thermally or by irradiation with visible light. This system functions as a NAND (NOT AND) logic gates with inputs being UV light and neutral pH. Retention of the payload was possible only when both the UV light and a neutral pH were present. Angelos et al. [49] reported pH and photo triggered release. Pore walls were decorated with azobenzene moieties, which undergo motion under irradiation with visible light, thus pushing the dye molecules out from the pores. The outer surface of silica was grafted with functional groups, which formed an inclusion complex with cucurbit[6]uril molecules. The complex was stable in 5 % EtOH in water, while cucurbit[6]uril dissociated by increasing the pH to 8. Coupled with light triggered azobenzenes, the payload was released only in presence of both stimuli. Recently, Wen et al. [50] developed an OR and AND logic gate on MS. Gold NPs were used as CAs, while hybridization between Au NP-attached deoxyribonucleic acid (DNA) and MS-attached DNA kept NPs on silica. In an OR system, potassium ions, or heat caused dissociation of DNA double strands, opening the pores. In an AND system, single-stranded DNA were exchanged for single-stranded DNA aptamers. Again, the hybridization kept Au NPs on the surface, however, only the addition of both aptamers’ targets caused dissociation and release of the reporting dye from the pores.


Drugs, which can be loaded inside mesopores and released in controlled fashion, have to survive certain conditions. Since mesopores of most commonly used type of MCM-41 are approximately 3–4 nm in diameter, larger molecules, such as proteins, cannot be loaded inside these pores. On the other side of the scale, too small molecules cannot be efficiently capped inside the pores. For example, coumarin leaked from the closed pores, while larger rhodamine B was successfully retained inside [51]. When the size of the drug is outside system’s working range, other closing mechanisms instead of steric hindrance, such as solubility of the drug, or ionic interactions with the vehicle, should be considered to achieve stimulus-induced release. Solubility and charge of the drug molecule also play an important role in loading, holding and release of the said drug [52]. Positively-charged molecules will adsorb to the negative surface charge of unmodified silica. Rhodamine B, fluorescein disodium salt, calcein, \( {\text{Ru}}\left( {\text{bipy}} \right)_{3}^{2 +} \), and Hoechst 33342 are the most popular choices of model drugs in studies of MS-based DDS. Their fluorescence properties enable tracking the release with fluorescence spectroscopy, while the good aqueous solubility enables a rapid release upon uncapping of the pores.

Capping agents

Although CAs serve the same purpose, their structure varies greatly from system to system. CAs can be divided into few major groups: NPs, macrocycles, polymers (nucleic acids, peptides, proteins, saccharides, and other synthetic polymers), small molecules, and crosslinking of functional groups. In addition to the gating function, this diverse group of materials can provide other functionalities, such as release reporting [53], active targeting of cell receptors [33], and magnetic resonance imaging probing [46].


Pores in the range of a few nanometers can be effectively capped with small NPs (~2 nm in diameter) [30]. A variety of materials can be synthesized to form NPs [54]. NPs composed of gold [45], CdS [30], and Fe2O3 [55] were shown to be an effective CA on MS. Among the first gated systems based on MS NPs was the one with CdS NP reported by Lai et al. [30]. NPs with a diameter of 2 nm were attached to MS NP through a disulfide bond. Cleaving the disulfide bond resulted in detachment of the CdS NP from MS NP and release of the model drug. Later, systems incorporating gold NP [53, 56, 57] and superparamagnetic Fe2O3 NP [58] were reported. The systems incorporated responsiveness to a variety of stimuli. The use of NPs as capping agents can be problematic from the safety standpoint. Before systems capped with NPs are considered for clinical use, the toxicity of NPs on silica surface and those NPs released from the surface need to be studied very carefully. To date (non-)toxicity of material at nanometer scale is not confirmed.

To retain cargo molecules inside the mesopores these NPs rely on steric hindrance. However, they can act as an active part of the system as well. As reported by Aznar et al. [45], this system was able to open its gates by irradiation of infrared light. Plasmonic heating of Au NPs caused cleavage of boronic ester, thus enabling the release of the payload. Au NPs served as CAs as well as mediators in stimulus responsiveness. Biocompatibility is an important issue when dealing with NPs. Gan et al. [58] presented a pH-responsive system based on MS NPs with covalently attached Fe2O3 NPs through acid-labile boronate ester linker. Better biocompatibility of such a system compared to the pure MS NPs was discovered and attributed to the saccharide derivative on the surface of MS NPs capped with Fe2O3 NPs. In a system reported by Zhu et al. [59] Au NPs modified with aptamer were kept on MS NPs by the affinity of the aptamer for adenosine molecules grafted on the silica surface. The system responded to two triggers: Adenosine triphosphate (ATP), which is recognized by the ATP aptamer and a complementary DNA strand, while a random DNA did not open the gates. Muhammad et al. [60] used luminescent ZnO quantum dots to cap doxorubicin inside mesopores. Lowering the pH of the medium decomposed the ZnO quantum dots and thus released the entrapped dye. The luminescent property of the CA enabled tracking of the release process, as luminescence rapidly decreased upon lowering the pH to 5.0. An interesting advantage of the NPs is the already-mentioned ability to use plasmonic heating and heating induced by alternating magnetic field. However, it is not necessary for these NPs to be used for capping [43, 61]. Inclusion into a silica matrix during the condensation process is often reported, thus yielding magnetic MS particles [47]. Incorporation of quantum dots or rare-earth nanophosphors forms a fluorescently-labeled system with several advantages over the organic fluorophores, such as greater bleaching stability [62]. Among CAs of few nanometer in size the system reported by Malvi et al. [63] is particularly interesting. They used large-pore-size SBA-15 microparticles of 5–8 μm in diameter and capped the entrapped enzyme with MS NPs of 100 nm. The system allows diffusion of the substrates and the products, but retains enzymes inside the pores. It was presented as a biocatalytic system, however, certain aspects can be considered suitable for drug delivery as well.


The largest group of CAs belongs to macrocycles, such as cyclodextrins, cucurbuturils, etc. Due to their ability to form inclusion complexes with their cavity, there is more than one way to use them as CAs. Different approaches can be grouped into three overlapping groups discussed in the following sections.

Covalent attachment

The straightforward covalent attachment of macrocycles on MS with a stimulus-responsive bond is similar to the attachment of NPs. A macrocycle forms a barrier against cargo molecules due to its size and surface charge [52]. Park et al. [44, 64] presented a system with β-cyclodextrins covalently attached to MS surface through the o-nitrobenzyl functional group, a motif known for its photocleavable properties. Irradiation with UV light (350 nm) cleaved the covalent bond resulting in dye release. In a separate experiment, ester bonds present in the linker between silica and β-cyclodextrin and the macrocycle itself were cleaved by lipase and α-amylase enzymes, respectively, thus demonstrating enzyme response of the system as well. An intriguing related system was recently reported by Wang et al. [65]. Here, β-cyclodextrin formed an extension of the mesopores by being attached with 7 disulfide bonds per molecule. The system is discussed in detail in Chapter 7 (Codelivery). An interesting system was presented by Zhang et al. [52]. Peramino-β-cyclodextrin was immobilized onto MS NPs with disulfide bonds and afterward poly(ethylene glycol) (PEG) chain with an adamantane group on one end and a folate group on the other end was attached onto β-cyclodextrin-modified MS NPs by forming an inclusion complex between the adamantane groups and the cavity of β-cyclodextrin. PEG provided a long-term stability, while the folate groups enabled active cancer targeting. Moreover, they discovered that free amine groups in β-cyclodextrin played an active role in drug release. When doxorubicin was used as a cargo molecule, leakage was minimal at pH 7.4; however, the release was enabled by adjusting the pH to acidic, even in the absence of reducing agent to cleave the disulfide bonds. Such behavior was explained by protonation of amine groups in acidic environment, which resulted in Coulombic repulsion forces toward positively charged doxorubicin molecules. Calcein, a negatively charged dye, showed the opposite behavior, that is, the retention of cargo at acidic pH and its release at neutral pH. Similarly, the reason is the protonation of β-cyclodextrin amine groups, which interact with calcein at lower pH values. Zhang et al. [66] recently reported a β-cyclodextrin capped MS NPs. The system illustrated in Fig. 2 had a polyanion protection layer surrounding the NPs attached to MS NPs via host–guest complex with β-cyclodextrin. Hydrolysis of the peptide connecting MS NPs and polyanion exposed the targeting peptide moiety, which increased particle uptake in cancer cells. Subsequently, glutathione reduced the bonds connecting β-cyclodextrin to MS and released doxorubicin from the mesopores. Recently, we have reported synthesis of a system with β-cyclodextrin caps attached via disulfide bonds [67]. The size of the substituents on the disulfide bonds influenced the rate of cargo release from the mesoporous voids.
Fig. 2

Schematics of a doxorubicin-loaded MS NPs capped with β-cyclodextrin. Targeting moiety on the outer surface of the particles is shielded by protective polymer. Proteinase exposes the targeting moiety and thus increases cellular uptake of NPs. Drug is released by removing β-cyclodextrin with disulfide-reducing agent. Adapted with permission from Ref. [66]. Copyright (2013) American Chemical Society

Stimulus sensitive inclusion complexes

Many of the above-mentioned macrocycles can form an inclusion complex with a variety of molecules or functional groups/guests. Adamantane, for example, forms a complex with β-cyclodextrin with a constant in the order of 105 [68]. While this can be an advantage in certain cases, guests with lower binding affinity are needed for formation of a stimulus sensitive complex. The underlying principle is to have a functional group covalently attached to the silica surface; addition of macrocycles to these MS particles in solution of a drug leads to formation of a complex between the said functional groups and macrocycles, thereby closing the entrances to the pores and trapping the drug molecules inside the mesopores. Upon a stimulus (such as a pH change, introduction of another guest molecule, etc.), the complex dissociates leading to opening of the pores. Many of these systems were reported by the Zink’s and Stoddart’s research groups. Some of the macrocycles used included cyclobis(paraquat-p-phenylene) [51, 69, 70], dibenzo[24]crown-8 [24, 71], α-cyclodextrins [72], and cucurbiturils [73, 74].

The use of benzimidazole amine stalk with β-cyclodextrin, and aniline stalk with α-cyclodextrin, has been well-studied. Du et al. [25] reported a system composed of aniline and p-methoxyaniline groups on hollow MS particles, which served as stalks for α-cyclodextrin. The latter formed an inclusion complex with the stalks, which was stable at neutral pH. Acidification resulted in protonation of nitrogen in the stalks leading to dissociation of α-cyclodextrin and consequently to dye release. Further optimization of this type of system was reported by Meng et al. [75]. In the heart of the system was a N-methylbenzimidazole stalk and β-cyclodextrin, a complex that was found stable at neutral pH, but dissociated at pH values lower than 6.0 leading to release of dye from the mesopores. A response to smaller pH changes is an important advantage as pH variations on the cellular level could be small, yet still medically-important.

However, not all complexes are pH sensitive. Ferris et al. [76] constructed a light responsive system based on an inclusion complex of azobenzene with β-cyclodextrin. The azobenzene moiety has the ability to isomerize from trans to cis under irradiation with UVA light. While β-cyclodextrin has a high binding affinity to the trans isomer, the affinity for the cis isomer is much lower. Similarly to the pH-responsive complexes, the macrocycle dissociated from the stalk as azobenzene was switched to the cis isomer. Complexes with a low dissociation constant can also be disrupted by introducing a guest with a higher binding constant; such a system was reported by Liu et al. [77]. They synthesized an enzyme-responsive system based on competitive binding of diamine. Cucurbit[7]uril was threaded onto the 1,4-butanediamine moiety, while cadaverine was introduced as a weak competitor. Only after the addition of decarboxylase the carboxylic group of cadaverine was removed resulting in 1,5-pentanediamine with a strong binding affinity for the cucurbit[7]uril cavity. Croissant and Zink [43] reported construction of a plasmonic heating induced release from MS support (see Fig. 3). Gold NPs were embedded into the mesoporous matrix. CA was composed of an amine stalk grafted on a silica surface and the cucurbit[6]uril ring forming a complex with the stalk, thus closing the pores. The system was irradiated at 514 nm to excite gold NPs which resulted in local heating and uncapping of cucurbit[6]uril rings. Recently, another system using azobenzene cistrans isomerization and complex formation was reported [15]. α-Cyclodextrin was complexed with an azobenzene stalk on MS NPs. Visible light irradiation moved α-cyclodextrin on the stalk further from the surface, allowing the release of curcumin from the pores. The bulky functional groups at the end of the stalk prevented a complete dissociation of the complex and thus enabled multiple open-close cycles.
Fig. 3

Heating causes dissociation of the macrocycle from the stalk and release of the dye. Source of heating can be either external or internal caused by laser actuation of gold NPs. Adapted with permission from Ref. [43]. Copyright (2013) American Chemical Society

Rotaxane structures and similar systems

Macrocycles can also form inclusion complexes with guests of lower binding affinity to prevent premature dissociation from such a stalk, bulky groups are introduced on one side of the stalk. In this way, a rotaxane is formed, the other bulky structure being the MS NPs itself. Rotaxanes are formed in a multiple step process: a surplus of a macrocycle is added to a suspension of the stalk-modified MS NPs. Afterward, the unthreading of macrocycle is prevented by addition of bulky groups which form a covalent bond with the stalk, capping the macrocycle, which in turn caps the cargo molecules inside the pores. The advantage of this approach is the possibility of locating the cleavable bond on the outer surface of the macrocycle. This way there is less steric hindrance directed toward the stimulus molecules.

The systems presented by Patel et al. [78] and Ambrogio et al. [32] use α-cyclodextrin and cucubut[6]uril threaded on the stalk and an adamantane moiety as a stopper. The authors demonstrated a reducing agent and enzyme-mediated removal of the adamantane moiety and a subsequent release of the dye. The addition of bulky groups is not always needed to prevent unthreading. Gao et al. [26] prevented premature release of doxorubicin by covalently bonding a PEG polymer via the pH sensitive benzoic-imine bond to silica and subsequently forming polypseudorotaxanes with α-cyclodextrin. Attraction forces between α-cyclodextrin and PEG were strong enough to make the bulky functional group at the end of the chain unnecessary. Benzoic-imine bonds were shown to be able to cleave by only a small variation of pH from the neutral value. Doxorubicine was released at a pH of 6.8 and a cell culture experiment showed an increased efficiency of drug compared to a medium with a pH of 7.4. Porta et al. [79] used a peptide to keep α-cyclodextrin in place. After the addition of a reducing agent, the disulfide bond was cleaved, leading to peptide detachment and α-cyclodextrin dissociation, followed by release of the dye from the mesopores. A different approach was realized by Zhao et al. [80], see Fig. 4 for schematics of their system. Contrary to other systems, β-cyclodextrin was immobilized onto a silica surface, serving as an extension of the mesopores. A rhodamine B-benzidine conjugate served as a piston, which formed a complex with the β-cyclodextrin cavity. Dissociation of the complex was achieved by lowering the pH to ~5, allowing passage of small molecules (disodium salt of 2,6-naphthalenedisulfonic acid) from the mesopores.
Fig. 4

MS NPs covered with β-cyclodextrin and piston acting as a CA. Decrease of pH causes dissociation of piston from β-cyclodextrin cavity. Small molecule dye can escape through the now-empty β-cyclodextrin cavity. Adapted with permission from Ref. [80]. Copyright (2013) American Chemical Society

Of course, each method of macrocycle gate construction has advantages and disadvantages. When a complex alone is used, attention has to be paid to the constant of the complex and how it is affected by the environment during the delivery phase to avoid premature drug leakage. It might be suitable in a buffer solution, but it is important to consider consequences of in vivo application. When using a covalent bond located between MS NPs and CA, the steric hindrance of CA to the stimulus molecules has to be considered. While this does not pose a problem for photocleavable bonds and is of little concern for pH sensitive bonds, it becomes an important issue for an enzyme responsive system. Unless macrocycle or NP is attached non-covalently, a covalent bond must be cleaved to allow the release of the payload. Popular choices are the disulfide bond [67], the imine bond [80], and o-nitrobenzyl fragments [44].


Peptides and proteins

Being abundant in nature, protein and peptides offer a safer alternative to NPs and CA based on molecules not normally found in human body. Luo et al. [81] prepared a redox responsive system with the collagen immobilized on silica surface with disulfide bonds. The outer surface of collagen was modified with lactobionic acid as a targeting moiety. The group demonstrated a dithiotreitol induced release of dye and cell internalization in cell culture. Coll et al. [82] presented a peptide-capped MS particles and an inherently peptidase mediated dye release. A peptide composed of 18 amino acid residues was able to retain the cargo, however shorter peptides of 6 and 11 amino acid residues experienced a considerable leakage of the dye. Given, the known specificity of peptidases peptide CA could be structurally tuned to respond to specific peptidases only. Climent et al. [83] reported an antibody-capped system. The antibody created an interaction with a hapten located on the surface of MS through two binding IgG regions. Antibodies were able to hold Rhodamine B guest molecules inside the mesopores. The release was achieved by adding finasteride, which acted as an antigen interacting with the antibody and breaking its interactions with the organic functional groups on silica. Geng et al. [84] developed an H2O2 sensitive system. Such a system could be used in treatment of Alzheimer’s disease as well as in treatment of other conditions where reactive oxygen species are formed. Glycoproteins were linked to MS particles via boronate ester bonds. They utilized human IgG with a hydrodynamic diameter of 11 nm as CA. In the presence of H2O2 arylboronic esters were oxidized to phenols. Cleavage of the ester bond between MS and antigen led to its dissociation and release of cargo molecules: metal chelator clioquinol, a drug used for treatment of Alzheimer’s disease. While enzymes can act as triggers for release, they can serve as CAs as well. In a recent study, [85] glucose oxidase was anchored on MS particles via d-glucosamine, which, in turn, was covalently attached to the material’s surface. While d-glucose caused the removal of the enzyme, other saccharides did not. Platforms with similar functionalities as those of DDS can be used in signal amplification [86]. Glucose oxidase was immobilized on MS surface via the interaction with cofactor flavin adenine dinucleotide. The protease cleaved the capping protein and released rhodamine B from the pores. The released dye indicated protease activity.

Nucleic acids

Being polymers themselves, nucleic acids are large enough to sufficiently cap the mesopores. Coupled with their ability to form dimers with complementary strand, nucleic acids can be used on MS to release the payload in response to the presence of complementary strand, as reported by Climent et al. [87]. MS NPs were functionalized with amine groups, which interacted with negatively charged oligonucleotides thereby closing the pores and entrapping the dye. Opening of the pores occurs as the complementary DNA strand is added and hybridizes with the strand on the silica surface. Complementary strands with one and two base mismatches opened the pores as well, although much less dye was released in comparison to the full complementary strand. A similar form of pore closing approach was reported by Zhu et al. [40], however, in this case the dye was released following the addition of endonuclease, which cleaved oligonucleotides adsorbed onto MS. Choi et al. [88] reported a polynucletiode-capped system based on a hollow MS. The pores were closed by addition of polyadenine leading to a Watson–Crick base pairing on the particle surface. While thymine groups were grafted on the silica, polyadenine served as a CA. Lowering the pH from 7 to 4 enabled the release of rhodamine B cargo molecules. Poly-cytosine, on the other hand, could not retain dye molecules in the pores, since it missed proper base pairing. A lower pH promoted a faster release. A zero order kinetics was achieved, which is seldom observed in capped MS systems. The percentage of released cargo molecules was directly proportional to the time. Yang et al. [61] recently reported a novel system capped with DNA oligonucleotides, which form a G-quadruplex with the surface attached oligonucleotides, thereby efficiently capping the pores. Part of this CA was a DNA aptamer, which exhibited a high binding affinity to nucleolin, a receptor overexpressed in tumor cells. Au nanorods incorporated into a mesoporous matrix were heated under irradiation with IR light. G-quadruplex DNA dehybridized because of the increased temperature and released the cargo from the mesopores. An advantage was also the use of less damaging IR light compared to the visual and UV light. Yuan et al. [89] constructed an oligonucleotide-capped DDS. While a short oligonucleotide was immobilized on a silica surface, a longer complementary oligonucleotide had azobenzene insertions between subsequent bases. The latter strand served as CA, which formed a complex with the immobilized strand only when azobenzene molecules were in the trans position. Upon irradiation with UV light, the conformation was changed to cis and strands dehybridized. Release of the payload followed. He et al. [90] designed a system based on a DNA forming an i-motif. The i-motif, grafted on MS, acted as a CA and prevented the release of a dye encapsulated in the mesopores. Switching of the DNA between the i-motif and a single strand was accomplished by neighborly attached malachite green carbinol base, which released hydroxide ions upon irradiation with UV light, thereby acting as a reversible photo-irradiated pH-jump system. Reversibility of the system was shown by alternating between irradiation with UV light and dark, which was followed by dye release and cessation of the release, respectively. Recently, He et al. [91] developed a pH-responsive DNA-capped system. Thymine bases were protonated in acidic medium (pH ~5.0) and thus unable to form T-Hg2+-T base pairs. The reversible nature of the gates was demonstrated by repeated exposure to acidic and neutral pH. Zhang et al. [92] reported a system with incorporated DNA using catalytic properties (DNA-zyme). As depicted in Fig. 5, fluorescent molecules were trapped in the mesopores of MS by hybridization of two single-stranded DNA. Addition of specific ion (either Mg2+ or Zn2+) enabled metal-dependent catalytic properties of the DNA-zyme, thereby cleaving MS-attached DNA strand and thus release of the cargo. Furthermore, they synthesized systems responsive to two stimuli in an AND logic: Mg2+ anions were able to release cargo only in combination with either ATP (for ATP-aptamer containing DNA) or Hg2+ ions (for thymine-rich sequence).
Fig. 5

Schematics of ion-responsive system releasing either methylene blue or thionine dye by addition of Mg2+ or Zn2+ ions, respectively. Ion enables metal-dependent catalytic properties of DNA-zyme, which in turn cleaves DNA and releases the dye. Adapted with permission from Ref. [92]. Copyright (2013) American Chemical Society


Polysaccharides range from linear to highly branched structures. Chen and Zhu [93] enclosed ibuprofen into mesopores by wrapping MS NPs with chitosan and forming hydrogen bonds between silanol hydroxyl groups and chitosan hydroxyl and amine groups. At pH 7.4 chitosan is in orderly aggregated state, which efficiently block the pores. However, lowering the pH to 6.8 weakens the hydrogen bonding and chitosan forms a gel network, which allows the release of ibuprofen. Certain saccharides can be cleaved with β-d-galactosidase. As demonstrated by Bernardos et al. [37] the hydrolyzed starch derivatives (Glucidex 47, 39, and 29) formed caps on a MS system. Addition of an enzyme hydrolyzed the caps, releasing the fluorescent dye that was entrapped in the mesopores. The functioning of the system is visualized in Fig. 6. Furthermore, the release profile could be tuned by controlling the degree of hydrolysis of the starch used to cap the pores. The objective of a recent study by Huang et al. [94] was to show the efficiency of photo-reaction between phenyazide and dextran. Coumarin loaded inside the pores was released after the removal of the covalently attached dextran by cleaving the disulfide bonds in the linker. Biocompatiblity of the whole system is an important issue in DDS design. Chen et al. [41] addressed this problem by using nonimmunogenic, biocompatible, and biodegradable hyaluronic acid polysaccharide as CA. While serving as a gate in enzyme-mediated release of the cargo (rhodamine B and doxorubicine), its targeting abilities provided active targeting of CD44 overexpressing cells.
Fig. 6

Schematics of enzyme-mediated release of dye from MS particles. Starch derivatives are cleaved with β-d-galactosidase thus enabling release of the dye. Adapted with permission from Ref. [37]. Copyright (2013) American Chemical Society

Dendrimers and other polymers

Dendrimers have been rarely used as CAs. Linear polymers, on the other hand, are often included in the reported systems. Martínez-Máñez and coworkers reported several polymer grafted MS systems. Primary amine containing polymers were shown to be responsive to changes in pH and also formed interaction with specific ions. Model drugs were released controllably based on pH and the presence of ions. We have recently evaluated the effect of CA size on the release of a model drug [95]. Poly(ethylene imine) dendrimers, generations I through V, were grafted onto MS surface. Generations I and II showed an excellent stimulus-responsive release of the anionic model drug, while the larger dendrimers exhibited a poorer performance. Aznar et al. [21] reported the utilization of MS NPs functionalized with a long alkyl chain. These alkyl chains do not close the pores but interact with paraffins through London forces. Paraffins of different chain lengths were used to cap the mesopores. Such paraffins are known to melt at different temperatures. Thus, with selection of suitable paraffins it was possible to fine-tune the release as a function of the temperature. In another study Aznar et al. [19] modified MS surface with alkyl chains with lengths ranging from 2 to 30 C atoms. MS NPs with short alkyl chains with up to 6 C atoms exhibited the fastest dye release, reaching a plateau after 30 min, whereas longer aklyl chains were able to retain the dye for longer periods of time. However, in contrast to the other systems discussed in this review, the systems in this particular study did not have a stimuli-induced release. This important achievement shows a possibility to control the release kinetics with small structural modifications. Recently, Zheng et al. [96] reported chitosan and F127 pluronic surfactant modified MS NPs. Danorubicine, used as a drug, and chitosan formed pH sensitive coordination bonds with zinc ions. Drug release was faster at pH 4 than at pH 7.4, owing to the cleavage of either the NH2–Zn or the Zn-danorubicine coordination bond or both. Mei et al. [97] doped hollow MS NPs with lanthanide rare-earth nanocrystals and the surface grafted with alkyl chain. This functionalization alone slowed down the release of hydrophobic drug ibuprofen. Further attachment of PEG capped the mesopores. Gate opening was achieved by incorporating acetal groups, which cleaved upon lowering of pH and allowed removal of PEG chains. Bringas et al. [47] recently presented a system in which external alternating magnetic field induces motion of magnetic NPs inside a MS core. MS NPs were synthesized in the presence of iron oxide superparamagnetic NPs to achieve their incorporation into mesoporous structure. MS NPs were later coated with a lipid bilayer to retain methylene blue inside the mesopores. When the system was placed in an alternating magnetic field, the motion of iron oxide NPs and the local increase of temperature disrupted the lipid bilayer around the MS NPs and allowed the release of the dye from inside the mesopores. Kang et al. [62] incorporated temperature-responsive poly(N-isopropylacrylamide) (PNIPAm) polymers into hollow rattle-type MS microspheres. Inclusion of Gd2O3:Eu3+ luminescent NPs in microspheres added the ability to track microspheres by emission of light. PNIPAm was incorporated inside the cavity and mesopores in the shell, thereby pushing the indomethacin into the medium upon temperature increase. Recently, Sun et al. [98] employed a reversible addition-fragmentation chain transfer polymerization to coat MS particles with zwitterionic polymer poly(3-dimethyl(methacryloyloxyethyl)ammonium propanesul-fonate) and its precursor poly(2-(dimethylamino)ethyl meth-acrylate), which is a temperature-responsive polymer with lower critical solution temperature. Although the system exhibited leakage of the dye at 30 °C, the release was increased upon heating. In addition, the copolymer is almost nontoxic at concentrations of up to 200 μg/mL.

Small functional groups

While diverse, this group includes functional groups on the surface of a mesoporous material or pore walls that do not belong to any other group and have a relatively low molecular weight. In certain instances the weight of the group is even less than the weight of the payload. An interesting construction was presented by Guo et al. [33]. They attached folate groups to mesopore openings to act as both a capping and a targeting agent, showing multifunctionality of the CA.It served not only as a gatekeeper, but also as an active targeting moiety toward folate-receptor overexpressing cells. Upon cell internalization disulfide bonds linking the silica surface and the folate group were cleaved by glutathione, which enabled drug release. Agostini et al. [39] functionalized the silica with rather small functional groups; however, they were still able to retain cargo molecules (\( {\text{Ru}}\left( {\text{bipy}} \right)_{3}^{2 + } \)). CA included amide and urea bonds, linking two tert-butyl groups to the silica surface. The cargo was released by treatment with either urease or amidase. The system exhibited different release profiles of \( {\text{Ru}}\left( {\text{bipy}} \right)_{3}^{2 + } \), dependent on the enzyme used. The release was slower with urease, since the urea bond was located nearer the silica surface, making it less accessible to the enzyme. An important system was synthesized by Angelos et al. [99] using the azobenzene ability to isomerize when irradiated with visible light. The dynamic motion of azobenzene groups in mesopores acted as nanoimpellers “pushing” the dye molecules from inside the pores. The system was able to be started and stopped on demand. Jin et al. [100] recently immobilized phenanthroline moieties onto MS surface to achieve pH-responsive release of curcumin. Cu2+ ions were added to form complex with the neighboring phenanthroline groups, thereby blocking the pore entrances. After adjusting the pH to 5, the phenanthroline groups became protonated, which resulted in Cu2+ dissociation and drug release.

Crosslinking of functional groups

One of the first reported stimulus responsive DDS on MS particles by Mal et al. [14] was based on dimerization of coumarins, grafted on silica. While coumarins were dimerized phenanthrene was not able to diffuse into the medium; however, upon irradiation with UV light of a wavelength around 250 nm, the dimers were cleaved into monomers, enabling release of guest molecules. A system based on crosslinking of functional groups was also reported by He et al. [101]. There thymine moieties were grafted onto silica as depicted in Fig. 7. Closing of the pore was achieved by dimerization of thymine derivatives with a 365-nm light. Irradiation with a 240-nm light cleaved the dimer, enabling guest molecule (Hoechst 33342) release.
Fig. 7

Schematics of light-responsive crosslinking system based on dimerization of thymine. UV light cleaves the dimer and enables dye release. Adapted with permission from Ref. [101]. Copyright (2013) American Chemical Society


Sometimes it is beneficial to deliver more than one drug at the same time. Simultaneous release of different-sized cargo molecules from MS pores presents a challenge. Some of the achievements are presented here. Zhao et al. [102] synthesized a MS-based system with cyclic adenosine monophosphate (cAMP) loaded in the material’s pores capped with insulin attached to the silica through a boronic ester bond. While the increase of pH from 6 to 8 could induce release of insulin, the ability of the system to respond to saccharides seems even more interesting. Phenylboronic acids form more stable cyclic esters with adjacent diols of saccharides than with acyclic diols. Therefore, the bond between silica support and insulin could be cleaved by addition of saccharides. Fructose and glucose were found the most efficient for insulin release. Further experiments showed that glucose could also trigger the release of cAMP from the mesopores. cAMP activates Ca2+ channels of pancreas beta cells and stimulates insulin secretion [102]. Another important achievement regarding the concept of codelivery was accomplished by Zhu et al. [103]. They used a hollow MS to load a model low-molecular-weight drug (fluorescein) and a model oligodeoxynucleotide, covering the layer of the latter with a poly(l-lysine) polymer. A simultaneous release of both molecules was enabled by addition of α-chymotrypsin, inducing the polymer degradation. A recently reported system by Wang et al. [65] exhibits a coupled pH and redox response. Two model drugs of different sizes were used—Hoechts 33342 (~20 A) and p-coumaric acid (~4.5 A). β-Cyclodextrins were attached to silica with a reducible disulfide bonds. As each β-cyclodextrin can form seven bonds, this structure formed an extension of the pores, albeit with a narrower aperture, similar to the system depicted in Fig. 4. The Hoechst dye was thus successfully retained inside the pores. Then, the smaller molecules of p-coumaric acid were added to fill the voids in the pores. To prevent their leakage, methyl orange was introduced to form an inclusion complex with β-cyclodextrins. Upon lowering the pH, only p-coumaric acid was released into the medium, while the Hoechst dye was retained. The increase of the pH with exchange for fresh water with addition of 2-mercaptoethanol triggered the release of the larger Hoechst dye. Baeza et al. [104] decorated the MS surface with a thermoresponsive copolymer of poly(ethyleneimine)-b-poly(N-isopropylacrylamide) (PEI/NIPAM). This polymer trapped the fluorescein molecules inside the mesopores while at the same time electrostatic interaction and hydrogen bonding between polymer and protein kept the latter in the shell surrounding the NPs. Increase in temperature served as a stimulus for release of both fluorescein and protein. Due to incorporated γ-Fe2O3 NPs an alternating magnetic field was able to release the cargo indirectly via localized heating of superparamagnetic nanocrystals.


Since its beginnings in 2003 the field of stimulus-responsive MS nanocontainers has advanced from model systems in a test tube to feature-rich DDSs with in vitro testing on cell cultures and in vivo testing in animal models. Simple CAs have advanced to more advanced systems that are both efficient in cell medium and biocompatible. However, the toxicity of nanostructured material is still under investigation and more conclusive results are needed before such systems can be approved for medical trials. While the experiments involving capped MS particles have found their way into in vivo testing in recent years, there are many aspects of safety, which should be addressed. The systems presented in previous chapters are relatively complex compared to simpler systems composed of only inorganic material and adsorbed drug. With more complex systems more safety issues can arise. In addition to the safety of nanoparticles themselves (including their size, surface charge, and shape) attention must be paid to safety of CAs; their own toxicity and the toxicity of their degradation products. Nevertheless, exciting discoveries await in the future. Moreover, the gated MS systems are not limited only to drug delivery, but have found their way also into the catalysis and sensing applications. We have witnessed the construction of various logic gates on MS. These logic gates can provide a basis for a simple computing power on nanometer level. Of course, such primitive computers cannot compete with silicon-based computers, but could nevertheless provide a mechanism for input processing and output generation. Such simple computing power coupled with other functionalities of MS particles could result in various interesting nano-devices.


The authors thank the Slovenian Research Agency for financial support.

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Peter Nadrah
    • 1
    • 5
  • Odon Planinšek
    • 2
  • Miran Gaberšček
    • 1
    • 3
    • 4
  1. 1.National Institute of ChemistryLjubljanaSlovenia
  2. 2.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  3. 3.Centre of Excellence for Low-Carbon TechnologiesLjubljanaSlovenia
  4. 4.Faculty of Chemistry and Chemical TechnologyUniversity of LjubljanaLjubljanaSlovenia
  5. 5.Slovenian National Building and Civil Engineering InstituteLjubljanaSlovenia