Mesoporous Silica Nanoparticles: Synthesis, Biocompatibility and Drug Delivery

Review: 267 refs.

There has been an ever increasing interest in developing stimuli-responsive mesoporous silica drug delivery systems to improve therapeutic efficacy and minimize the adverse effects of drugs. This paper reports the works of our research group on valved and gated mesoporous silica drug delivery systems. Biocompatible mesoporous silica nanoparticles (MSNs), as drug carriers, were modified with active group-terminated silanes via self-assembly followed by diverse functionalization, a variety of macrocyclic hosts, proteins, DNA, and quantum dots were bound to the MSN surfaces to develop nanovalves and nanogates, through multiple noncovalent interactions, dynamic covalent bonds, and even strong covalent bonds, for the encapsulation of drugs within MSN pores, thus smart valved and gated MSN drug delivery systems were constructed. Under the stimuli of pH, redox, competitive binding, enzymes, and near infrared lights, controlled release of the encapsulated drugs was realized, because of the destruction of multiple noncovalent interactions, the cleavage of dynamic covalent bonds, and the disassociation of gatekeeping scaffolds. The carboxylate-substituted pillar [6] arene (CPA [6] )-valved dimethylbenzimidazolium or bipyridinium-functionalized MSN drug delivery systems were constructed for acidic pH, competitive binding, and metal chelating-responsive controlled release. The γ -CD-gated MSN delivery system functionalized with disulfide-linked carbamoylphenylboronic acid moieties and amines via dual dynamic covalent bonds with dual drug loading was constructed for simultaneous and cascade release of two drugs. It is a smart strategy to take advantage of the specific structures and properties of cyclodextrins (CDs) for use in the MSN drug delivery systems not only as gatekeepers but also as drug carriers. The γ -CD-gated MSN delivery system provided a smart platform for combination drug therapy, in addition to resistance to serum and normal blood glucose levels. The concanavalin A (Con A)-gated mannose-functionalized MSN drug delivery system via multivalent carbohydrate - protein interactions was constructed for the controlled release of drugs either by acidic pH or by competitive binding of glucose at high concentrations. The long and flexible spacers linked with the mannose ligands played an important role in adjusting the local spatial arrangement of the ligands to favor multivalent protein binding, as did the surface density of the ligands. The MSN drug delivery systems functionalized with N -(3-trimethoxysilylpropyl)ethylenediamine triacetate ligands, in the presence of metal ions with and without myoglobin containing surface-accessible histidine residues, were constructed for pH-responsive controlled release. Both the metal-latching ligands and the metal-chelating proteins played a synergetic role in gating MSNs for high-loading drug delivery and stimuli-responsive controlled release. The DNA-gated MSN drug delivery system functionalized with disulfide-linked acridinamine intercalators was constructed for multi-responsive controlled release under different stimuli, including disulfide reducing agents, elevated temperature, and deoxyribonuclease I. The DNA-gated MSN drug delivery system integrated multiple responses and AND logic gate operations into a single smart nanodevice not only for codelivery of drugs and DNA/genes but also for cascade release of two drugs in combination of dual stimuli. The DNA-gated gold nanorod-embedded MSN delivery system functionalized with titanium(IV)-chelating phosphonates with dual drug loading was constructed for simultaneous and cascade release of two drugs. Coordination chemistry is the first strategy for DNA cappings through multivalent chelating interactions in drug delivery systems not only as gatekeepers but also as drug carriers. The two drugs were simultaneously released upon triggering of endonuclease degradation or photothermal dehybridization and were successively released upon first triggering of basic pH and subsequent triggering of photothermal heating. The combination of NIR light-based thermotherapy and triggered chemotherapy (thermo-chemotherapy) could maximize therapeutic efficacy. In addition, the ZnO quantum dot (QD)-gated hollow mesoporous silica drug delivery system was constructed for pH and redox- responsive controlled release, and the ZnO QD-gated mesoporous carbon nanoparticle (MCN) drug delivery system was for pH-responsive controlled release. These constructed stimuli-responsive MSN drug delivery systems have promising applications in targeted tumor therapy.

In the past decade, mesoporous silica nanoparticles (MSNs) have attracted more and more attention for their potential biomedical applications. With their high surface area and tailored mesoporous structure, MSNs as drug delivery systems (DDSs) show significant advantages over traditional drug nanocarriers. In this review, we discuss the progress in the synthesis and drug delivery of mesoporous silica nanoparticles for cancer therapy. The review also explains their multifunctional counterparts as drug carriers and the prominent achievements using mesoporous silica nanoparticles in drug delivery.

Drug molecules with lack of specificity and solubility lead patients to take high doses of the drug to achieve sufficient therapeutic effects. This is a leading cause of adverse drug reactions, particularly for drugs with narrow therapeutic window or cytotoxic chemotherapeutics. To address these problems, there are various functional biocompatible drug carriers available in the market, which can deliver therapeutic agents to the target site in a controlled manner. Among the carriers developed thus far, mesoporous materials emerged as a promising candidate that can deliver a variety of drug molecules in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles are widely used as a delivery reagent because silica possesses favourable chemical properties, thermal stability and biocompatibility. Currently, sol-gel-derived mesoporous silica nanoparticles in soft conditions are of main interest due to simplicity in production and modification and the capacity to maintain function of bioactive agents. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release. The properties of mesopores, including pore size and porosity as well as the surface properties, can be altered depending on additives used to fabricate mesoporous silica nanoparticles. Active surface enables functionalisation to modify surface properties and link therapeutic molecules. The tuneable mesopore structure and modifiable surface of mesoporous silica nanoparticle allow incorporation of various classes of drug molecules and controlled delivery to the target sites. This review aims to present the state of knowledge of currently available drug delivery system and identify properties of an ideal drug carrier for specific application, focusing on mesoporous silica nanoparticles.

With the rapid development of nanotechnology, nanomaterials with unique physical and chemical characteristics, have offered tremendous potential for biomedical application. Among them, mesoporous silica nanoparticles (MSNs), a class of well-established nanoplatforms with different structures and compositions, have been widely used to develop drug delivery systems owing to their unique physical-chemical properties, such as tunable particle/pore size, high surface area and pore volume, easy surface modification, remarkable stability and biocompatibility, and high drug loading efficiency. Moreover, MSN-based nanocarriers with “zero premature release” property have proven to be excellent devices for drug delivery. A variety of fluorescent dyes and pharmaceutical drugs were encapsulated in MSNs for controlled release. In addition, numerous efforts have been made to develop smart nanovalves on the surface of MSN to provide on-command release of drug in response to different stimuli, including light, enzymes, pH, redox, temperature, and competitive molecules. Furthermore, the outer surface of MSN can be modified with various functional groups, that play critical roles (stealth or targeting) in overcoming the multistage barriers found in the drug delivery process. Fabrication of MSN-based, multifunctional, stimuli-responsive drug delivery systems can effectively encapsulate anticancer drugs and can maintain “zero premature release” before reaching the diseased site. Once they arrive at the tumor site with the aid of targeting groups, the nanodevice can be activated by a specific stimulus to release the drug. The delivery of anticancer drugs to a specific target site can alleviate toxic side effects and improve the therapeutic index of drugs; thus, achieving significantly enhanced anticancer efficiency. Herein, we reviewed various strategies for the design of stimuli-responsive, MSN-based drug delivery systems, and multifunctional MSN for targeted cancer therapy.

In drug delivery systems, nanocarriers could reduce the degradation and renal clearance of drugs, increase the half-life in the bloodstream and payload of drugs, control the release patterns, and improve the solubility of some insoluble drugs. In particular, mesoporous silica nanoparticles (MSNs) are considered to be attractive nanocarriers for application of delivery systems because of their large surface areas, large pore volume, tunable pore sizes, good biocompatibility, and the ease of surface functionalization. However, the large-scale synthesis of monodisperse MSNs that are smaller than 200 nm remains a challenge. In this study, monodisperse walnut kernel-like MSNs with diameters of approximately 100 nm were synthesized by a sol–gel route on a large scale. The morphology and structure of MSNs were characterized by scanning electron microscope, and transmission electron microscopy, N2 adsorption–desorption isotherms, Zeta potentials, and dynamic light scattering. Drug loading and release profile, cellular uptake, subcellular localization, and anticancer effect in vitro were further investigated. The results indicated that the loading efficiency of doxorubicinhydrochloride (DOX) into the MSNs was 57 %. The MSNs–DOX delivery system exhibited a drug-pronounced initial burst release within 12 h, followed by the slow sustained release of DOX molecules; moreover, MSNs could improve DOX release efficiency in acidic medium. Most free DOX was localized in the cytoplasm, whereas the MSNs–DOX was primarily distributed in lysosome. MSNs–DOX exhibited a potential anticancer effect against MCF-7, HeLa, and A549 cells in dose- and time-dependent manners. In summary, the as-synthesized MSNs may have well function as a promising drug carrier in drug delivery fields.

The comparative effects of mesoporous silica nanoparticles and colloidal silica on inflammation and apoptosis

Mesoporous silica nanoparticles (MSNs) are one of the most promising carriers for drug delivery. MSNs have been widely used in pharmaceutical research as drug carriers because of their large pore volume, high surface area, excellent biocompatibility, nontoxicity, ease to functionalize, and sustained release effects. MSNs have attracted much attention during drug delivery because of their special structure. The present study aimed to synthesize mesoporous silica nanoparticles (MSNs), dendritic mesoporous silica nanoparticles (DMSN), and hollow mesoporous silica nanoparticles (HMSN) through facile methods, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug. MSN, DMSN, and HMSN were characterized by SEM, TEM, FT-IR, nitrogen adsorptiondesorption isotherms, XRD, and zeta potential methods. Subsequently, puerarin (PUE) was used as the active ingredient and loaded into the three mesoporous materials, respectively. And, the drug delivery behavior was measured in PBS solution with different pH values. The sustained-release properties of MSN, DMSN, and HMSN loaded with PUE were investigated. Finally, the biocompatibility and stability of MSN, DMSN, and HMSN were studied by MTT assay and hemolysis assay. Our results showed that MSN, DMSN, and HMSN were successfully synthesized and the three types of mesoporous silica nanoparticles had higher drug loading and encapsulation efficiency. According to the first-order release equation curve and Higuchi equation parameters, the results showed that the PUE-loaded MSN, DMSN, and HMSN exhibited sustained-release properties. Finally, MTT and hemolysis methods displayed that MSN, DMSN, and HMSN had good biocompatibility and stability. In this study, MSN, DMSN, and HMSN were successfully synthesized, and to compare the drug release properties of nano-porous silica with different pore structures as a stroma for PUE drug, we provided a theoretical and practical basis for the application of PUE.

Mesoporous silica nanoparticles (MSNs) are considered a highly promising candidate for novel the drug delivery systems (DDSs) due to the possibility of controlling their functionalizable pores, their large pore volume, high loading cavities and biocompatibility. MSNs functionalized with stimuli-responsive polymers have been demonstrated to represent a controllable and smart drug delivery application able to release drugs in response to certain stimuli, including pH, temperature, light, enzyme or redox. The surface of the MSNs is coated with stimuli-responsive polymer brushes so as to increase the stability and extend the release period of the loaded drug. This minireview highlights the latest research developments of polymer-brush-grafted MSNs and their potential biomedical applications in this area.

Mesoporous silica nanoparticles (MSNs) have great potential for applications as a drug delivery system (DDS) due to their unique properties such as large pore size, high surface area, biocompatibility, biodegradability, and stable aqueous dispersion. The MSN-mediated DDS can carry chemotherapeutic agents, optical sensors, photothermal agents, short interfering RNA (siRNA), and gene therapeutic agents. The MSN-assisted imaging techniques are applicable in cancer diagnosis. However, their synthesis via a chemical route requires toxic chemicals and is challenging, time-consuming, and energy-intensive, making the process expensive and non-viable. Fortunately, nature has provided a viable alternative material in the form of biosilica from marine resources. In this review, the applications of biosilica nanoparticles synthesized from marine diatoms in the field of drug delivery, biosensing, imaging agents, and regenerative medicine, are highlighted. Insights into the use of biosilica in the field of DDSs are elaborated, with a focus on different strategies to improve the physico-chemical properties with regards to drug loading and release efficiency, targeted delivery, and site-specific binding capacity by surface functionalization. The limitations, as well as the future scope to develop them as potential drug delivery vehicles and imaging agents, in the overall therapeutic management, are discussed.

Mesoporous silica (MPS) nanoparticle was prepared as carriers for drug delivery systems by sol–gel method from sodium silicate as inexpensive precursor of silica and Cocamidopropyl betaine (CABP) as template. The silica particles were characterized by SEM, TEM, AFM, XRD, and N2adsorption–desorption isotherms. The results show that the MPS particle in the nanorange (40-80 nm ) with average diameter equal to 62.15 nm has rods particle morphology, specific surface area is 1096.122 m2/g, pore volume 0.900 cm3/g, with average pore diameter 2.902 nm, which can serve as efficient carriers for drugs. The adsorption kinetic of Ciprofloxacin (CIP) drug was studied and the data were analyzed and found to match well with pseudo-first order kinetic model. The CIP drug-loaded mesoporous silica (CIP-mSiO2) nanoparticles has capacity of about 16.3 mg drug/ mg mSiO2 were achieved, and capable of releasing 26% and 98.6% of their drug content after 90 min in water and PBS solution(pH,7.4) respectively. In-vitro controlled release studies of CIP in Simulated Body Fluid were carried out under stirring conditions. A study on release kinetics and mechanism using Koresmeyer-Pepps model, first order kinetic, and kopcha model shows that the Korsmeyer-Peppas and Kopcha models, both conform more closely to the release data.

Reduction-responsive drug delivery based on mesoporous silica nanoparticle core with crosslinked poly(acrylic acid) shell

Nanotechnology provides the means to design and fabricate delivery vehicles capable of overcoming physiologically imposed obstacles and undesirable side effects of systemic drug delivery. This protocol allows maximal targeting effectiveness and therefore enhances therapeutic efficiency. In recent years, Mesoporous Silica Nanoparticles (MSNPs) have sparked interest in nanomedicine research community, particularly for their promising applications in cancer treatment. The intrinsic physio-chemical stability, facile functionalization, high surface area, low toxicity, and great loading capacity for a wide range of chemotherapeutic agents make MSNPs very appealing candidates for controllable drug delivery systems. Importantly, the peculiar nanostructures of MSNPs enabled them to serve as an effective drug, gene, protein and antigen delivery vehicle for a variety of therapeutic regimens. For these reasons, in this review article, we underscore the recent progress in the design and synthesis of MSNPs along with the parameters influencing their characteristic features and activities. In addition, the process of absorption, dissemination and secretion by injection or oral management of MSNPs are also discussed, as they are key directions for potential utilization of MSNPs. Factors influencing the in vivo fate of MSNPs will also be highlighted, with a main focus on particle size, morphology, porosity, surface functionality and oxidation. Given that combining other functional materials with MSNPs may increase their biological compatibility, monitor drug discharge, or improve absorption by tumor cells coated MSNPs; these aspects are also covered and discussed herein.

Hybrid smart mesoporous silica nanoparticles for theranostics.

The biological applications of mesoporous silica nanoparticles (MSNPs) in drug delivery and bio-imaging applications have been developing for decades. The continuous developments in this field are achieved by virtue of the attractive properties of MSNPs such as large surface area and volume, tunable particle and pore size and easy surface functionalization. However, the conventional MSNPs based drug delivery systems are mainly focusing on delivering drug molecules to target cells. More specific delivery applications such as sub-cellular delivery based on MSNPs have not been fully investigated and developed. In choosing the target of sub-cellular delivery of MSNPs, mitochondria appear to be a good candidate. As an important organelle in almost all living cells, mitochondria have many features that make them the possible and attractive target for cancer treatment. Such features involve energy production, cellularmetabolism and apoptotic signal transduction. In view of that, my primary research focus during Ph.D study is design, fabrication and characterization of MSNP-based system in targeted delivery of anticancer drugs to mitochondria for anticancer study as well as overcoming drug resistance. In Chapter 2, in order to validate the application of MSNPs in sub-cellular delivery, we fabricated and characterized the obtained well-ordered MSNPs. By conjugating mitochondria targeting ligand, mitochondria targeted MSNPs were obtained and characterized. Doxorubicin (DOX) was loaded into MSNPs and the mitochondria targeting property was demonstrated by the co-localization study of mitochondria and fluorescent MSNPs or DOX loaded MSNPs. In addition, the anticancer effect of DOX loaded MSNPs was further investigated. After proving that the availability of MSNPs in sub-cellular drug delivery, we further chose one mitochondria specific hydrophobic anticancer drug, α-Tocopheryl Succinate (α-TOS) as payload to be delivered by MSNPs with reduced particle size. In Chapter 3, we applied α-TOS as effective mitochondria specific anticancer drug and its hydrophobicity drawback could be overcome by MSNPs. Thus, the anticancer effectiveness of α-TOS was maximized by MSNPs after targeted delivery to mitochondria. The maximized anticancer effectiveness of α-TOS was demonstrated by cytotoxicity study. In addition, the α-TOS loaded MSNPs with mitochondria targeting property also showed effectiveness in inducing programmed cell death, further validating the application potential of MSNPs in sub-cellular drug delivery. In order to broaden the biological application of mitochondria targeted MSNPs system, their application in overcoming drug resistance was further investigated. In Chapter 4, we aim to change the target site of DOX molecules intracellularly from nucleus DNAs to mitochondria DNAs (mtDNAs) to overcome DOX resistance. After targeted delivery of DOX molecule to mitochondria, such delivered DOX molecules were found to be able to induce the decrease in ATP supply and depletion of mitochondrial membrane potential, leading to the dysfunction of P-glycoprotein (P-gp) on cell membrane which is responsible for DOX efflux, and the induction of apoptosis. As such, the current research may be helpful in providing new insight in developing MSNPs in sub-cellular drug delivery and their applications in anticancer treatment including overcoming drug resistance.