Igor I. Slowing

Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers

In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chemical functionalization for biotechnological and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.

Mesoporous Silica Nanoparticles for Intracellular Controlled Drug Delivery

The application of nanotechnology in the field of drug delivery has attracted much attention in the latest decades. Recent breakthroughs on the morphology control and surface functionalization of inorganic-based delivery vehicles, such as mesoporous silica nanoparticles (MSNs), have brought new possibilities to this burgeoning area of research. The ability to functionalize the surface of mesoporous-silica-based nanocarriers with stimuli-responsive groups, nanoparticles, polymers, and proteins that work as caps and gatekeepers for controlled release of various cargos is just one of the exciting results reported in the literature that highlights MSNs as a promising platform for various biotechnological and biomedical applications. This review focuses on the most recent progresses in the application of MSNs for intracellular drug delivery. The latest research on the pathways of entry into live mammalian and plant cells together with intracellular trafficking are described. One of the main areas of interest in this field is the development of site-specific drug delivery vehicles; the contribution of MSNs toward this topic is also summarized. In addition, the current research progress on the biocompatibility of this material in vitro and in vivo is discussed. Finally, the latest breakthroughs for intracellular controlled drug release using stimuli-responsive mesoporous-silica-based systems are described.

Mesoporous Silica Nanoparticle-Based Double Drug Delivery System for Glucose-Responsive Controlled Release of Insulin and Cyclic AMP

A boronic acid-functionalized mesoporous silica nanoparticle-based drug delivery system (BA-MSN) for glucose-responsive controlled release of both insulin and cyclic adenosine monophosphate (cAMP) was synthesized. Fluorescein isothiocyanate-labeled, gluconic acid-modified insulin (FITC-G-Ins) proteins were immobilized on the exterior surface of BA-MSN and also served as caps to encapsulate cAMP molecules inside the mesopores of BA-MSN. The release of both G-Ins and cAMP was triggered by the introduction of saccharides. The selectivity of FITC-G-Ins release toward a series of carbohydrate triggers was determined to be fructose > glucose > other saccharides. The unique feature of this double-release system is that the decrease of FITC-G-Ins release with cycles can be balanced by the release of cAMP from mesopores of MSN, which is regulated by the gatekeeper effect of FITC-G-Ins. In vitro controlled release of cAMP was studied at two pH conditions (pH 7.4 and 8.5). Furthermore, the cytotoxicity of cAMP-loaded G-Ins-MSN with four different cell lines was investigated by cell viability and proliferation studies. The cellular uptake properties of cAMP-loaded FITC-BA-MSN with and without G-Ins capping were investigated by flow cytometry and fluorescence confocal microscopy. We envision that this glucose-responsive MSN-based double-release system could lead to a new generation of self-regulated insulin-releasing devices.

Mesoporous silica nanoparticles for reducing hemolytic activity towards mammalian red blood cells.

Recent reports on the design of silica-based nanomaterials, such as sol–gel, colloidal, and mesoporous silica nanoparticles (MSNs), have shown promising potential in utilizing these materials for controlled release, drug delivery, and other biotechnological applications. Several studies have demonstrated that the biocompatibility of these silica nanoparticles with a variety of cell types in vitro is fairly high. However, the low in vitro cytotoxicity offers no guarantee on the desired high biocompatibility in vivo. In fact, silica materials with amorphous particle morphology are known to cause the hemolysis of mammalian red blood cells (RBCs). This kind of hemolytic behavior raised serious bio-safety concerns regarding the application of amorphous silica for drug delivery involving intravenous administration and transport. Various explanations for the hemolytic effect have been proposed, including the generation of reactive oxygen species induced by the surface of silica, denaturation of membrane proteins through electrostatic interactions with silicate, and the high affinity of silicate for binding with the tetra-alkyl ammonium groups that are abundant in the membranes of RBCs. While the exact mechanism is still under investigation, most researchers agree that the hemolytic activity of silica is related to surface silanol groups. For example, a recent study by Murashov et al. demonstrated that the hemolytic activity of amorphous silica is proportional to the concentration of surface silanol groups of these solid materials. Given the fact that most, if not all, of the aforementioned silica nanoparticles with defined shapes and sizes also have abundant silanols on their surfaces, it is important to investigate the hemolytic properties of these materials with RBCs for potential intravenous applications. Herein, we describe an investigation of the hemolytic properties of a previously reported MSN material with mammalian

Interaction of Mesoporous Silica Nanoparticles with Human Red Blood Cell Membranes: Size and Surface Effects

The interactions of mesoporous silica nanoparticles (MSNs) of different particle sizes and surface properties with human red blood cell (RBC) membranes were investigated by membrane filtration, flow cytometry, and various microscopic techniques. Small MCM-41-type MSNs (∼100 nm) were found to adsorb to the surface of RBCs without disturbing the membrane or morphology. In contrast, adsorption of large SBA-15-type MSNs (∼600 nm) to RBCs induced a strong local membrane deformation leading to spiculation of RBCs, internalization of the particles, and eventual hemolysis. In addition, the relationship between the degree of MSN surface functionalization and the degree of its interaction with RBC, as well as the effect of RBC-MSN interaction on cellular deformability, were investigated. The results presented here provide a better understanding of the mechanisms of RBC-MSN interaction and the hemolytic activity of MSNs and will assist in the rational design of hemocompatible MSNs for intravenous drug delivery and in vivo imaging.

Mesoporous silica nanoparticles: structural design and applications

The structural properties of mesoporous silica nanoparticles are reviewed. Different strategies for the introduction of functional groups are considered. Based on the architectural features of the material, the functionalization at defined regions of the particles is described, along with the properties emerging from the corresponding site-specific modifications of their chemistry. Many applications derived from the unique architecture and chemistry of these nanostructured composite materials are shown.

Structurally Ordered Mesoporous Carbon Nanoparticles as Transmembrane Delivery Vehicle in Human Cancer Cells

A structurally ordered, CMK-1 type mesoporous carbon nanoparticle (MCN) material was successfully synthesized by using a MCM-48 type mesoporous silica nanoparticle as template. The structure of MCN was analyzed by a series of different techniques, including the scanning and transmission electron microscopy, powder X-ray diffraction, and N2 sorption analysis. To the best of our knowledge, no study has been reported prior to our investigation on the utilization of these structurally ordered mesoporous carbon nanoparticles for the delivery of membrane impermeable chemical agents inside of eukaryotic cells. The cellular uptake efficiency and biocompatibility of MCN with human cervical cancer cells (HeLa) were investigated. Our results show that the inhibitory concentration (IC50) value of MCN is very high (>50 microg/mL per million cells) indicating that MCN is fairly biocompatible in vitro. Also, a membrane impermeable fluorescence dye, Fura-2, was loaded to the mesoporous matrix of MCN. We demonstrated that the MCN material could indeed serve as a transmembrane carrier for delivering Fura-2 through the cell membrane to release these molecules inside of live HeLa cells. We envision that further developments of this MCN material will lead to a new generation of nanodevices for transmembrane delivery and intracellular release applications.

Mesoporous silica nanoparticle based controlled release, drug delivery, and biosensor systems

Recent advancements in controlling the surface properties and particle morphology of the structurally defined mesoporous silica materials with high surface area (>700 m(2) g(-1)) and pore volume (>1 cm(3) g(-1)) have significantly enhanced their biocompatibility. Various methods have been developed for the functionalization of both the internal pore and exterior particle surfaces of these silicates with a tunable pore diameter ranging from 2 to 30 nm and a narrow pore size distribution. Herein, we review the recent research progress on the design of functional mesoporous silica materials for stimuli-responsive controlled release delivery of pharmaceutical drugs, genes, and other chemicals. Furthermore, the recent breakthroughs in utilizing these nanoscale porous materials as sensors for selective detections of various neurotransmitters and biological molecules are summarized.

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery.

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property. Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed. What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices. Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.

Ordered Mesoporous Polymer−Silica Hybrid Nanoparticles as Vehicles for the Intracellular Controlled Release of Macromolecules

A two-dimensional hexagonal ordered mesoporous polymer-silica hybrid nanoparticle (PSN) material was synthesized by polymerization of acrylate monomers on the surface of SBA-15 mesoporous silica nanoparticles. The structure of the PSN material was analyzed using a series of different techniques, including transmission electron microscopy, powder X-ray diffraction, and N(2) sorption analysis. These structurally ordered mesoporous polymer-silica hybrid nanoparticles were used for the controlled release of membrane-impermeable macromolecules inside eukaryotic cells. The cellular uptake efficiency and biocompatibility of PSN with human cervical cancer cells (HeLa) were investigated. Our results show that the inhibitory concentration (IC(50)) of PSN is very high (>100 μg/mL per million cells), while the median effective concentration for the uptake (EC(50)) of PSN is low (EC(50) = 4.4 μg/mL), indicating that PSNs are fairly biocompatible and easily up-taken in vitro. A membrane-impermeable macromolecule, 40 kDa FITC-Dextran, was loaded into the mesopores of PSNs at low pH. We demonstrated that the PSN material could indeed serve as a transmembrane carrier for the controlled release of FITC-Dextran at the pH level inside live HeLa cells. We believe that further developments of this PSN material will lead to a new generation of nanodevices for intracellular controlled delivery applications.