Victor S.-Y. Lin

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 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

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.

Tuning the cellular uptake and cytotoxicity properties of oligonucleotide intercalator-functionalized mesoporous silica nanoparticles with human cervical cancer cells HeLa

A series of organically functionalized, MCM-41 type mesoporous silica nanoparticle materials (PAP-LP-MSN and AP-PAP-MSN) with different pore sizes (5.7 nm and 2.5 nm, respectively) were synthesized and characterized. We selectively decorated the exterior particle surface of PAP-LP-MSN and the interior pore surface of AP-PAP-MSN with an oligonucleotide intercalating phenanthridinium functionality. While phenanthridinium itself is a cell membrane impermeable molecule, we demonstrated that both phenanthridinium-immobilized PAP-LP-MSN and AP-PAP-MSN materials could indeed be internalized by live human cervical cancer cells (HeLa). We discovered that the PAP-LP-MSN nanoparticles with the phenanthridium groups located on the exterior surface were able to bind to cytoplasmic oligonucleotides, such as messenger RNAs, of HeLa cells resulting in severe cell growth inhibition. In contrast, the cytotoxicity of AP-PAP-MSN, where the same oligonucleotide intercalating molecules were anchored inside the pores, was significantly lowered upon the endocytosis by HeLa cells. We envision that this approach of combining the selective functionalization of the two different surfaces (exterior particle and interior pore surfaces) with morphology control of mesoporous silica nanoparticles would lead to a new generation of nanodevices with tunable biocompatibility and cell membrane trafficking properties for many biomedical applications.

Exocytosis of Mesoporous Silica Nanoparticles from Mammalian Cells: From Asymmetric Cell-to-Cell Transfer to Protein Harvesting

Mesoporous silica nanoparticles (MSNs) have attracted considerable interest as vehicles for drug delivery because of their capacity to encapsulate large amounts of bioactive species and the ease with which their surface can be chemically modifi ed. [ 1 , 2 ] The versatile chemistry of MSNs has enabled their functionalization with several groups to render a variety of gated nanodevices, capable of controlling the loading and release of guest molecules in a stimuli-responsive fashion. [ 3–17 ]

Surfactant-assisted controlled release of hydrophobic drugs using anionic surfactant templated mesoporous silica nanoparticles

A series of mesoporous silica nanoparticles (MSNs) were synthesized using the co-structure directing method. A non-cytotoxic anionic surfactant, undec-1-en-11-yltetra(ethylene glycol) phosphate monoester surfactant (PMES), was used as a structure directing agent (SDA) together with aminopropyltrimethoxysilane that functioned as a co-structure directing agent (CSDA). The morphology and mesoporous structure of these materials were tuned by changing the molar ratio of CSDA and SDA. These mesoporous nanomaterials containing PMES inside the pores showed excellent biocompatibility in vitro. The cellular internalization and endosome escape of PMES-MSNs in cervical cancer cells (HeLa) was demonstrated by flow cytometry and confocal microscopy, respectively. The PMES-MSNs were used as drug delivery carriers for resveratrol, a low water solubility drug, by taking advantage of the hydrophobic environment created by the PMES micelle inside the pores. This surfactant-assisted delivery strategy was tested under physiological conditions showing an increase of the drug loading compared to the material without surfactant and steady release of resveratrol. Finally, the therapeutic properties of resveratrol-loaded PMES-MSNs were evaluated in vitro using HeLa and Chinese hamster ovarian cells. We envision that this surfactant-assisted drug delivery method using MSNs as nanovehicles would lead to a new generation of carrier materials for intracellular delivery of a variety of hydrophobic therapeutic agents.

One-pot reaction cascades catalyzed by base- and acid-functionalized mesoporous silica nanoparticles

Mesoporous silica nanoparticles (MSNs) containing base (primary amine) and sulfonic acid inside the MCM-41 type porous channels were successfully used as compatible catalysts for one-pot reaction cascades.

Ligand Conformation Dictates Membrane and Endosomal Trafficking of Arginine‐Glycine‐Aspartate (RGD)‐Functionalized Mesoporous Silica Nanoparticles

Recent breakthrough research on mesoporous silica nanoparticle (MSN) materials has illustrated their significant potential in biological applications due to their excellent drug delivery and endocytotic behavior. We set out to determine if MSN, covalently functionalized with conformation specific bioactive molecules (either linear or cyclic RGD ligands), behave towards mammalian cells in a similar manner as the free ligands. We discovered that RGD immobilized on the MSN surface did not influence the integrity of the porous matrix and improved the endocytosis efficiency of the MSN materials. Through competition experiments with free RGD ligands, we also discovered a conformation specific receptor-integrin association. The interaction between RGD immobilized on the MSN surface and integrins plays an important role in endosome trafficking, specifically dictating the kinetics of endosomal escape. Thus, covalent functionalization of biomolecules on MSN assists in the design of a system for controlling the interface with cancer cells.

Parameters affecting the efficient delivery of mesoporous silica nanoparticle materials and gold nanorods into plant tissues by the biolistic method.

Applying nanotechnology to plant science requires efficient systems for the delivery of nanoparticles (NPs) to plant cells and tissues. The presence of a cell wall in plant cells makes it challenging to extend the NP delivery methods available for animal research. In this work, research is presented which establishes an efficient NP delivery system for plant tissues using the biolistic method. It is shown that the biolistic delivery of mesoporous silica nanoparticle (MSN) materials can be improved by increasing the density of MSNs through gold plating. Additionally, a DNA-coating protocol is used based on calcium chloride and spermidine for MSN and gold nanorods to enhance the NP-mediated DNA delivery. Furthermore, the drastic improvement of NP delivery is demonstrated when the particles are combined with 0.6 μm gold particles during bombardment. The methodology described provides a system for the efficient delivery of NPs into plant cells using the biolistic method.