Mesoporous Silica Nanoparticles for Drug Delivery

In recent years, nanomedicine has emerged at the forefront of nanotechnology, generating great expectations in the biomedical field. Researchers are developing novel nanoparticles for both diagnostic applications using imaging technology and treatment purposes through drug delivery technologies. Among all the available nanoparticles, inorganic mesoporous silica nanoparticles are the newcomers to the field, contributing with their unique and superlative properties. A brief overview of the most recent progress in the synthesis of mesoporous silica nanoparticles and their use as drug delivery nanocarriers is provided. The latest trends in this type of nanoparticles and their use in modern medicine are discussed, highlighting the significant impact that this technology might have in the near future.     

Multifunctional Mesoporous Silica Nanoparticles for Cancer‐Targeted and Controlled Drug Delivery

Multifunctional mesoporous silica nanoparticles are developed in order to deliver anticancer drugs to specific cancer cells in a targeted and controlled manner. The nanoparticle surface is functionalized with amino‐β‐cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. Poly(ethylene glycol) polymers, functionalized with an adamantane unit at one end and a folate unit at the other end, are immobilized onto the nanoparticle surface through strong β‐cyclodextrin/adamantane complexation. The non‐cytotoxic nanoparticles containing the folate targeting units are efficiently trapped by folate‐receptor‐rich HeLa cancer cells through receptormmediated endocytosis, while folate‐receptor‐poor human embryonic kidney 293 normal cells show much lower endocytosis towards nanoparticles under the same conditions. The nanoparticles endocytosed by the cancer cells can release loaded doxorubicin into the cells triggered by acidic endosomal pH. After the nanoparticles escape from the endosome and enter into the cytoplasm of cancer cells, the high concentration of glutathione in the cytoplasm can lead to the removal of the β‐cyclodextrin capping rings by cleaving the pre‐installed disulfide bonds, further promoting the release of doxorubicin from the drug carriers. The high drug‐delivery efficacy of the multifunctional nanoparticles is attributed to the co‐operative effects of folate‐mediated targeting and stimuli‐triggered drug release. The present delivery system capable of delivering drugs in a targeted and controlled manner provides a novel platform for the next generation of therapeutics.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Noncovalent Polymer‐Gatekeeper in Mesoporous Silica Nanoparticles as a Targeted Drug Delivery Platform

Selective targeting of tumor cells and release of drug molecules inside the tumor microenvironment can reduce the adverse side effects of traditional chemotherapeutics because of the lower dosages required. This can be achieved by using stimuli‐responsive targeted drug delivery systems. In the present work, a robust and simple one‐pot route is developed to synthesize polymer‐gatekeeper mesoporous silica nanoparticles by noncovalent capping of the pores of drug‐loaded nanocontainers with disulfide cross‐linkable polymers. The method offers very high loading efficiency because chemical modification of the mesoporous nanoparticles is not required; thus, the large empty pore volume of pristine mesoporous silica nanoparticles is entirely available to encapsulate drug molecules. Furthermore, the polymer shell can be easily decorated with a targeting ligand for selective delivery to specific cancer cells by subsequent addition of the thiol‐containing ligand molecule. The drug molecules loaded in the nanocontainers can be released by the degradation of the polymer shell in the intracellular reducing microenvironment, which consequentially induces cell death.     

Bacterial Outer Membrane-Coated Mesoporous Silica Nanoparticles for Targeted Delivery of Antibiotic Rifampicin against Gram-Negative Bacterial Infection In Vivo

The efficacy of conventional antibiotics therapeutics has declined rapidly due to the emerged antibiotic resistance. There is an urgent need to develop novel approaches to address the problem of antibiotic shortage, particularly for Gram-negative bacteria. Herein, a biomimetic nanodelivery system is proposed to enhance the bacterial targeting and uptake of rifampicin (Rif), a traditional antibiotic but not effective against Gram-negative bacteria. The biomimetic nanodelivery system (Rif@MSN@OMV) is composed of outer membrane vesicles (OMVs) isolated from E. coli as shell and rifampicin-loaded mesoporous silica nanoparticles (MSNs) as core. The OMVs greatly improve the uptake of MSNs in E. coli, but not in Gram-positive bacteria S. aureus, owing to the homotypic targeting function of the OMVs. The Rif@MSN@OMV exhibits enhanced antimicrobial activity against E. coli and completely eradicates bacteria at an equivalent rifampicin concentration (4 µg mL⁻¹) while free rifampicin shows weak bactericidal activity. Meanwhile, the Rif@MSN@OMV maintains good biocompatibility both in vitro and in vivo. More importantly, the Rif@MSN@OMV elevates survival rate of infected mice and reduces bacterial load in intraperitoneal fluid and organs. Overall, the OMVs-coated nanodelivery system provides a novel strategy to improve the antimicrobial efficacy of conventional antibiotic or repurpose drugs for treatment of Gram-negative bacterial infections.     

Cancer‐Targeted Monodisperse Mesoporous Silica Nanoparticles as Carrier of Ruthenium Polypyridyl Complexes to Enhance Theranostic Effects

Mesoporous silica nanoparticles (MSNs) have been well‐demonstrated as excellent carriers for anticancer drug delivery. Presented here is a cancer‐targeted MSNs drug delivery system that allows the direct fluorescence monitoring of the cellular uptake and localization of theranostic agents in cancer cells. Specifically, the anticancer action mechanisms of RGD peptide‐functionalized MSNs carrying ruthenium polypyridyl complexes (RuPOP@MSNs) are elucidated in detail. RGD peptide surface decoration significantly enhances the cellular uptake of the nanoparticles through receptor‐mediated endocytosis, and increases the selectivity between cancer and normal cells. RuPOP@MSNs exhibits unprecedented enhanced cytotoxicity toward cancer cells overexpressing integrin receptor, which is significantly higher than that of free RuPOP, through induction of apoptosis. The important contribution of extrinsic pathway to cell apoptosis is confirmed by increase in expression levels of death receptors, activation of caspase‐8 and truncation of Bid. The internalized nanoparticles release free RuPOP into the cytoplasm, where they modulate the phosphorylation of p53, AKT, and MAPKs pathways to promote cell apoptosis. Moreover, the strong autofluorescence of RuPOP permits the direct monitoring of drug delivery, and extends the power of theranostics to subcellular level. Taken together, this study provides an effective strategy for the design and development of cancer‐targeted theranostic agents.     

Dual Bioresponsive Mesoporous Silica Nanocarrier as an “AND” Logic Gate for Targeted Drug Delivery Cancer Cells

Despite the rapid development of drug delivery vehicles that react to a specific biological environment, the complexity of triggering drug release in a particular target area remains an enduring challenge. Here, the engineering of bioresponsive polymer‐mesoporous silica nanoparticles (MSNs) with function akin to an AND logic gate is described. Polycaprolactone (esterase degradable) is immobilized into the core of MSNs while polyacrylic acid (PAA), which is pH responsive, covered the outside of the MSNs to create a PAA‐PCL‐MSNs construct. Fluorescence spectroscopy indicates that the construct releases the payload (doxorubicin, cancer drugs) in the presence of, and only in the presence of, both low pH AND esterase. Confocal microscopy and fluorescence lifetime microscopy (FLIM) demonstrate uptake of the intact construct and subsequent intracellular doxorubicin (DOX) delivery into the nucleus. Further in vitro IC₅₀ studies demonstrate the AND logic gate delivery system results in more than an eightfold efficacy against neuroblastoma (SK‐N‐BE(2)) cells in comparison with normal fibroblasts (MRC‐5). These results demonstrate the utility of MSN‐polymer construct to create an AND gate capable of selectively delivering a drug payload.     

Robust Nanovaccine Based on Polydopamine-Coated Mesoporous Silica Nanoparticles for Effective Photothermal-Immunotherapy Against Melanoma

Nanoparticle-based combination therapy strategy of photothermal therapy (PTT) and immunotherapy is an attractive cancer treatment for ablating tumors and eliciting host immune responses. However, this strategy is often hampered by tedious treatment process and limited immune response, and usually needs to be combined with checkpoint blockades to enhance therapeutic effect. Herein, a nanoplatform with mesoporous silica nanoparticles (MSNs) as a vector, which integrated photothermal agent polydopamine (PDA), model antigen ovalbumin (OVA), and antigen release promoter ammonium bicarbonate (ABC) in an easy way for melanoma PTT-immunotherapy is designed. The formulated MSNs-ABC@PDA-OVA nanovaccine exhibits excellent photothermal properties and effectively eliminates primary tumors. Under laser irradiation, the MSNs-ABC@PDA-OVA nanovaccine realizes rapid antigen release and endosome escape, enhances dendritic cells activation and maturation, facilitates migration to tumor-draining lymph nodes, and induces robust antitumor immune responses. Impressively, single injection of MSNs-ABC@PDA-OVA combines with single round of PTT successfully eradicates melanoma tumors with a cure rate of 75% and generates strong immunological memory to inhibit tumor recurrence and lung metastasis. Hence, the research offers a simple and promising strategy of synergistic PTT-immunotherapy to effectively treat cancer.     

Mesoporous Silica Nanoparticles: Selective Surface Functionalization for Optimal Relaxometric and Drug Loading Performances

Mesoporous silica nanoparticles (MSNs) have emerged as promising biomaterials for drug delivery and cell tracking applications, for which MRI is the medical imaging modality of choice. In this contribution, MRI contrast agents (DTPA‐Gd) and polyethylene glycol (PEG) are grafted selectively at the surface of MSNs, in order to achieve optimal relaxometric and drug loading performances. In fact, DTPA and PEG grafting procedures reported until now, have resulted in significant pore obstruction, which is detrimental to the drug delivery function of MSNs. This usually induces a dramatic decrease in surface area and pore volume, thus limiting drug loading capacity. Therefore, these molecules must be selectively grafted at the outer surface of MSNs. In this study, 3D pore network MSNs (MCM‐48‐type) are synthesized and functionalized with a straightforward and efficient grafting procedure in which DTPA and PEG are selectively grafted at the outer surface of MSNs. No pore blocking is observed, and more than 90% of surface area, pore volume and pore diameter are retained. The thus‐treated particles are colloidally stable in SBF and cell culture media, they are not cytotoxic and they have high drug loading capacity. Upon labeling with Gd, the nanoparticle suspensions have strong relaxometric properties (r₂/r₁ = 1.47, r₁ = 23.97 mM^?1 s^?1), which confers a remarkable positive contrast enhancement potential to the compound. The particles could serve as efficient drug carriers, as demonstrated with a model of daunorubicin submitted to physiological conditions. The selective nanoparticle surface grafting procedures described in the present article represent a significant advance in the design of high colloidal stability silica‐based vectors with high drug loading capacity, which could provide novel theranostic nanocompounds.     

Synthesis and Characterization of Positive‐Charge Functionalized Mesoporous Silica Nanoparticles for Oral Drug Delivery of an Anti‐Inflammatory Drug

We synthesized mesoporous silica nanoparticles (MSN) with different densities of surface positive charges. The positive surface charge was generated by incorporating trimethylammonium (TA) functional groups into the framework of MSN (MSN–TA) via direct co‐condensation of a TA‐silane and tetraethoxysilane (TEOS) in the presence of a base as a catalyst. These MSN–TA samples have well‐defined hexagonal structures with an average particle diameter of 100 nm, pore size of 2.7 nm, and surface area of about 1000 m² g^?1. Anionic drug molecules, Orange II (a fluorescent tracing molecule), and sulfasalazine (an anti‐inflammatory prodrug used for bowel disease), were effectively loaded into these MSN–TA samples and remained inside of the MSN–TA under acidic environment (pH 2–5). The amounts of loading of both Orange II and sulfasalazine were increased with increasing positive charge densities resulting from the increasing number of TA groups. When these drug‐loaded MSN–TA nanoparticles were placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the MSN–TA was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules. MSN–TA as a nanovehicle for pH‐dependent loading and controllable release of anionic drug molecules can be used as an oral delivery drug systems targeting at intestine. These drugs can be remained trapped in the nanovehicle when passing through the stomach's acidic environment and be released in intestine where the environmental pH is close to neutral.     

Ultrabright Fluorescent Silica Mesoporous Silica Nanoparticles: Control of Particle Size and Dye Loading

The synthesis of ultrabright fluorescent mesoporous silica nanoparticles (UFSNPs) of various sizes loaded with different amounts of fluorescent dye (Rhodamine 6G) is reported here. The dye is physically entrapped inside the nanochannels of the silica matrix created during templated sol–gel self assembly. Due to the specific nanoenvironment, the fluorescence of the encapsulated dye molecules remains unquenched up to very high concentrations, which results in relatively high fluorescence. The particle size (ranging from 20–50 nm) and dye loading (0.8–9.3 mg dye per g particles) are controlled by the timing of the synthesis and the concentration of several organotriethoxysilanes, which are coprecursors of silica. The quantum yields of the encapsulated dye range from 0.65 to 1.0. The relative brightness of a single particle is equivalent to the fluorescence of 30–770 free nondimerized R6G dye molecules in water, or to that of 1.5–39 CdSe/ZnS quantum dots. Despite the presence of some hydrophobic groups on the particles' surfaces, colloidal suspensions of the particles are relatively stable (as monitored for 120 days).     

Metal Species–Encapsulated Mesoporous Silica Nanoparticles: Current Advancements and Latest Breakthroughs

Despite their advantageous morphological attributes and attractive physicochemical properties, mesoporous silica nanoparticles (MSNs) are merely supported as carriers or vectors for a reason. Incorporating various metal species in the confined nanospaces of MSNs (M‐MSNs) significantly enriches their mesoporous architecture and diverse functionalities, bringing exciting potentials to this burgeoning field of research. These incorporated guest species offer enormous benefits to the MSN hosts concerning the reduction of their eventual size and the enhancement of their performance and stability, among other benefits. Substantially, the guest species act through contributing to reduced aggregation, augmented durability, ease of long‐term storage, and reduced toxicity, attributes that are of particular interest in diverse fields of biomedicine. In this review, the first aim is to discuss the current advancements and latest breakthroughs in the fabrication of M‐MSNs, emphasizing the pros and cons, the confinement of various metal species in the nanospaces of MSNs, and various factors influencing the encapsulation of metal species in MSNs. Further, an emphasis on potential applications of M‐MSNs in various fields, including in adsorption, catalysis, photoluminescence, and biomedicine, among others, along with a set of examples is provided. Finally, the advances in M‐MSNs with perspectives are summarized.     

A Photon‐Fueled Gate‐Like Delivery System Using i‐Motif DNA Functionalized Mesoporous Silica Nanoparticles

A novel photon‐fueled gate‐like mesoporous silica nanoparticles (MSN)‐based delivery system is reported. In this system, the malachite green carbinol base (MGCB) is immobilized on the nanochannel wall of MSN as a light‐induced hydroxide ion emitter and i‐motif DNA is grafted on the surface of MSN as a cap. Photoirradiation with 365 nm wavelength UV light makes MGCB molecules dissociate into malachite green (MG) cations and OH^? ions, which induce the i‐motif DNA to unfold into the single‐stranded form due to the increase of the pH in the solution. Therefore, the pores are uncapped and the entrapped guest molecules are released. After the light is turned off, the MG cations recombine with the OH^? ions and return to the MGCB forms. The pH value thus decreases and the single‐stranded DNA switches back to i‐motif structure to cap the pore again. Because of the photon‐fueled MGCB‐dependent DNA conformation changes, the i‐motif DNA‐gated switch can be easily operated by turning the light on or off. Importantly, the opening/closing protocol is highly reversible and a partial cargo release can be easily achieved at will. This proof‐of‐concept may promote the application of DNA in the controlled release and can also provide a way to design various photon‐fueled controlled‐release systems using a combination of some photoirradiated pH‐jump systems and other kinds of pH‐sensitive linkers.     

Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy

Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.     

Use of Ferritin Capped Mesoporous Silica Nanoparticles for Redox and pH Triggered Drug Release In Vitro and In Vivo

Mesoporous silica nanoparticles (MSNs) functionalized with redox‐sensitive or pH‐sensitive nanovalves for doxorubicin delivery and release by using recombinant human H chain ferritin (HFn) as a cap have been designed and fabricated. In both cases, transmission electron microscope observatory, dynamic light scattering change, Fourier transform infrared spectra examination, thermogravimetric analysis show that HFn can be chemically bonded to MSNs while retaining its ability to target transferrin receptor 1 (TfR1). Cargo loading and release studies demonstrate that HFn is an efficient capping agent, blocking the pores of MSN preventing cargo molecules from diffusing out, and is responsive to redox stimuli or pH changes. More importantly, HFn can not only cap the MSNs, but also enables targeted cargo delivery to malignant cells by binding to the TfR1 that has been overexpressed in various tumors, which can be reflected by the cell viability and fluorescence microscope analysis results comparing with cyclodextrin as the capping agent and TfR1 blocking assay. The in vivo study reveals the excellent efficacy of doxorubicin loaded and HFn capped MSNs on suppression of tumor growth. The new developed drug delivery system features mutually benefit and mutually support, providing strategy for achieving specific‐site therapeutics delivery systems.     

Mesoporous Silica Nanoparticles for Drug Delivery and Biosensing Applications

Recent advancements in morphology control and surface functionalization of mesoporous silica nanoparticles (MSNs) have enhanced the biocompatibility of these materials with high surface areas and pore volumes. Several recent reports have demonstrated that the MSNs can be efficiently internalized by animal and plant cells. The functionalization of MSNs with organic moieties or other nanostructures brings controlled release and molecular recognition capabilities to these mesoporous materials for drug/gene delivery and sensing applications, respectively. Herein, we review recent research progress on the design of functional MSN materials with various mechanisms of controlled release, along with the ability to achieve zero release in the absence of stimuli, and the introduction of new characteristics to enable the use of nonselective molecules as screens for the construction of highly selective sensor systems.     

Multifunctional Mesoporous Nanoellipsoids for Biological Bimodal Imaging and Magnetically Targeted Delivery of Anticancer Drugs

A general polyelectrolyte‐mediated self‐assembly technique is adopted to prepare multifunctional mesoporous nanostructures as an effective biological bimodal imaging probe and magnetically targeted anticancer drug (doxorubicin) delivery systems (DDSs). A positively charged polyelectrolyte (PAH) and negatively charged fluorescent quantum dots (QDs) are successfully assembled onto the surface of ellipsoidal Fe₃O₄@SiO₂@mSiO₂ composite nanostructures to combine the merits of tunable fluorescent/magnetic properties, mesoporous nanostructures for drug loading, and the uniform ellipsoidal morphology for enhanced uptake by cancer cells. The resultant nanoellipsoids are homogeneously coated with four layers of PAH/QDs, with an additional PAH layer to make the ellipsoidal surface positively charged. This acts to enhance cellular uptake, which is driven by electrostatic interactions between the positive nanoparticle surface and the negative cell surface. The high biocompatibility of the achieved multifunctional nanoellipsoids is demonstrated by a cell‐cytotoxicity assay, hemolyticity against human red blood cells, and coagulation evaluation of fresh human blood plasma after exposure to the nanoparticles. Moreover, confocal microscopy and bio‐TEM observations show that the cell uptake of nanocarriers is dose‐dependent, and the nanoparticles accumulate mostly in the cytoplasm. The excellent capability of the nanocarriers as contrast agents for MRI is demonstrated by the relatively high r₂ value (143 mM^?1s^?1) and preliminary in vivo characterization. More importantly, the doxorubicin‐loaded DDSs show higher cytotoxicity than the free doxorubicin drug as contributed by the intracellular release pathway of doxorubicin from the DDSs, indicating the potential application of the obtained multifunctional mesoporous nanoellipsoids as highly effective bimodal imaging probes and DDSs for cancer diagnosis and chemotherapy, simultaneously.