Mesoporous Silica-based Nanoparticles Research Articles

A shift in focus towards precision oncology, driven by revolutionary nanodiagnostics; revealing mysterious pathways in colorectal carcinogenesis.

Multiple molecular mechanisms contribute to the development of colorectal cancer (CRC), with chromosomal instability (CIN) playing a significant role. CRC is influenced by mutations in several important genes, including APC, TP53, KRAS, PIK3CA, BRAF, and SMYD4. The three molecular subtypes of this disease are CIN, MSI-H, and CIMP (CpG-island phenotype). p53 dysfunction and aberrant Wnt signalling are common characteristics of CRC carcinogenesis. Despite advances in conventional therapy, metastatic CRC remains difficult to treat due to toxicity and resistance. Theranostics for cancer could significantly benefit from nanotechnology, as it would enable more targeted, individualised care with fewer side effects. Utilising functionalized nanoparticles has enabled MRI-guided gene therapy, magnetic hyperthermia, chemotherapy, immunotherapy, and photothermal/photodynamic therapy, thereby radically modifying the way cancer is treated. Active targeting using ligands or peptides on nanoparticles improves the delivery of drugs to cancer cells. Nanostructures such as drug peptide conjugates, chitosan nanoparticles, gold nanoparticles, carbon nanotubes, mesoporous silica-based nanoparticles, silver nanoparticles, hybrid lipid-polymer nanoparticles, iron oxide nanoparticles, and quantum dots may enable targeted drug delivery and enhanced therapeutic efficacy against CRC. Nanomedicines are presently being evaluated in clinical trials for the treatment of colorectal cancer, with the promise of more effective and individualised therapies. This article examines current nanomedicine patents for CRC, including the work of Delta-Fly, Merrimack, and Pfenning, Meaning & Partner, among others. In terms of future nanomedicine research and development, ligand production, particle size, and clearance are crucial factors. Lastly, the numerous nanostructures utilized in nanomedicine for targeted drug administration and diagnostics indicate optimistic prospects for enhancing CRC treatment. The successes of nanomedicine research and development for existing colon cancer treatments are also highlighted in this review.

Inside Front Cover: Mesoporous silica/organosilica nanoparticles for cancer immunotherapy (EXP2 3/2023)

Mesoporous silica-based nanoparticles, including silica, organosilica and metal doped silica and organosilica nanoparticles, have widespread applications in biomedical applications. This review summarizes the applications of mesoporous silica-based nanoparticles in the field of cancer immunotherapy. Strategies to regulate the tumour microenvironment for immune activation are presented by highlighting the structural and compositional attributes of the silica-based nanoparticles.

Engineered mesoporous silica-based nanoparticles as smart chemotherapy nanodevice for bortezomib administration

Engineered mesoporous silica-based nanostructures for selective and pH-sensitive release of the anticancer drug bortezomib. The developed “smart chemotherapy” showed higher efficacy in vivo compared to traditional free bortezomib administration.

Mesoporous Silica-Based Nanoparticles as Non-Viral Gene Delivery Platform for Treating Retinitis Pigmentosa.

Background: Gene therapy is a therapeutic possibility for retinitis pigmentosa (RP), in which therapeutic transgenes are currently delivered to the retina by adeno-associated viral vectors (AAVs). Although their safety and efficacy have been demonstrated in both clinical and preclinical settings, AAVs present some technical handicaps, such as limited cargo capacity and possible immunogenicity in repetitive doses. The development of alternative, non-viral delivery platforms like nanoparticles is of great interest to extend the application of gene therapy for RP. Methods: Amino-functionalized mesoporous silica-based nanoparticles (N-MSiNPs) were synthesized, physico-chemically characterized, and evaluated as gene delivery systems for human cells in vitro and for retinal cells in vivo. Transgene expression was evaluated by WB and immunofluorescence. The safety evaluation of mice subjected to subretinal injection was assessed by ophthalmological tests (electroretinogram, funduscopy, tomography, and optokinetic test). Results: N-MSiNPs delivered transgenes to human cells in vitro and to retinal cells in vivo. No adverse effects were detected for the integrity of the retinal tissue or the visual function of treated eyes. N-MSiNPs were able to deliver a therapeutic transgene candidate for RP, PRPF31, both in vitro and in vivo. Conclusions: N-MSiNPs are safe for retinal delivery and thus a potential alternative to viral vectors.

Chlorogenic Acid-Loaded Mesoporous Silica Nanoparticles Modified with Hexa-Histidine Peptides Reduce Skin Allergies by Capturing Nickel

Nickel-induced contact dermatitis is a severe allergic reaction to objects or environments that contain nickel. Many nanomaterials have been developed to reduce skin allergies by capturing nickel, but few agents are effective and safe. In this work, mesoporous silica nanoparticles (MSN) were synthesized and decorated with hexa-histidine peptides (denoted as MSN-His6), making it a strong nickel chelator. Subsequently, a dietary polyphenol, chlorogenic acid, was loaded into the mesopores of MSN (denoted as MSN-His6@CGA), realizing the potential of its anti-inflammatory properties. In vitro and in vivo experiments revealed that the synthesized MSN-His6@CGA nanoparticles exhibited more stable and stronger chelation, better biocompatibility, and ideal allergy-relieving ability, whether for environmental metal contamination or for allergic contact dermatitis caused by prolonged nickel exposure. Thus, the application of mesoporous silica-based nanoparticles may represent an ideal approach to alleviate skin allergies by capturing nickel, which would benefit people who suffer from metal-induced contact dermatitis.

Egg-yolk core-shell mesoporous silica nanoparticles for high doxorubicin loading and delivery to prostate cancer cells.

Mesoporous silica-based nanoparticles (MSNs) have gained rapid interest as a drug delivery system (DDS) and demonstrated their versatility in delivering drugs for the treatment of various cancers. However, the drug loading efficiency of MSNs is low and is usually improved by improving textural properties through complicated synthesis methods or by post synthesis modification of the surface that can result in the loss of surface area and modify its drug release properties. In this study, we report a direct single-step synthesis of MSNs with a unique egg-yolk core-shell morphology, large pore volume and a hydrophilic surface, decorated with nitrogen rich surface functionalities for increasing its drug loading capacity. This combination of excellent textural properties and surface functionalisation was achieved by a simple soft templating method using dual surfactants and the silica sources assisted by employing either triethylamine (TEA) or triethanolamine (TEO) as the hydrolysis agent. The morphology and well-ordered mesoporous structure can simply be tuned by changing the pH of the synthesis medium that affects the self-assembly mechanism of the micelles. HRTEM image of samples clearly revealed an egg-yolk core-shell morphology with a thin mesoporous silica shell. The optimised MSN samples synthesized at a pH of 11 using either TEA or TEO depicted a higher doxorubicin (Dox) loading capacity of 425 μg mg-1 and 481 μg mg-1 respectively, as compared to only 347 μg mg-1 for MSN samples due to the uniform distribution of nitrogen functionalities. The anticancer activity of Dox loaded MSNs evaluated in two different prostate cancer cell lines (PC-3 and LNCaP) showed a higher cytotoxicity of the drug loaded on optimised MSN samples as compared to pristine MSNs without affecting the cellular uptake of the particles. These results suggest that the unique single-step synthesis and functionalisation method resulted in successfully achieving higher drug loading in egg-yolk core-shell nitrogen functionalised MSNs and could be implemented as an effective carrier of chemotherapeutic drugs.

Targeting Colon Cancer Cells with Enzyme-Triggered Casein-Gated Release of Cargo from Mesoporous Silica-Based Nanoparticles.

Colorectal cancer (CRC) is one of the most widely diagnosed cancers worldwide. Despite notable improvements in therapeutic strategies available to CRC patients, late stages of CRC have a higher incidence rate of drug resistance, which is associated with a higher mortality rate. The development of therapeutic strategies that use nanoparticles as a drug delivery system has become one of the most promising potential approaches for cancer therapy. Previous studies have shown that a natural plant alkaloid, veratridine (VTD), suppresses colon cancer cell migration and invasion, two essential factors in tumor metastasis, through activation of the gene that encodes the tumor-suppressor protein UBXN2A. The goal of this study is to develop a nanoassembly to selectively deliver VTD to cancer cells and release it on demand while leaving normal cells intact. We packaged the targeted therapy anticancer molecule VTD inside mesoporous silica nanoparticles (MSNs) impermeable to the blood-brain barrier (BBB) and with selective affinity to CRC cells and sealed the VTD-loaded nanoparticles with an enzymatically cleavable protein. The particles will deliver and release VTD only at the targeted colorectal tumor sites. Since the enzyme MMP-7 protease is dominantly secreted by CRC cells, the release triggered by the enzymes will increase VTD concentration at tumor cells, enhancing the efficiency of the new therapy. We have proven the selective affinity of two types of VTD-carrying particles to CRC cells and enzyme- or acid-triggered VTD release. Negatively surface-charged MSNs showed significant affinity toward positively charged cancer cells but not negatively charged normal fibroblast colon cells, making VTD-MSNs a promising anticancer drug with minimal side effects.

Synthesis and Characterization of Mesoporous Mg- and Sr-Doped Nanoparticles for Moxifloxacin Drug Delivery in Promising Tissue Engineering Applications.

Mesoporous silica-based nanoparticles (MSNs) are considered promising drug carriers because of their ordered pore structure, which permits high drug loading and release capacity. The dissolution of Si and Ca from MSNs can trigger osteogenic differentiation of stem cells towards extracellular matrix calcification, while Mg and Sr constitute key elements of bone biology and metabolism. The aim of this study was the synthesis and characterization of sol–gel-derived MSNs co-doped with Ca, Mg and Sr. Their physico-chemical properties were investigated by X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray fluorescence spectroscopy (XRF), Brunauer Emmett Teller and Brunauer Joyner Halenda (BET/BJH), dynamic light scattering (DLS) and ζ-potential measurements. Moxifloxacin loading and release profiles were assessed with high performance liquid chromatography (HPLC) cell viability on human periodontal ligament fibroblasts and their hemolytic activity in contact with human red blood cells (RBCs) at various concentrations were also investigated. Doped MSNs generally retained their textural characteristics, while different compositions affected particle size, hemolytic activity and moxifloxacin loading/release profiles. All co-doped MSNs revealed the formation of hydroxycarbonate apatite on their surface after immersion in simulated body fluid (SBF) and promoted mitochondrial activity and cell proliferation.

PH-sensitive and bubble-generating mesoporous silica-based nanoparticles for enhanced tumor combination therapy

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH4HCO3; abc) and chemotherapeutic agent doxorubicin (DOX) were loaded into the pores of mesoporous silica. Indocyanine green (ICG) as a photothermal and photodynamic agent was loaded onto the polydopamine (PDA) layer surface. The synthesized nanoparticles displayed a narrow polydispersity (PDI) and small particle size as characterized through dynamic light scattering-autosizer analysis. The nanoparticles also showed high targeting efficacy through RGD modification as indicated by cellular uptake and animal studies. DOX release analysis confirmed that the nanoparticles were pH-dependent and that NH4HCO3 accelerated drug release. At the same time, the nanoparticles had obvious photothermal and photodynamic effects performed by ICG which restrained tumor growth remarkably. In summary, the multifunctional nanoparticles presented a promising system for combination therapy.

Mesoporous Silica-Based Nanoparticles in Pharmaceutical Sciences: A Mini-Review

The sustained and comprehensive need in the field of materials having immense thermal, chemical, and mechanical stability lead to the evolution of mesoporous silica nanoparticles (MSNs). Due to higher surface area and ridged tuneable particular size, silica-based mesoporous (2-50nm) drug delivery system recently becomes a prime orb for loading different guest molecules such as peptides, proteins, anticancer drugs. The most common type of mesoporous nanoparticles is MCM-41 and SBA-15. MSMs has a wide range of applications in drug delivery, imaging, and catalysis. It was in the 1970’s, when the first patent was field related to MSMs, however during 1990, the full-fledged research started for MSMs. During that era, Mobil Corporation Laboratories, Japan started synthesizing of MSMs. Yet, the University of California also pioneered in MSMs synthesis, as they claimed to prepare 4.6-30 nm MSMs with a hexagonal array of pores; they further named it as SBA-15. MSMs has huge application in drug delivery system. Because of its larger surface area of the pores, the cytotoxin or drug can be filed within the pores like a Trojan Horse. Within the intercellular environment, by the endocytosis process, the small particles will be engulfed by biological cell membranes depending on what ligands attached within MSMs i.e., loaded RNA, loaded DNA, surface protein, PEG, and monoclonal antibody. Surprisingly, advanced research on MSMs concluded that cancerous cells have the tendencies to take MCM-41 than the healthy cells of the host; giving scientists a new hope that MCM-41 will one day be used commercially to treat a certain type of cancers. Modern research also shows that for the poorly water-soluble drug, SBA-15, TUD-1, HMM-33 and FSM-16 of MSMs has tremendous potential to improve in-vitro dissolution profiling i.e., upon loading of itraconazole (a poorly water-soluble drug) within SBA-15, it can able to stimulate GI fluid and facilitate transepithelial intestinal transport which ultimately results in higher drug absorption. In this mini-review, we attempted to discuss MSNs synthesis methods, morphology, preparations, mechanisms and recent research in the MSNs Drug delivery system. Thus, we concluded that more in vivo biocompatibility studies, biodistribution studies, toxicity studies, and clinical research is the fundamental prerequisite for further advancement in mesoporous silica-based nanoparticles (MSNs).

Studies on the Exposure of Gadolinium Containing Nanoparticles with Monochromatic X-rays Drive Advances in Radiation Therapy

While conventional radiation therapy uses white X-rays that consist of a mixture of X-ray waves with various energy levels, a monochromatic X-ray (monoenergetic X-ray) has a single energy level. Irradiation of high-Z elements such as gold, silver or gadolinium with a synchrotron-generated monochromatic X-rays with the energy at or higher than their K-edge energy causes a photoelectric effect that includes release of the Auger electrons that induce DNA damage—leading to cell killing. Delivery of high-Z elements into cancer cells and tumor mass can be facilitated by the use of nanoparticles. Various types of nanoparticles containing high-Z elements have been developed. A recent addition to this growing list of nanoparticles is mesoporous silica-based nanoparticles (MSNs) containing gadolinium (Gd–MSN). The ability of Gd–MSN to inhibit tumor growth was demonstrated by evaluating effects of irradiating tumor spheroids with a precisely tuned monochromatic X-ray.

Strategies to Regulate the Degradability of Mesoporous Silica-based Nanoparticles for Biomedical Applications

Cancer is the second major threat to human health, and more effective cancer therapy strategies are imperative. With the development of nanotechnology, mesoporous silica-based nanoparticles (MSNs) have seen unprecedented development in cancer treatment, such as drug delivery, bioimaging and biosensing. They have received extensive attention because of their easy preparation, adjustable morphology, homogeneous pore structure, high surface areas and good biocompatibility. However, cumulative toxicity for organism caused by the low degradability of MSNs heavily hinders their translation from bench to beside. Enhancing the degradability of MSNs has provided an effective solution to solve this problem. This review aims at summarizing the effective strategies utilized to regulate the degradability of MSNs during the last few years, giving a complete overview on the recent progress and remaining challenges of degradable MSNs.

Silica/gold nanoplatform combined with a thermosensitive gel for imaging-guided interventional therapy in PDX of pancreatic cancer

Imaging-guided interventional therapy is a promising means of minimally invasive and targeted drug delivery for patients with advanced pancreatic cancer. The effectiveness of the method depends on clear imaging and complete removal of cancer cells, especially peripheral infiltration and distant metastasis, to prevent recurrence. We synthesized hollow mesoporous silica-based nanoparticles, Gem-PFH-Au star-HMS-IGF1, with gemcitabine (Gem) and perfluorohexane (PFH) encapsulated internally, gold nanostars (Au NSs) and insulin-like growth factor-1 (IGF1) modified outwardly, to enhance multimode ultrasound (US)/computed tomography (CT)/photoacoustic (PA)/thermal imaging, guide photothermal therapy, and evaluate the effect in real time. We also prepared a type of thermosensitive gel that solidified at body temperature to facilitate the controlled release of Gem and achieve a single-administration interventional therapy. A patient-derived xenograft (PDX) mouse model was established in this study. The PDX was precisely ablated by photothermal therapy under the guidance of US/CT/PA imaging, and the residual pancreatic cancer cells were completely inhibited by Gem to prevent recurrence. This strategy ingeniously simulated the approach of surgical resection and postoperative chemotherapy in clinical procedures to treat malignancy and paves the way for interventional therapy.

Large Pore Mesoporous Silica and Organosilica Nanoparticles for Pepstatin A Delivery in Breast Cancer Cells.

(1) Background: Nanomedicine has recently emerged as a new area of research, particularly to fight cancer. In this field, we were interested in the vectorization of pepstatin A, a peptide which does not cross cell membranes, but which is a potent inhibitor of cathepsin D, an aspartic protease particularly overexpressed in breast cancer. (2) Methods: We studied two kinds of nanoparticles. For pepstatin A delivery, mesoporous silica nanoparticles with large pores (LPMSNs) and hollow organosilica nanoparticles (HOSNPs) obtained through the sol–gel procedure were used. The nanoparticles were loaded with pepstatin A, and then the nanoparticles were incubated with cancer cells. (3) Results: LPMSNs were monodisperse with 100 nm diameter. HOSNPs were more polydisperse with diameters below 100 nm. Good loading capacities were obtained for both types of nanoparticles. The nanoparticles were endocytosed in cancer cells, and HOSNPs led to the best results for cancer cell killing. (4) Conclusions: Mesoporous silica-based nanoparticles with large pores or cavities are promising for nanomedicine applications with peptides.

Nanoparticle-based targeted cancer strategies for non-invasive prostate cancer intervention.

Prostate cancer is screened by testing circulating levels of the prostate-specific antigen (PSA) biomarker, monitoring changes over time, or a digital rectal exam. Abnormal results often lead to prostate biopsy. Prostate cancer positive patients are stratified into very low-risk, low-risk, intermediate-risk, and high-risk, based on clinical classification parameters, to assess therapy options. However, there remains a gap in our knowledge and a compelling need for improved risk stratification to inform clinical decisions and reduce both over-diagnosis and over-treatment. Further, current strategies for clinical intervention do not distinguish clinically aggressive prostate cancer from indolent disease. This mini-review takes advantage of a large number of functionally characterized microRNAs (miRNA), epigenetic regulators of prostate cancer, that define prostate cancer cell activity, tumor stage, and circulate as biomarkers to monitor disease progression. Nanoparticles provide an effective platform for targeted delivery of miRNA inhibitors or mimics specifically to prostate tumor cells to inhibit cancer progression. Several prostate-specific transmembrane proteins expressed at elevated levels in prostate tumors are under investigation for targeting therapeutic agents to prostate cancer cells. Given that prostate cancer progresses slowly, circulating miRNAs can be monitored to identify tumor progression in indolent disease, allowing identification of miRNAs for nanoparticle intervention before the crucial point of transition to aggressive disease. Here, we describe clinically significant and non-invasive intervention nanoparticle strategies being used in clinical trials for drug and nucleic acid delivery. The advantages of mesoporous silica-based nanoparticles and a number of candidate miRNAs for inhibition of prostate cancer are discussed.

Hyperbranched Polyglycerol-Induced Porous Silica Nanoparticles as Drug Carriers for Cancer Therapy In Vitro and In Vivo.

Mesoporous silica‐based nanoparticles are generally accepted as a potential platform for drug loading with a lot of advantages, except for their complex purification procedures and structures that are difficult to decompose. In this work, biocompatible hyperbranched polyglycerol is introduced to synthesize mesoporous silica nanoparticles (MSNs). The materials possess good biocompatibility, controlled release, and biodegradability. They also show passive targeting capability through the enhanced permeability and retention effect and can be excreted from the biological system. The method avoids the needs to employ traditional surfactants and complicated purified procedures, which make these MSNs an efficient delivery system for cancer therapy.

Broadening the antibacterial spectrum of histidine kinase autophosphorylation inhibitors via the use of ε-poly-L-lysine capped mesoporous silica-based nanoparticles

Two-component systems (TCS) regulate diverse processes such as virulence, stress responses, metabolism and antibiotic resistance in bacteria but are absent in humans, making them promising targets for novel antibacterials. By incorporating recently described TCS histidine kinase autophosphorylation inhibitors (HKAIs) into ε-poly-L-lysine capped nanoparticles (NPs) we could overcome the Gram negative (Gr−) permeability barrier for the HKAIs. The observed bactericidal activity against Gr− bacteria was shown to be due to the enhanced delivery and internalization of the HKAIs and not an inhibitory or synergistic effect of the NPs. The NPs had no adverse effects on mammalian cell viability or the immune function of macrophages in vitro and showed no signs of toxicity to zebrafish larvae in vivo. These results show that HKAIs are promising antibacterials for both Gr− and Gr+pathogens and that NPs are a safe drug delivery technology that can enhance the selectivity and efficacy of HKAIs against bacteria.

"Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles.

Biodegradability of inorganic nanoparticles is one of the most critical issues in their further clinical translations. In this work, a novel "metal ion-doping" approach has been developed to endow inorganic mesoporous silica-based nanoparticles with tumor-sensitive biodegradation and theranostic functions, simply by topological transformation of mesoporous silica to metal-doped composite nanoformulations. "Manganese extraction" sensitive to tumor microenvironment was enabled in manganese-doped hollow mesoporous silica nanoparticles (designated as Mn-HMSNs) to fast promote the disintegration and biodegradation of Mn-HMSNs, further accelerating the breakage of Si-O-Si bonds within the framework. The fast biodegradation of Mn-HMSNs sensitive to mild acidic and reducing microenvironment of tumor resulted in much accelerated anticancer drug releasing and enhanced T1-weighted magnetic resonance imaging of tumor. A high tumor-inhibition effect was simultaneously achieved by anticancer drug delivery mediated by PEGylated Mn-HMSNs, and the high biocompatibility of composite nanosystems was systematically demonstrated in vivo. This is the first demonstration of biodegradable inorganic mesoporous nanosystems with specific biodegradation behavior sensitive to tumor microenvironment, which also provides a feasible approach to realize the on-demand biodegradation of inorganic nanomaterials simply by "metal ion-doping" strategy, paving the way to solve the critical low-biodegradation issue of inorganic drug carriers.

Dermal delivery of HSP47 siRNA with NOX4-modulating mesoporous silica-based nanoparticles for treating fibrosis

Fibrotic diseases such as scleroderma have been linked to increased oxidative stress and upregulation of pro-fibrotic genes. Recent work suggests a role of NADPH oxidase 4 (NOX4) and heat shock protein 47 (HSP47) in inducing excessive collagen synthesis, leading to fibrotic diseases. Herein, we elucidate the relationship between NOX4 and HSP47 in fibrogenesis and propose to modulate them altogether as a new strategy to treat fibrosis. We developed a nanoparticle platform consisting of polyethylenimine (PEI) and polyethylene glycol (PEG) coating on a 50-nm mesoporous silica nanoparticle (MSNP) core. The nanoparticles effectively delivered small interfering RNA (siRNA) targeting HSP47 (siHSP47) in an in vitro model of fibrosis based on TGF-β stimulated fibroblasts. The MSNP core also imparted an antioxidant property by scavenging reactive oxygen species (ROS) and subsequently reducing NOX4 levels in the in vitro fibrogenesis model. The nanoparticle was far superior to n-acetyl cysteine (NAC) at modulating pro-fibrotic markers. In vivo evaluation was performed in a bleomycin-induced scleroderma mouse model, which shares many similarities to human scleroderma disease. Intradermal administration of siHSP47-nanoparticles effectively reduced HSP47 protein expression in skin to normal level. In addition, the antioxidant MSNP also played a prominent role in reducing the pro-fibrotic markers, NOX4, alpha smooth muscle actin (α-SMA), and collagen type I (COL I), as well as skin thickness of the mice.