Mesoporous silica nanoparticles facilitate delivery of siRNA to shutdown signaling pathways in mammalian cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Hom C
PROVIDER: S-EPMC2953950 | biostudies-literature | 2010 Jun
REPOSITORIES: biostudies-literature
Publications
Mesoporous silica nanoparticles facilitate delivery of siRNA to shutdown signaling pathways in mammalian cells.
Hom Christopher C Lu Jie J Liong Monty M Luo Hanzhi H Li Zongxi Z Zink Jeffrey I JI Tamanoi Fuyuhiko F
Small (Weinheim an der Bergstrasse, Germany) 20100601 11
Similar Datasets
Project description:In the present study, we designed a nanoscale platform for the sustained and controlled delivery of nutrients to pancreatic islets-upon transplantation. Our platform consists of a mesoporous silica nanoparticle (MSNP), loaded with glutamine (G), an essential amino acid required for islet survival and function, and capped with polydopamine (PD). To control the release of glutamine, various concentrations (0.5 - 2 mg/mL) of PD and incubation times (0.5 – 2 h) with MSNPs were investigated in terms of pharmacological properties and biological functions. After extensive testing, PD-G-MSNPs made using PD coating of 0.5 mg/mL incubated for 0.5 h resulted in the optimal platform to maintain the islet viability and functionality in vitro. Following syngeneic renal sub-capsule islet transplantation in STZ-diabetic mice, PD-G-MSNPs improved the engraftment of pancreatic islets as well as their function, resulting in re-establishment of glycemic control. Collectively, our data shows that PD-G-MSNPs can support transplanted islets by providing them with a controlled and sustained supply of nutrients.
2023-12-04 | GSE247020 | GEO
Project description:Effective delivery holds the key to successful in vivo application of therapeutic small interfering RNA (siRNA). In this work, we have developed a universal siRNA carrier consisting of a mesoporous silica nanoparticle (MSNP) functionalized with cyclodextrin-grafted polyethylenimine (CP). CP provides positive charge for loading of siRNA through electrostatic interaction and enables effective endosomal escape of siRNA. Using intravital microscopy we were able to monitor tumor enrichment of CP-MSNP/siRNA particles in live mice bearing orthotopic MDA-MB-231 xenograft tumors. CP-MSNP delivery of siRNA targeting the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) resulted in effective knockdown of gene expression in vitro and in vivo. Suppression of PKM2 led to inhibition of tumor cell growth, invasion, and migration.
| S-EPMC3966054 | biostudies-literature
Project description:PurposeTo prepare mesoporous silica-based delivery systems capable of simultaneous delivery of drugs and nucleic acids.MethodsThe surface of mesoporous silica nanoparticles (MSN) was modified with poly(ethylene glycol) (PEG) and poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) or poly(2-(diethylamino)ethylmethacrylate) (PDEAEMA). The particles were then loaded with a lysosomotropic agent chloroquine (CQ) and complexed with plasmid DNA or siRNA. The ability of the synthesized particles to deliver combinations of CQ and nucleic acids was evaluated using luciferase plasmid DNA and siRNA targeting luciferase and GAPDH.ResultsThe results show a slow partial MSN dissolution to form hollow silica nanoparticles in aqueous solution. The biological studies show that polycation-modified MSN are able to simultaneously deliver CQ with DNA and siRNA. The co-delivery of CQ and the nucleic acids leads to a significantly increased transfection and silencing activity of the complexes compared with MSN not loaded with CQ.ConclusionPEGylated MSN modified with polycations are promising delivery vectors for combination drug/nucleic acid therapies.
| S-EPMC4108588 | biostudies-literature
Project description:In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. We now describe a new nanoparticle construct that has been engineered for efficient delivery of siRNA to tumors. The construct is comprised of a 47-nm mesoporous silica nanoparticle (MSNP) core coated with a cross-linked PEI-PEG copolymer, carrying siRNA against the HER2 oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct has been engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2-nanoparticles produced apoptotic death in HER2 positive (HER2+) breast cancer cells grown in vitro, but not in HER2 negative (HER2-) cells. One dose of the siHER2-nanoparticles reduced HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Multiple doses administered intravenously over 3 weeks significantly inhibited tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.
| S-EPMC4469082 | biostudies-literature
Project description:RNA interference (RNAi) is a powerful tool for understanding and manipulating signaling pathways in plant science, potentially facilitating the accelerated development of novel plant traits and crop yield improvement. The common strategy for delivering siRNA into intact plants using agrobacterium or viruses is complicated and time-consuming, limiting the application of RNAi in plant research. Here, a novel delivery method based on mesoporous silica nanoparticles (MSNs) is reported, which allows for the efficient delivery of siRNA into mature plant leaves via topical application without the aid of mechanical forces, achieving transient gene knockdown with up to 98% silencing efficiency at the molecular level. In addition, this method is nontoxic to plant leaves, enabling the repeated delivery of siRNA for long-term silencing. White spots and yellowing phenotypes are observed after spraying the MSN-siRNA complex targeted at phytoene desaturase and magnesium chelatase genes. After high light treatment, photobleaching phenotypes are also observed by spraying MSNs-siRNA targeted at genes into the Photosystem II repair cycle. Furthermore, the study demonstrated that MSNs can simultaneously silence multiple genes. The results suggest that MSN-mediated siRNA delivery is an effective tool for long-term multi-gene silencing, with great potential for application in plant functional genomic analyses and crop improvement.
| S-EPMC10916655 | biostudies-literature
Project description: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.
| S-EPMC4522385 | biostudies-literature
Project description:Although siRNA is a promising technology for cancer gene therapy, effective cytoplasmic delivery has remained a significant challenge. In this paper, a potent siRNA transfer system with active targeting moieties toward cancer cells and a high loading capacity is introduced to inhibit drug resistance. Mesoporous silica nanoparticles are of great potential for developing targeted gene delivery. Amino-modified MSNs (NH2-MSNs) were synthesized using a modified sol-gel method and characterized by FTIR, BET, TEM, SEM, X-ray diffraction, DLS, and 1H-NMR. MDR1-siRNA was loaded within NH2-MSNs, and the resulting negative surface was capped by functionalized chitosan as a protective layer. Targeting moieties such as TAT and folate were anchored to chitosan via PEG-spacers. The loading capacity of siRNA and the protective effect of chitosan for siRNA were determined by gel retardation assay. MTT assay, flow cytometry, real-time PCR, and western blot were performed to study the cytotoxicity, cellular uptake assay, targeting evaluation, and MDR1 knockdown efficiency. The synthesized NH2-MSNs had a particle size of ≈ 100 nm and pore size of ≈ 5 nm. siRNA was loaded into NH2-MSNs with a high loading capacity of 20% w/w. Chitosan coating on the surface of siRNA-NH2-MSNs significantly improved the siRNA protection against enzyme activity compared to naked siRNA-NH2-MSNs. MSNs and modified MSNs did not exhibit significant cytotoxicity at therapeutic concentrations in the EPG85.257-RDB and HeLa-RDB lines. The folate-conjugated nanoparticles showed a cellular uptake of around two times higher in folate receptor-rich HeLa-RDB than EPG85.257-RDB cells. The chitosan-coated siRNA-NH2-MSNs produced decreased MDR1 transcript and protein levels in HeLa-RDB by 0.20 and 0.48-fold, respectively. The results demonstrated that functionalized chitosan-coated siRNA-MSNs could be a promising carrier for targeted cancer therapy. Folate-targeted nanoparticles were specifically harvested by folate receptor-rich HeLa-RDB and produced a chemosensitized phenotype of the multidrug-resistant cancer cells.
| S-EPMC8519957 | biostudies-literature
Project description:Even though cancer treatment has improved over the recent decades, still more specific and effective treatment concepts are mandatory. Surgical removal is not always possible, metastases are challenging and chemo- and radiotherapy can not only have severe side-effects but also resistances may occur. To cope with these challenges more efficient therapies with fewer side-effects are required. One promising approach is the use of drug delivery vehicles. Here, mesoporous silica nanoparticles (MSN) are discussed as biodegradable drug carrier to improve efficacy and reduce side-effects. MSN excellently fulfill the criteria for nanoparticulate carriers: their distinct structure allows high loading capacity and a plethora of surface modifications. MSN synthesis permits fine-tuning of particle and pore sizes. Moreover, drug release can be tailored through various gatekeeper systems which are for example pH-sensitive or redox-sensitive. Furthermore, MSN can either enter tumors passively by the enhanced permeability and retention effect or can be actively targeted by various ligands. PEGylation prolongs circulation time and availability. A huge advantage of MSN is their explicitly low toxic profile in vivo. Yet, clinical translation remains challenging. Overall, mesoporous silica nanoparticles are a promising tool for innovative, more efficient and safer cancer therapies.
| S-EPMC5535255 | biostudies-literature
Project description:Considerable progress in the fabrication of quasicrystals demonstrates that they can be realized in a broad range of materials. However, the development of chemistries enabling direct experimental observation of early quasicrystal growth pathways remains challenging. Here, we report the synthesis of four surfactant-directed mesoporous silica nanoparticle structures, including dodecagonal quasicrystalline nanoparticles, as a function of micelle pore expander concentration or stirring rate. We demonstrate that the early formation stages of dodecagonal quasicrystalline mesoporous silica nanoparticles can be preserved, where precise control of mesoporous silica nanoparticle size down to <30 nm facilitates comparison between mesoporous silica nanoparticles and simulated single-particle growth trajectories beginning with a single tiling unit. Our results reveal details of the building block size distributions during early growth and how they promote quasicrystal formation. This work identifies simple synthetic parameters, such as stirring rate, that may be exploited to design other quasicrystal-forming self-assembly chemistries and processes.Probing the growth pathways of quasicrystalline materials, where tiling units arrange with local but no long-range order, remains challenging. Here, the authors demonstrate that dodecagonal tiling of mesoporous silica nanoparticles occurs via irreversible packing of micelles with non-uniform size distribution.
| S-EPMC5558005 | biostudies-literature
Project description:Surface-functionalized mesoporous silica nanoparticles (MSNP) can be used as an efficient and safe carrier for bioactive molecules. In order to make the MSNP a more efficient delivery system, we modified the surface of the particles by a functional group that enhances cellular uptake and allows nucleic acid delivery in addition to traditional drug delivery. Noncovalent attachment of polyethyleneimine (PEI) polymers to the surface not only increases MSNP cellular uptake but also generates a cationic surface to which DNA and siRNA constructs could be attached. While efficient for intracellular delivery of these nucleic acids, the 25 kD PEI polymer unfortunately changes the safety profile of the MSNP that is otherwise very safe. By experimenting with several different polymer molecular weights, it was possible to retain high cellular uptake and transfection efficiency while reducing or even eliminating cationic MSNP cytotoxicity. The particles coated with the 10 kD PEI polymer were particularly efficient for transducing HEPA-1 cells with a siRNA construct that was capable of knocking down GFP expression. Similarly, transfection of a GFP plasmid induced effective expression of the fluorescent protein in >70% cells in the population. These outcomes were quantitatively assessed by confocal microscopy and flow cytometry. We also demonstrated that the enhanced cellular uptake of the nontoxic cationic MSNP enhances the delivery of the hydrophobic anticancer drug, paclitaxel, to pancreatic cancer cells. In summary, we demonstrate that, by a careful selection of PEI size, it is possible to construct cationic MSNP that are capable of nucleotide and enhanced drug delivery with minimal or no cytotoxicity. This novel use of a cationic MSNP extends its therapeutic use potential.
| S-EPMC3900639 | biostudies-literature