Scalable synthesis of multicomponent multifunctional inorganic core@mesoporous silica shell nanocomposites

Integrating multiple materials with different functionalities in a single nanostructure enables advances in many scientific and technological applications. However, such highly sophisticated nanomaterials usually require complex synthesis processes that complicate their preparation in a sustainable and industrially feasible manner. Herein, we designed a simple general method to grow a mesoporous silica shell onto any combination of hydrophilic nanoparticle cores. The synthetic strategy, based on the adjustment of the key parameters of the sol-gel process for the silica shell formation, allows for the embedment of single, double, and triple inorganic nanoparticles within the same shell, as well as the size-control of the obtained nanocomposites. No additional interfacial adhesive layer is required on the nanoparticle surfaces for the embedding process. Adopting this approach, electrostatically stabilized, small-sized (from 4 to 15 nm) CeO2, Fe3O4, Gd2O3, NaYF4, Au, and Ag cores were used to test the methodology. The mean diameter of the resulting nanocomposites could be as low as 55 nm, with high monodispersity. These are very feasible sizes for biological intervention, and we further observed increased nanoparticle stability in physiological environments. As a demonstration of their increased activity as a result of this, the antioxidant activity of CeO2 cores was enhanced when in core-shell form. Remarkably, the method is conducted entirely at room temperature, atmospheric conditions, and in aqueous solvent with the use of ethanol as co-solvent. These facile and even "green" synthesis conditions favor scalability and easy preparation of multicomponent nanocomposite libraries with standard laboratory glassware and simple benchtop chemistry, through this sustainable and cost-effective fabrication process.This work was financially supported by the National Natural Science Foundation of China (31950410536 to E.C. and 22005221 to M.Z.), the Wuyi University (2018TP010 to E.C., 2018TP011 and 2020FKZX05 to M.Z., and 2019TD02 to J.P.), Guangdong Science and Technology Department (2019A050512006 to E.C.), the Academy of Finland (309374 to J.M.R.), and the Instituto de Salud Carlos III of Spain (PI19/00774 to G.F-V and G.C.), co-financed by FEDER, European Union, “A way of making Europe”

Comparative safety evaluation of silica-based particles

PURPOSE: Silica nanoparticles (SNPs) are increasingly used as drug delivery systems (DDS) and for biomedical imaging. Therapeutic and diagnostic agents can be incorporated into the silica matrix to improve the stability and dissolution of drug substances in biological systems. However, the safety of SNPs as drug carriers remains controversial. To date, no validated and accepted nano-specific tests exist to predict the potentially harmful impact of these materials on the human body. METHODS: We synthesized by a systematic approach 12 different types of SNPs with varying size, surface topology (porous vs non-porous), and surface modifications. We characterized these particles in terms of dry state and hydrodynamic diameter, specific surface area, and net surface charge (ζ-potential). For cellular studies, we exposed non-phagocytic (HepG2) cells, phagocytic (THP-1) cells, and erythrocytes to SNPs. Cellular uptake and stability of fluorescently labeled SNPs were analyzed by confocal microscopy and flow cytometry. RESULTS: SNPs with a porous surface and negative net surface charge had the strongest impact on cell viability. This is in contrast to non-porous SNPs. None of the studied particles induced oxidative stress in either cell lines. Particles with a negative surface charge induced hemolysis in a concentration-dependent manner. CONCLUSIONS: Physico-chemical properties promoting cytotoxicity and hemolysis were investigated. Our study revealed potential hazards of spherical amorphous SNPs

Circumventing Drug Treatment? : Intrinsic Lethal Effects of Polyethyleneimine (PEI)-Functionalized Nanoparticles on Glioblastoma Cells Cultured in Stem Cell Conditions

Glioblastoma (GB) is the most frequent malignant tumor originating from the centralnervous system. Despite breakthroughs in treatment modalities for other cancer types, GB remainslargely irremediable due to the high degree of intratumoral heterogeneity, infiltrative growth, andintrinsic resistance towards multiple treatments. A sub-population of GB cells, glioblastoma stem cells(GSCs), act as a reservoir of cancer-initiating cells and consequently, constitute a significant challengefor successful therapy. In this study, we discovered that PEI surface-functionalized mesoporoussilica nanoparticles (PEI-MSNs), without any anti-cancer drug, very potently kill multiple GSClines cultured in stem cell conditions. Very importantly, PEI-MSNs did not affect the survival ofestablished GB cells, nor other types of cancer cells cultured in serum-containing medium, even at25 times higher doses. PEI-MSNs did not induce any signs of apoptosis or autophagy. Instead, asa potential explanation for their lethality under stem cell culture conditions, we demonstrate thatthe internalized PEI-MSNs accumulated inside lysosomes, subsequently causing a rupture of thelysosomal membranes. We also demonstrate blood–brain-barrier (BBB) permeability of the PEI-MSNs in vitroandin vivo. Taking together the recent indications for the vulnerability of GSCs for lysosomaltargeting and the lethality of the PEI-MSNs on GSCs cultured under stem cell culture conditions,the results enforcein vivotesting of the therapeutic impact of PEI-functionalized nanoparticles infaithful preclinical GB models.Peer reviewe

Targeted delivery of a novel anticancer compound anisomelic acid using chitosan-coated porous silica nanorods for enhancing the apoptotic effect

Targeted cancer therapies are currently a strong focus in biomedical research. The most common approach is to use nanocarrier-based targeting to specifically deliver conventional anticancer drugs to enhance their therapeutic efficacy, increase bioavailability, and decrease the side-effects on normal cells. A step further towards higher specificity and efficacy would be to employ specific novel drugs along with specific nanocarrier-based targeting. Our recent studies have demonstrated that a plant-derived diterpenoid compound, anisomelic acid (AA), induces apoptosis in cervical cancer cells. In this work, we describe the development of a folic acid (FA)-targeted AA delivery system using chitosan-coated rod-shaped mesoporous silica particles (Chitosan-NR-MSP). The cellular internalization and uptake enhancement of the FA-Chitosan-NR-MSP towards cancerous folate receptor (FR)-positive (SiHa and HeLa) and/or normal FR-negative (HEK 293) cells were assessed, which indicated that the intracellular uptake of FA-conjugated Chitosan-NR-MSP was more target-specific. Furthermore, the induction of apoptosis by AA-loaded chitosan-coated rod-shaped particles on SiHa cells was studied. By employing caspase-3 activation and PARP cleavage as measure of apoptosis, the FA-particle mediated AA treatment was clearly more effective, significantly enhancing apoptosis in comparison to non-targeted Chitosan-NR-MSP or free AA in SiHa cells, suggesting that the FA-Chitosan-NR-MSPs can be potentially utilized as a drug delivery system for cervical cancer treatment.Funding Agencies|Sigrid Juselius Foundation; Center of Excellence for Functional Materials; Nanolith Sverige AB; Academy of Finland [140193, 260599, 278812]</p

Size, Stability, and Porosity of Mesoporous Nanoparticles Characterized with Light Scattering

Silicon-based mesoporous nanoparticles have been extensively studied to meet the challenges in the drug delivery. Functionality of these nanoparticles depends on their properties which are often changing as a function of particle size and surrounding medium. Widely used characterization methods, dynamic light scattering (DLS), and transmission electron microscope (TEM) have both their weaknesses. We hypothesize that conventional light scattering (LS) methods can be used for a rigorous characterization of medium sensitive nanoparticles' properties, like size, stability, and porosity. Two fundamentally different silicon-based nanoparticles were made: porous silicon (PSi) from crystalline silicon and silica nanoparticles (SN) through sol-gel process. We studied the properties of these mesoporous nanoparticles with two different multiangle LS techniques, DLS and static light scattering (SLS), and compared the results to dry-state techniques, TEM, and nitrogen sorption. Comparison of particle radius from TEM and DLS revealed significant overestimation of the DLS result. Regarding to silica nanoparticles, the overestimation was attributed to agglomeration by analyzing radius of gyration and hydrodynamic radius. In case of PSi nanoparticles, strong correlation between LS result and specific surface area was found. Our results suggest that the multiangle LS methods could be used for the size, stability, and structure characterization of mesoporous nanoparticles

Shape engineering vs organic modification of inorganic nanoparticles as a tool for enhancing cellular internalization

In nanomedicine, physicochemical properties of the nanocarrier affect the nanoparticles pharmacokinetics and biodistribution, which are also decisive for the passive targeting and nonspecific cellular uptake of nanoparticles. Size and surface charge are, consequently, two main determining factors in nanomedicine applications. Another important parameter which has received much less attention is the morphology (shape) of the nanocarrier. In order to investigate the morphology effect on the extent of cellular internalization, two similarly sized but differently shaped rod-like and spherical mesoporous silica nanoparticles were synthesized, characterized and functionalized to yield different surface charges. The uptake in two different cancer cell lines was investigated as a function of particle shape, coating (organic modification), surface charge and dose. According to the presented results, particle morphology is a decisive property regardless of both the different surface charges and doses tested, whereby rod-like particles internalized more efficiently in both cell lines. At lower doses whereby the shape-induced advantage is less dominant, charge-induced effects can, however, be used to fine-tune the cellular uptake as a prospective secondary uptake regulator for tight dose control in nanoparticle-based drug formulations.Funding Agencies|Academy of Finland|140193140759126161137101|Centre of Excellence for Functional Materials||Centre for International Mobility India-Finland Fellowship||Sigrid Juselius Foundation||Nanolith Sverige AB||FP7 IRG||AAU Center of Excellence||Liv och Halsa Foundation||</p

Feasibility study of the permeability and uptake of mesoporous silica nanoparticles across the blood-brain barrier

Drug delivery into the brain is impeded by the blood-brain-barrier (BBB) that filters out the vast majority of drugs after systemic administration. In this work, we assessed the transport, uptake and cytotoxicity of promising drug nanocarriers, mesoporous silica nanoparticles (MSNs), in in vitro models of the BBB. RBE4 rat brain endothelial cells and Madin-Darby canine kidney epithelial cells, strain II, were used as BBB models. We studied spherical and rod-shaped MSNs with the following modifications: bare MSNs and MSNs coated with a poly(ethylene glycol)-poly(ethylene imine) (PEG-PEI) block copolymer. In transport studies, MSNs showed low permeability, whereas the results of the cellular uptake studies suggest robust uptake of PEG-PEI-coated MSNs. None of the MSNs showed significant toxic effects in the cell viability studies. While the shape effect was detectable but small, especially in the real-time surface plasmon resonance measurements, coating with PEG-PEI copolymers clearly facilitated the uptake of MSNs. Finally, we evaluated the in vivo detectability of one of the best candidates, i.e. the copolymer-coated rod-shaped MSNs, by two-photon in vivo imaging in the brain vasculature. The particles were clearly detectable after intravenous injection and caused no damage to the BBB. Thus, when properly designed, the uptake of MSNs could potentially be utilized for the delivery of drugs into the brain via transcellular transport