In Vitro Dissolution, Cellular Membrane Permeability, and Anti-Inflammatory Response of Resveratrol-Encapsulated Mesoporous Silica Nanoparticles.

Sizing drugs down to the submicron and nanometer scale using nanoparticles has been extensively used in pharmaceutical industries to overcome the poor aqueous solubility of potential therapeutic agents. Here, we report the encapsulation and release of resveratrol, a promising anti-inflammatory and anticancer nutraceutical, from the mesopores of MCM-48-type silica nanospheres of various particle sizes, i.e., 90, 150, and 300 nm. Furthermore, the influence of the carrier pore size on drug solubility was also evaluated (3.5 vs 7 nm). From our results, it is observed that the saturated solubility could depend not only on the pore size but also on the particle size of the nanocarriers. Moreover, with our resveratrol-mesoporous silica nanoparticles formulation, we have observed that the permeability of resveratrol encapsulated in MCM-48 nanoparticles (90 nm) can be enhanced compared to a resveratrol suspension when tested through the human colon carcinoma cell monolayer (Caco-2). Using an in vitro NF-κB assay, we showed that resveratrol encapsulation did not alter its bioactivity and, at lower concentration, i.e., 5 µg mL-1, resveratrol encapsulation provided higher anti-inflammatory activity compared to both resveratrol suspension and solution. All combined, the reported results clearly highlight the potential of small size mesoporous silica nanoparticles as next generation nanocarriers for hydrophobic drugs and nutraceuticals.

Fluorinated Mesoporous Silica Nanoparticles for Binuclear Probes in 1H and 19F Magnetic Resonance Imaging.

The development of molecular and cellular magnetic resonance imaging (MRI) procedures has always represented a challenge because of the fact that conventional MRI contrast agents are not directly detected in vivo; in proton MRI (e.g., with the nucleus 1H), their local concentration is measured through the effect they exert on the signal of hydrogen protons present in their immediate vicinity. Because the contrast effects generated by conventional MRI probes superpose to and can often impede the anatomical information contained in 1H MRI images, new probes based on a nucleus other than 1H, are being developed. In this study, we report on the development of fluorinated mesoporous silica nanoparticles (MSNs), which could represent an interesting dual probe that allows two MRI modes: 1H for high-resolution anatomical information and 19F for the detection of MSNs used as drug delivery agents. MSNs were synthesized and covalently functionalized either with fluorosilane (FMSNs) or polyfluorosiloxane (polyFMSNs) to enable their detection in 19F MRI. Then, gadolinium chelates were grafted on the particles to enhance their detectability in 1H MRI. The physicochemical, textural, and relaxometric properties (1H and 19F relaxation times) of the nanoparticles were measured and compared. The 19F relaxation properties were found to be dependent on the concentration of fluorine; they were also highly sensitive to the presence of gadolinium. The shortest relaxation times were obtained with polyFMSNs. At clinical magnetic field strengths, high 1H relaxivities and low relaxometric ratios (r2/r1 = 1.45; 2.2 for nanoparticles entrapped in hydrogel) were found for both nanoparticle systems. Finally, the visibility of both systems was confirmed in 1H, and the detectability of polyFMSNs was confirmed in 19F MRI. This physicochemical and relaxometric study opens the door to the applications of fluorinated silica nanoparticles as theranostic materials allowing dual MRI (1H and 19F).

Antibody-conjugated mesoporous silica nanoparticles for brain microvessel endothelial cell targeting.

Brain microvessel endothelial cells (BMECs) are the main structural and dynamic components of the blood-brain barrier (BBB), preventing the majority of drugs from reaching the brain. Since BMECs are involved in a wide range of central nervous system diseases, the development of nanocarriers that trigger receptor-mediated uptake in these cells has been suggested as a promising approach to an increased drug delivery to the brain. Here, we report the size and the bioconjugation effects of antibody-conjugated mesoporous silica nanoparticles (MSNs) on in vitro and in vivo targeting ability to BMECs. For this, Ri7 antibody was conjugated to MSNs of two different sizes (50 nm and 160 nm in diameter) through a polyethylene glycol (PEG) linker. The particles were also functionalized with a MRI contrast agent (gadolinium chelate) and with a fluorescent label. The functionalized MSN suspensions showed good colloidal stability. The Ri7 antibody immobilized on the MSN surface maintained its high specific activity and high binding affinity, as demonstrated in vitro. Cells incubated with gadolinium-chelated Ri7-MSNs showed a significant MRI positive contrast enhancement, highlighting the potential of such nanoparticles for theranostic applications. To measure the uptake and affinity of Ri7-MSNs to brain endothelial and neuronal cells, cell uptake studies were performed and a quantitative cellular assay was developed. The results revealed that endocytosis of nanoparticles is mediated by transferrin receptors and that Ri7-MSN cellular uptake is size- and time-dependent. A highest specific uptake was found with 50 nm Ri7-MSNs. Upon intravenous injection, 50 nm Ri7-MSNs were specifically accumulated in BMECs, suggesting the strong potential of antibody-coated nanoparticles for targeting BMECs in vivo. These findings open the door to therapeutic targeting of BMECs, enabling potential therapeutic drug delivery to the brain.

Mesoporous Silica Nanoparticles under Sintering Conditions: A Quantitative Study.

Thin films made of mesoporous silica nanoparticles (MSNs) are finding new applications in catalysis, optics, as well as in biomedicine. The fabrication of MSNs thin films requires a precise control over the deposition and sintering of MSNs on flat substrates. In this study, MSNs of narrow size distribution (150 nm) are synthesized, and then assembled onto flat silicon substrates, by means of a dip-coating process. Using concentrated MSN colloidal solutions (19.5 mg mL(-1) SiO2), withdrawal speed of 0.01 mm s(-1), and well-controlled atmospheric conditions (ambient temperature, ∼ 70% of relative humidity), monolayers are assembled under well-structured compact patterns. The thin films are sintered up to 900 °C, and the evolution of the MSNs size distributions are compared to those of their pore volumes and densities. Particle size distributions of the sintered thin films were precisely fitted using a model specifically developed for asymmetric particle size distributions. With increasing temperature, there is first evidence of intraparticle reorganization/relaxation followed by intraparticle sintering followed by interparticle sintering. This study is the first to quantify the impact of sintering on MSNs assembled as thin films.

Metal chelate grafting at the surface of mesoporous silica nanoparticles (MSNs): physico-chemical and biomedical imaging assessment.

Mesoporous silica nanoparticles (MSNs) are being developed as drug delivery vectors. Biomedical imaging (MRI and PET) enables their tracking in vivo, provided their surface is adequately grafted with imaging probes (metal chelates). However, MSNs are characterized by huge specific surfaces, and high-quality metal chelate anchoring procedures must be developed and validated, to demonstrate that their detection in vivo is associated to the presence of nanoparticles and not to detached metal chelates. MCM-48 nanospheres (M48SNs, 150 nm diam., 3-D pore geometry) were synthesized and functionalized with diethylenetriaminepentaacetic acid (DTPA). The strong grafting of DTPA was confirmed by 29Si MAS-NMR, XPS, FTIR and TGA. The particles were labeled with paramagnetic ions Gd3+ (for MRI) as well as radioactive ions 64Cu2+ (for PET; half-life: 12.7 h). Gd3+-DTPA-M48SNs formed a stable colloid in saline media for at least 6 months, without any sign of aggregation. The relaxometric properties were measured at various magnetic fields. The strength of DTPA binding at the surface of MSNs was also assessed in vivo, by injecting mice (i.v.) with Gd3+/64Cu2+-DTPA-M48SNs. Vascular retention and urinary clearance were monitored by MRI, whereas the PET modality provided dynamic and quantitative assessment of biodistribution and blood/organ clearance. No significant 64Cu activity was detectable in the bladder. The study confirmed the very limited detachment of DTPA from M48SNs cores once injected in vivo. The transit of MSNs through the liver and intestinal tract, does not lead to evidence of Gd3+/64Cu2+-DTPA in the urine. This physico-chemical and biodistribution study confirms the quality of DTPA attachment at the surface of the particles, necessary to allow further development of PET/MRI-assisted MSN-vectorized drug delivery procedures.