Examining Insulin Adsorption onto Mesoporous Silica Microparticles for Oral Delivery.

BACKGROUND: Microencapsulation is one of the most common techniques for the delivery of macromolecules; however, it can cause various stability problems, such as degradation or loss of bioactivity of the loaded molecules. For this reason, several techniques were investigated to load insulin into pre-formed porous microparticles (MPs). OBJECTIVE: The high loading of insulin is a prerequisite of its delivery in sufficient concentration; hence we examined insulin loading in mesoporous silica (SBA15-NH2) as a model for uniformly porous microparticles using different loading methods and factors. METHOD: The MPs were characterized with respect to their morphology, porosity and pore diameter while insulin adsorption into the porous substrates was investigated using immersion and freeze-drying at different pH and initial peptide concentrations. MPs were further coated with Chitosan as a technique for pore blocking. RESULTS: The results showed that the extent of insulin adsorption by freeze-drying varied depending on substrate affinity to insulin and pH where it could achieve the highest loading capacity at a pH near its isoelectric point. A significant increase in drug loading along with slower drug release was observed with Chitosan coated SBA15-NH2 MPs. In addition, the structural integrity of insulin was maintained after loading into the MPs, as confirmed by gel electrophoresis and fluorescent spectroscopy together with the in vivo study which in turn confirmed the preservation of insulin bioactivity in lowering blood glucose after oral administration. CONCLUSION: The present work displays the various factors that can control insulin loading in mesoporous silica MPs and their effects in enhancing the efficiency of insulin oral delivery using such substrates.

Immune response to functionalized mesoporous silica nanoparticles for targeted drug delivery.

Multifunctional mesoporous silica nanoparticles (MSN) have attracted substantial attention with regard to their high potential for targeted drug delivery. For future clinical applications it is crucial to address safety concerns and understand the potential immunotoxicity of these nanoparticles. In this study, we assess the biocompatibility and functionality of multifunctional MSN in freshly isolated, primary murine immune cells. We show that the functionalized silica nanoparticles are rapidly and efficiently taken up into the endosomal compartment by specialized antigen-presenting cells such as dendritic cells. The silica nanoparticles showed a favorable toxicity profile and did not affect the viability of primary immune cells from the spleen in relevant concentrations. Cargo-free MSN induced only very low immune responses in primary cells as determined by surface expression of activation markers and release of pro-inflammatory cytokines such as Interleukin-6, -12 and -1ß. In contrast, when surface-functionalized MSN with a pH-responsive polymer capping were loaded with an immune-activating drug, the synthetic Toll-like receptor 7 agonist R848, a strong immune response was provoked. We thus demonstrate that MSN represent an efficient drug delivery vehicle to primary immune cells that is both non-toxic and non-inflammagenic, which is a prerequisite for the use of these particles in biomedical applications.

Multifunctional polymer-capped mesoporous silica nanoparticles for pH-responsive targeted drug delivery.

A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The functionality of the system was demonstrated in several cell studies, showing pH-triggered release in the endosome, light-triggered endosomal escape with an on-board photosensitizer, and efficient folic acid-based cell targeting.

Lipid-bilayer coated nanosized bimodal mesoporous carbon spheres for controlled release applications.

Highly mesoporous nanosized carbon spheres (MCS) equipped with an active lipid bilayer demonstrate pronounced molecular release behavior, and excellent potential for drug delivery applications. We report a facile synthesis route for the creation of colloidal MCS with a bimodal pore size distribution, featuring a high BET surface area combined with high pore volume. Bimodal mesoporosity was achieved by a simultaneous co-assembly of a polymer resin (resol), tetraethyl orthosilicate (TEOS) and a block copolymer (Pluronic F127). The spherical geometry originates from casting the precursor mixture into a macroporous silica hard template, having a mean pore size of 60 nm, followed by thermopolymerization and final carbonization at 900 °C in nitrogen atmosphere. The final bimodal mesoporous MCS were obtained after removal of inorganic compounds by etching with hydrofluoric acid. Colloidal suspensions of MCS were prepared by oxidation with ammonium persulfate. MCS were loaded with calcein as a model drug. Efficient sealing of the MCS was achieved with a supported lipid bilayer (SLB). The SLB acts as a diffusion barrier against the uncontrolled release of encapsulated dye molecules until the release is triggered via the addition of a surface active agent. The high surface area and pore volume and the excellent release characteristics make the SLB-coated MCS a promising release-on-demand system.

Tailoring nanostructures using copolymer nanoimprint lithography.

The generation of defect-free polymer nanostructures by nanoimprinting methods is described. Long-range nanorheology and shorter-range surface energy effects can be efficiently combined to provide alignment of copolymer lamellae over several micrometers. As an example, a perpendicular organization with respect to circular tracks is shown, demonstrating the possibility of writing ordered radial nanostructures over large distances.

Are nanoscale ion aggregates present in aqueous solutions of guanidinium salts?

A detailed investigation using broadband dielectric relaxation spectroscopy (DRS) has been made of the aqueous solutions of guanidinium chloride and carbonate, GdmCl(aq) and Gdm2CO3(aq), at 25 °C. The spectra indicate that Gdm(+) ions, C(NH2)3(+), do not bind strongly to water nor are they hydrophobically hydrated; rather they appear to have a most unusual ability to dissolve in water without altering its dynamics. Although DRS is particularly sensitive to the presence of ion pairs, only weak ion pairing was detected in Gdm2CO3(aq) solutions and none at all in GdmCl(aq). Surprisingly, no evidence was found for the existence of the higher order homo- and heteroionic nanoscale aggregates that have been identified in recent years by Mason and co-workers using molecular dynamics simulations and neutron diffraction. Possible reasons for this discrepancy are discussed. The present DR spectra and other solution properties of GdmCl(aq) and Gdm2CO3(aq), such as apparent molar volumes and electrical conductivities, are shown to have strong similarities to those of the corresponding Na+ salts. However, such solutions also differ remarkably from their Na(+) analogues (and all other simple electrolytes in aqueous solution) in that their average water relaxation times correlate strongly with their bulk viscosities. The biological implications of the present results are briefly discussed.