Nanologica (Sweden)

Migraine is a highly prevalent neurological disease affecting circa 1 billion patients worldwide with severe incapacitating symptoms, which significantly diminishes the quality of life. As self-medication practice, oral administration of triptans is the most common option, despite its relatively slow therapeutic onset and low drug bioavailability. To overcome these issues, here we present, to the best of our knowledge, the first study on the possibility of oral transmucosal delivery of one of the safest triptans, namely eletriptan hydrobromide (EB). Based on a comprehensive set of in vitro and ex vivo experiments, we highlight the conditions required for oral transmucosal delivery, potentially giving rise to similar, or even higher, drug plasma concentrations expected from conventional oral administration. With histology and tissue integrity studies, we conclude that EB neither induces morphological changes nor impairs the integrity of the mucosal barrier following 4 h of exposure. On a cellular level, EB is internalized in human oral keratinocytes within the first 5 min without inducing toxicity at the relevant concentrations for transmucosal delivery. Considering that the pKa of EB falls within the physiologically range, we systematically investigated the effect of pH on both solubility and transmucosal permeation. When the pH is increased from 6.8 to 10.4, the drug solubility decreases drastically from 14.7 to 0.07 mg/mL. At pH 6.8, EB gave rise to the highest drug flux and total permeated amount across mucosa, while at pH 10.4 EB shows greater permeability coefficient and thus higher ratio of permeated drug versus applied drug. Permeation experiments with model membranes confirmed the pH dependent permeation profile of EB. The distribution of EB in different cellular compartments of keratinocytes is pH dependent. In brief, high drug ionization leads to higher association with the cell membrane, suggesting ionic interactions between EB and the phospholipid head groups. Moreover, we show that the chemical permeation enhancer DMSO can be used to enhance the drug permeation significantly (i.e., 12 to 36-fold increase). Taken together, this study presents important findings on transmucosal delivery of eletriptan via the oral cavity and paves the way for clinical investigations for a fast and safe migraine treatment.

When applied to skin, particulate matter has been shown to accumulate in hair follicles. In addition to follicles, the skin topography also incorporates trench-like furrows where particles potentially can accumulate; however, the furrows have not been as thoroughly investigated in a drug delivery perspective. Depending on body site, the combined follicle orifices cover up to 10% of the skin surface, while furrows can easily cover 20%, reaching depths exceeding 25 µm. Hence, porous particles of appropriate size and porosity could serve as carriers for drugs to be released in the follicles prior to local or systemic absorption. In this paper, we combine multiphoton microscopy, scanning electron microscopy, and Franz cell diffusion technology to investigate ex-vivo skin accumulation of mesoporous silica particles (average size of 400–600 nm, 2, and 7 µm, respectively), and the potential of which as vehicles for topical delivery of the broad-spectrum antibiotic metronidazole. We detected smaller particles (400–600 nm) in furrows at depths of about 25 µm, also after rinsing, while larger particles (7 µm) where located more superficially on the skin. This implies that appropriately sized porous particles may serve as valuable excipients in optimizing bioavailability of topical formulations. This work highlights the potential of skin furrows for topical drug delivery.

A mesoporous silica material prepared by using folic acid (FA) as a template enables the effective encapsulation of meso-tetrakis(4-carboxyphenyl)porphyrin (TCPP) in its interior. Combination of steady-state and time-resolved absorption and emission spectroscopy demonstrate that FA and TCPP are released from the silica material to the aqueous phase in the form of a non-covalent assembly. This assembly does not form by simple mixing of the two components in the absence of silica, suggesting the key role of the material in the assembling process. The FA/TCPP assembly exhibits dual color fluorescence in the visible region, good photosensitization capability of singlet oxygen, and enhanced photo-induced mortality in KB cancer cells overexpressing folate receptor, if compared with the free components.

Amino-terminated mesoporous silica nanoparticles embedding carbon dots (MSCD) formed by calcination were functionalized with a nitric oxide (NO) photodonor (1) to give a robust MSCD-1 conjugate. The intense fluorescence of MSCDs was strongly quenched in MSCD-1 by effective energy transfer. Visible light excitation of MSCD-1 liberates NO, suppresses the energy transfer mechanism and leads to concomitant fluorescence restoration of the MSCD scaffold, which acts as an optical reporter for the released NO. The MSCD-1 hybrid is also able to encapsulate the highly hydrophobic photosensitizer temoporfin, preserving the fluorescence reporting function.

We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P ≤ 0.05; fold change ≥ 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property-specific biological/toxicity responses induced by nanomaterials.

The release of dust generated during sanding or sawing of nanocomposites was compared with conventional products without nanomaterials. Epoxy-based polymers with and without carbon nanotubes, and paints with different amounts of nano-sized titanium dioxide, were machined in a closed aerosol chamber. The temporal evolution of the aerosol concentration and size distribution were measured simultaneously. The morphology of collected dust by scanning electron microscopy was different depending on the type of nanocomposites: particles from carbon nanotubes (CNTs) nanocomposites had protrusions on their surfaces and aggregates and agglomerates are attached to the paint matrix in particles emitted from alkyd paints. We observed no significant differences in the particle size distributions when comparing sanding dust from nanofiller containing products with dust from conventional products. Neither did we observe release of free nanomaterials. Instead, the nanomaterials were enclosed or partly enclosed in the matrix. A source strength term Si (cm(-3) s(-1)) that describes particle emission rates from continuous sources was introduced. Comparison between the Si parameters derived from sanding different materials allows identification of potential effects of addition of engineered nanoparticles to a composite.

There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.