Disordered mesoporous silica particles: an emerging platform to deliver proteins to the lungs.

Pulmonary delivery and formulation of biologics are among the more complex and growing scientific topics in drug delivery. We herein developed a dry powder formulation using disordered mesoporous silica particles (MSP) as the sole excipient and lysozyme, the most abundant antimicrobial proteins in the airways, as model protein. The MSP had the optimal size for lung deposition (2.

Influence of particle diameter on aerosolization performance and release of budesonide loaded mesoporous silica particles.

The potential of micron-sized amorphous mesoporous silica particles as a novel controlled release drug delivery system for pulmonary administration has been investigated. Mesoporous silica formulations were demonstrated to provide a narrower particle size distribution and (spherical) shape uniformity compared to commercial micronized formulations, which is critical for repeatable and targeted aerosol delivery to the lungs. The release profiles of a well-known pulmonary drug loaded into mesoporous particles of different mean particle diameters (2.

Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis.

Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.

Heteromultivalent Ligand Display on Reversible Self-Assembled Monolayers (rSAMs): A Fluidic Platform for Tunable Influenza Virus Recognition.

We report on the design of heteromultivalent influenza A virus (IAV) receptors based on reversible self-assembled monolayers (SAMs) featuring two distinct mobile ligands. The principal layer building blocks consist of α-(4-amidinophenoxy)alkanes decorated at the ω-position with sialic acid (SA) and the neuraminidase inhibitor Zanamivir (Zan), acting as two mobile ligands binding to the complementary receptors hemagglutinin (HA) and neuraminidase (NA) on the virus surface. From ternary amphiphile mixtures comprising these ligands, the amidines spontaneously self-assemble on top of carboxylic acid-terminated SAMs to form reversible mixed monolayers (rSAMs) that are easily tunable with respect to the ligand ratio.

The Onset of Molecule-Spanning Dynamics in Heat Shock Protein Hsp90.

Protein dynamics have been investigated on a wide range of time scales. Nano- and picosecond dynamics have been assigned to local fluctuations, while slower dynamics have been attributed to larger conformational changes. However, it is largely unknown how fast (local) fluctuations can lead to slow global (allosteric) changes.

Three-Dimensional Oral Mucosal Equivalents as Models for Transmucosal Drug Permeation Studies.

Oral transmucosal administration, where drugs are absorbed directly through the non-keratinized, lining mucosa of the mouth, represents a solution to drug delivery with several advantages. Oral mucosal equivalents (OME) developed as 3D in vitro models are of great interest since they express the correct cell differentiation and tissue architecture, simulating the in vivo conditions better than monolayer cultures or animal tissues. The aim of this work was to develop OME to be used as a membrane for drug permeation studies.

Effects of flexibility in coarse-grained models for bovine serum albumin and immunoglobulin G.

We construct a coarse-grained, structure-based, low-resolution, 6-bead flexible model of bovine serum albumin (BSA, PDB: 4F5S), which is a popular example of a globular protein in biophysical research. The model is obtained via direct Boltzmann inversion using all-atom simulations of a single molecule, and its particular form is selected from a large pool of 6-bead coarse-grained models using two suitable metrics that quantify the agreement in the distribution of collective coordinates between all-atom and coarse-grained Brownian dynamics simulations of solutions in the dilute limit. For immunoglobulin G (IgG), a similar structure-based 12-bead model has been introduced in the literature [Chaudhri et al.

Probing Cage Relaxation in Concentrated Protein Solutions by X-Ray Photon Correlation Spectroscopy.

Diffusion of proteins on length scales of their size is crucial for understanding the machinery of living cells. X-ray photon correlation spectroscopy (XPCS) is currently the only way to access long-time collective diffusion on these length scales, but radiation damage so far limits the use in biological systems. We apply a new approach to use XPCS to measure cage relaxation in crowded α-crystallin solutions.

Oral transmucosal delivery of eletriptan for neurological diseases.

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).

Short-Time Transport Properties of Bidisperse Suspensions of Immunoglobulins and Serum Albumins Consistent with a Colloid Physics Picture.

The crowded environment of biological systems such as the interior of living cells is occupied by macromolecules with a broad size distribution. This situation of polydispersity might influence the dependence of the diffusive dynamics of a given tracer macromolecule in a monodisperse solution on its hydrodynamic size and on the volume fraction. The resulting size dependence of diffusive transport crucially influences the function of a living cell.

Reversible Self-Assembled Monolayers with Tunable Surface Dynamics for Controlling Cell Adhesion Behavior.

Cells adhering onto surfaces sense and respond to chemical and physical surface features. The control over cell adhesion behavior influences cell migration, proliferation, and differentiation, which are important considerations in biomaterial design for cell culture, tissue engineering, and regenerative medicine. Here, we report on a supramolecular-based approach to prepare reversible self-assembled monolayers (rSAMs) with tunable lateral mobility and dynamic control over surface composition to regulate cell adhesion behavior.

Wearable Electronic Tongue for Non-Invasive Assessment of Human Sweat.

Sweat is a promising biofluid in allowing for non-invasive sampling. Here, we investigate the use of a voltammetric electronic tongue, combining different metal electrodes, for the purpose of non-invasive sample assessment, specifically focusing on sweat. A wearable electronic tongue is presented by incorporating metal electrodes on a flexible circuit board and used to non-invasively monitor sweat on the body.

Molecular Flexibility of Antibodies Preserved Even in the Dense Phase after Macroscopic Phase Separation.

Antibody therapies are typically based on high-concentration formulations that need to be administered subcutaneously. These conditions induce several challenges, inter alia a viscosity suitable for injection, sufficient solution stability, and preservation of molecular function. To obtain systematic insights into the molecular factors, we study the dynamics on the molecular level under strongly varying solution conditions.

Temperature and salt controlled tuning of protein clusters.

The formation of molecular assemblies in protein solutions is of strong interest both from a fundamental viewpoint and for biomedical applications. While ordered and desired protein assemblies are indispensable for some biological functions, undesired protein condensation can induce serious diseases. As a common cofactor, the presence of salt ions is essential for some biological processes involving proteins, and in aqueous suspensions of proteins can also give rise to complex phase diagrams including homogeneous solutions, large aggregates, and dissolution regimes.

A novel versatile flow-donor chamber as biorelevant ex-vivo test assessing oral mucoadhesive formulations.

Oral transmucosal drug delivery is a non-invasive administration route for rapid therapeutic onset and greater bioavailability avoiding the first-pass metabolism. Mucoadhesive formulations are advantageous as they may retain the drug at the administration site. Proper equipment to assess mucoadhesive properties and corresponding drug absorption is fundamental for the development of novel drug delivery systems.

Extraction of natural moisturizing factor from the stratum corneum and its implication on skin molecular mobility.

The natural moisturizing factor (NMF) is a mixture of small water-soluble compounds present in the upper layer of the skin, stratum corneum (SC). Soaking of SC in water leads to extraction of the NMF molecules, which may influence the SC molecular properties and lead to brittle and dry skin. In this study, we investigate how the molecular dynamics in SC lipid and protein components are affected by the removal of the NMF compounds.

Can mesoporous nanoparticles promote bioavailability of topical pharmaceutics?

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.

Probing Skin Barrier Recovery on Molecular Level Following Acute Wounds: An In Vivo/Ex Vivo Study on Pigs.

Proper skin barrier function is paramount for our survival, and, suffering injury, there is an acute need to restore the lost barrier and prevent development of a chronic wound. We hypothesize that rapid wound closure is more important than immediate perfection of the barrier, whereas specific treatment may facilitate perfection. The aim of the current project was therefore to evaluate the quality of restored tissue down to the molecular level.

Self-diffusion of nonspherical particles fundamentally conflicts with effective sphere models.

Modeling diffusion of nonspherical particles presents an unsolved and considerable challenge, despite its importance for the understanding of crowding effects in biology, food technology and formulation science. A common approach in experiment and simulation is to map nonspherical objects on effective spheres to subsequently use the established predictions for spheres to approximate phenomena for nonspherical particles. Using numerical evaluation of the hydrodynamic mobility tensor, we show that this so-called effective sphere model fundamentally fails to represent the self-diffusion in solutions of ellipsoids as well as rod-like assemblies of spherical beads.

Multivalent ions and biomolecules: Attempting a comprehensive perspective.

Ions are ubiquitous in nature. They play a key role for many biological processes on the molecular scale, from molecular interactions, to mechanical properties, to folding, to self-organisation and assembly, to reaction equilibria, to signalling, to energy and material transport, to recognition etc. Going beyond monovalent ions to multivalent ions, the effects of the ions are frequently not only stronger (due to the obviously higher charge), but qualitatively different.

Lipid Bilayer-like Mixed Self-Assembled Monolayers with Strong Mobility and Clustering-Dependent Lectin Affinity.

Glycans at the surface of cellular membranes modulate biological activity via multivalent association with extracellular messengers. The lack of tuneable simplified models mimicking this dynamic environment complicates basic studies of these phenomena. We here present a series of mixed reversible self-assembled monolayers (rSAMs) that addresses this deficiency.

Highly Efficient Synthesis and Assay of Protein-Imprinted Nanogels by Using Magnetic Templates.

We report an approach integrating the synthesis of protein-imprinted nanogels ("plastic antibodies") with a highly sensitive assay employing templates attached to magnetic carriers. The enzymes trypsin and pepsin were immobilized on amino-functionalized solgel-coated magnetic nanoparticles (magNPs). Lightly crosslinked fluorescently doped polyacrylamide nanogels were subsequently produced by high-dilution polymerization of monomers in the presence of the magNPs.

Reversible Self-Assembled Monolayers (rSAMs) as Robust and Fluidic Lipid Bilayer Mimics.

Lipid bilayers, forming the outer barrier of cells, display a wide array of proteins and carbohydrates for modulating interfacial biological interactions. Formed by the spontaneous self-assembly of lipid molecules, these bilayers feature liquid crystalline order, while retaining a high degree of lateral mobility. Studies of these dynamic phenomena have been hampered by the fragility and instability of corresponding biomimetic cell membrane models.