α/ß-Peptides as Nanomolar Triggers of Lipid Raft-Mediated Endocytosis through GM1 Ganglioside Recognition.

Cell delivery of therapeutic macromolecules and nanoparticles is a critical drug development challenge. Translocation through lipid raft-mediated endocytic mechanisms is being sought, as it can avoid rapid lysosomal degradation. Here, we present a set of short α/ß-peptide tags with high affinity to the lipid raft-associated ganglioside GM1. These sequences induce effective internalization of the attached immunoglobulin cargo. The structural requirements of the GM1-peptide interaction are presented, and the importance of the membrane components are shown. The results contribute to the development of a receptor-based cell delivery platform.

Special Issue 'Advanced and High Performance Metallic Foams'.

Metallic foams are developing more and more [...].

Fracture Toughness of Hollow Glass Microsphere-Filled Iron Matrix Syntactic Foams.

In this study, iron-based metal matrix syntactic foam (MMSF) containing hollow glass microspheres as filler was investigated with respect to notch sensitivity aspects. The MMSF was produced by means of metal powder injection molding. The notch sensitivity was studied via (i) elastic-plastic fracture mechanics measurements (determination of R-curves based on three-point bending tests) and (ii) Charpy impact tests. In both cases, the samples were machined with two different (U- and V-shaped) notch geometries. The critical J-integral value was determined for both notch types, which resulted in lower fracture toughness values in the case of the V-shaped notches and thus notch sensitivity of the material. This finding can be connected to the characteristics of the deformation zone and the associated stress concentration at the tip of the machined notches. The results were confirmed by Charpy impact tests showing ~30% higher impact energy in the case of the U-shaped notch. The failure modes were investigated by means of scanning electron microscopy. In contrast to the bulk material, the MMSF showed brittle fracture behavior.

Routing Nanomolar Protein Cargoes to Lipid Raft-Mediated/Caveolar Endocytosis through a Ganglioside GM1-Specific Recognition Tag.

There is a pressing need to develop ways to deliver therapeutic macromolecules to their intracellular targets. Certain viral and bacterial proteins are readily internalized in functional form through lipid raft-mediated/caveolar endocytosis, but mimicking this process with protein cargoes at therapeutically relevant concentrations is a great challenge. Targeting ganglioside GM1 in the caveolar pits triggers endocytosis. A pentapeptide sequence WYKYW is presented, which specifically captures the glycan moiety of GM1 (K D = 24 nm). The WYKYW-tag facilitates the GM1-dependent endocytosis of proteins in which the cargo-loaded caveosomes do not fuse with lysosomes. A structurally intact immunoglobulin G complex (580 kDa) is successfully delivered into live HeLa cells at extracellular concentrations ranging from 20 to 160 nm, and escape of the cargo proteins to the cytosol is observed. The short peptidic WYKYW-tag is an advantageous endocytosis routing sequence for lipid raft-mediated/caveolar cell delivery of therapeutic macromolecules, especially for cancer cells that overexpress GM1.

Synthesis and Statistical Optimization of Poly (Lactic-Co-Glycolic Acid) Nanoparticles Encapsulating GLP1 Analog Designed for Oral Delivery.

PURPOSE: To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. METHODS: PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. RESULTS: Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. CONCLUSION: Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract.

Dual Action of the PN159/KLAL/MAP Peptide: Increase of Drug Penetration across Caco-2 Intestinal Barrier Model by Modulation of Tight Junctions and Plasma Membrane Permeability.

The absorption of drugs is limited by the epithelial barriers of the gastrointestinal tract. One of the strategies to improve drug delivery is the modulation of barrier function by the targeted opening of epithelial tight junctions. In our previous study the 18-mer amphiphilic PN159 peptide was found to be an effective tight junction modulator on intestinal epithelial and blood⁻brain barrier models. PN159, also known as KLAL or MAP, was described to interact with biological membranes as a cell-penetrating peptide. In the present work we demonstrated that the PN159 peptide as a penetration enhancer has a dual action on intestinal epithelial cells. The peptide safely and reversibly enhanced the permeability of Caco-2 monolayers by opening the intercellular junctions. The penetration of dextran molecules with different size and four efflux pump substrate drugs was increased several folds. We identified claudin-4 and -7 junctional proteins by docking studies as potential binding partners and targets of PN159 in the opening of the paracellular pathway. In addition to the tight junction modulator action, the peptide showed cell membrane permeabilizing and antimicrobial effects. This dual action is not general for cell-penetrating peptides (CPPs), since the other three CPPs tested did not show barrier opening effects.

Notch (In)Sensitivity of Aluminum Matrix Syntactic Foams.

Aluminum alloy (Al99.5 or AlSi12)-based metal matrix syntactic foams (MMSFs) were produced by pressure infiltration with ~65 vol % Globocer filler (33 wt % Al2O3, 48 wt % SiO2, 19 wt % Al2O3∙SiO2). The infiltrated blocks were machined by different geometry tools in order to produce notched samples. The samples were loaded in three-point bending, and the loading force values were recorded against the cross-head displacements and the crack opening displacements. To measure up the notch sensitivity and toughness of the MMSFs, the fracture energies and the fracture toughness values were determined. The results showed that the mentioned quantities are needed to describe the behavior of MMSFs. The fracture energies were shown to be notch-sensitive, while the fracture toughness values were dependent only on the matrix material and were insensitive to the notch geometry. The complex investigation of the fracture surfaces revealed strong bonding between the hollow spheres and the Al99.5 matrix due to a chemical reaction, while this bonding was found to be weaker in the case of the AlSi12 matrix. This difference resulted in completely different crack propagation modes in the case of the different matrices.

Foldameric probes for membrane interactions by induced ß-sheet folding.

Design strategies were devised for α/ß-peptide foldameric analogues of the antiangiogenic anginex with the goal of mimicking the diverse structural features from the unordered conformation to a folded ß-sheet in response to membrane interactions. Structure-activity relationships were investigated in the light of different ß-sheet folding levels.

Compressive Behavior and Microstructural Characteristics of Iron Hollow Sphere Filled Aluminum Matrix Syntactic Foams.

Iron hollow sphere filled aluminum matrix syntactic foams (AMSFs) were produced by low pressure, inert gas assisted infiltration. The microstructure of the produced AMSFs was investigated by light and electron microscopy, extended by energy dispersive X-ray spectroscopy and electron back-scattered diffraction. The investigations revealed almost perfect infiltration and a slight gradient in the grain size of the matrix. A very thin interface layer that ensures good bonding between the hollow spheres and the matrix was also observed. Compression tests were performed on cylindrical specimens to explore the characteristic mechanical properties of the AMSFs. Compared to other (conventional) metallic foams, the investigated AMSFs proved to have outstanding mechanical properties (yield strength, plateau strength, etc.) and energy absorbing capability.