Jürgen Linders

pH-switchable vesicles from a serine-derived guanidiniocarbonyl pyrrole carboxylate zwitterion in DMSO.

This work describes a new type of vesicles that can be reversibly opened and closed by changing the protonation state of a self-assembling zwitterion. Vesicles are interesting nanomaterials with potential applications such as delivery systems for drug targeting. For this purpose, however, external control of vesicle formation is required. To date, vesicle formation has often been based on the self-assembly of amphiphilic macromolecules such as lipid derivatives or block copolymers. 2] Recently, vesicle formation from other types of building blocks, such as shape-persistent macrocyles, cyclodextrins, or small peptides has also been reported. Most of these molecules are still classical amphiphiles and their self-assembly is mainly driven by hydrophobic or aromatic interactions. We have recently introduced a new type of vesicle forming-molecule, namely a self-complementary guanidiniocarbonyl pyrrole carboxylate zwitterion derived from alanine. We have shown by NOESY NMR studies in combination with TEM and AFM experiments that, in DMSO, the zwitterion forms ion-paired dimers that then further aggregate into hollow vesicles of approximately 40–50 nm diameter. We have also used this special type of hydrogen-bond-assisted ion-pair formation between the guanidiniocarbonyl pyrrole cation and a carboxylate unit for the construction of other types of nanostructures such as dimers, loops, and supramolecular polymers. As the guanidiniocarbonyl pyrrole moiety has an approximate pKa value of 6–7, ion-pair formation with a carboxylate (pKa ca. 3–5) only occurs within a narrow pH range. This restriction offers the possibility to deliberately turn the ion-pair formation on or off by changing the pH from neutral to slightly acidic or basic. We therefore wanted to explore whether we can also trigger vesicle formation by using pH as an external signal. To test this hypothesis, we have synthesized a serine-derived guanidiniocarbonyl pyrrole carboxylate zwitterion 3 and studied its vesicle formation on surface with AFM as well as in solution by using dynamic light scattering (DLS) and a pulsed field gradient(PFG)-based NMR method. The latter method allows us to selectively detect the solvent molecules encapsulated in the vesicles and also to quantify the permeability of the vesicle membranes. We show herein that vesicle formation of 3 can indeed be switched on and off in a controlled manner by reversible changes of its protonation state. Furthermore, we found that the vesicles are rather impermeable and the measured exchange rate of solvent molecules across the membrane is very small. The synthesis of the serine-derived guanidiniocarbonyl pyrrole carboxylate zwitterion 3 is shown in Scheme 1. l-serine methyl ester hydrochloride 2 was coupled with the

Hydrogels from phospholipid vesicles.

It is shown that phospholipid dispersions with a few percent of diacylphosphocholine PC in water can be swollen to single-phase lyotropic liquid crystalline Lα-phases by the addition of co-solvents like glycerol, 1,3-butyleneglycol BG or 1,2-propyleneglycol PG. The birefringent Lα-phases contain small unilamellar and multilamellar vesicles if the temperature of the samples is above the Krafft-Temperature Tm of the phospholipid. When such transparent birefringent viscous samples are cooled down below Tm the samples are transformed into birefringent gels. Cryo-TEM and FF-TEM measurements show that the bilayers of the vesicles are transformed from the liquid to the crystalline state during the transformation while the vesicle structure remains. The bilayers of the crystalline vesicles form adhesive contacts in the gel. Pulsed-field gradient NMR measurements show that two different kinds of water or co-solvent can be distinguished in the gels. One type of solvent molecules can diffuse like normal solvent in a continuous bulk phase. A second type of water diffuses much more slowly. This type of solvent is obviously trapped in the vesicles. The permeability of the crystalline vesicles for water and solvent molecules is much lower in the crystalline state than in the fluid state. Maximum swelling of the diacylphosphocholin dispersions occurs when the refractive index of the solvent is matched to the refractive index of the bilayers. The attraction between the bilayers is at a minimum in this state and the liquid crystalline Lα-phases undulation forces between the bilayers push the bilayers apart. On transformation to the gel state the crystalline bilayers assume a high elastic bending rigidity. Undulations of the bilayers are now suppressed, and the bilayers can form adhesive contacts. Oscillating rheological measurements show that the gels with only 1% of phospholipids can have a storage modulus of 1000Pa. The gels are very brittle. They break when they are deformed by a few percent.

Polyalkylcyanoacrylate Nanocapsules: Variation of Membrane Permeability by Chemical Cross-Linking

The permeability of the polymer walls of polyalkylcyanoacrylate nanocapsules varies by different degrees of chemical cross-linking. For this reason, different amounts of bivalent alkylcyanoacrylates are added to the monovalent alkylcyanoacrylate prior to an interfacial polymerization step in order to generate capsules with various cross-linking densities. The obtained nanocapsules are characterized by observing the water molecules via pulsed field-gradient nuclear magnetic resonance using a stimulated echo sequence. The resulting echo decay plots reveal the exchange rate of the water molecules between the free and encapsulated states. The observed dwell times of water molecules in the encapsulated state are characteristic parameters for the permeability of the given capsule membranes. They show a clear dependence on the degree of cross-linking, proving the potential of this approach for a controlled variation of the capsule permeability. Also, the cross-linked nanocapsules exhibit a significantly decreased solubility in tetrahydrofuran which may lead to new applications for polyalkylcyanoacrylate nanocapsules in organic solvents.

PFG-NMR self-diffusion measurements in the single phase channels of a microemulsion system with an anionic–nonionic surfactant mixture

The single phase channels of a presently reported microemulsion system were investigated by electrical conductivity and pulsed-field gradient nuclear magnetic resonance (PFG-NMR) spectroscopy. The system consists of a mixed anionic–non-ionic surfactant mixture, water and decane. At constant surfactant concentration and temperature, the phase diagram exhibits two single phase microemulsion channels, separated by an anisotropic lamellar channel. The lower microemulsion channel starts from the water side of the phase diagram with a micellar L1 phase and reaches the middle of the phase diagram with increasing mass fraction of decane in the solvent mixture and increasing mass fraction of lipophilic co-surfactant in the surfactant mixture. The upper microemulsion channel passes from the aqueous side with an L3 phase to the oil side of the diagram. Conductivity data and self-diffusion coefficients, obtained by PFG-NMR, support the previously made conclusion that the nanostructure in the upper channel undergoes an abrupt transition from a bicontinuous structure to a water-in-oil High Internal Phase Microemulsion (HIPME) with already less than 10% of oil in the solvent mixture, while the structures in the lower microemulsion channel are oil-in-water droplets. The HIPME structure is a feature of the surfactant mixture and probably formed due to a high interfacial tension between the aqueous diluted surfactant phase and the oil. By the addition of salt, the HIPME structures are obviously disturbed, resulting in an increased conductivity and self-diffusion rate for the water fraction.

Functionality of albumin-derived perfluorocarbon-based artificial oxygen carriers in the Langendorff-heart†

Abstract The aim of this study was to prove whether albumin-derived perfluorocarbon-based nanoparticles (capsules) can operate as a novel artificial oxygen carrier in a rat Langendorff-heart perfusion model. Hearts perfused with capsules showed increased left ventricular pressure and rate pressure product compared to hearts perfused with pure Krebs–Henseleit (KH)-buffer. The capsules prevented the myocardium from functional fail when in their absence a noxious ischemia was observed. Capsules did not change rheological properties of KH-buffer and could repeatedly reload with oxygen. This albumin-derived perfluorocarbon-based artificial oxygen carrier preserved the function of rat hearts due to the transport of oxygen in a satisfactory manner. Because of these positive results, the functionality of the applied capsules should be verified in living animals.

Albumin-derived perfluorocarbon-based artificial oxygen carriers: A physico-chemical characterization and first in vivo evaluation of biocompatibility

&NA; Until today, artificial oxygen carriers have not been reached satisfactory quality for routine clinical treatments. To bridge this gap, we designed albumin‐derived perfluorocarbon‐based nanoparticles as novel artificial oxygen carriers and evaluated their physico‐chemical and pharmacological performance. Our albumin‐derived perfluorocarbon‐based nanoparticles (capsules), composed of an albumin shell and a perfluorodecalin core, were synthesized using ultrasonics. Their subsequent analysis by physico‐chemical methods such as scanning electron‐, laser scanning‐ and dark field microscopy as well as dynamic light scattering revealed spherically‐shaped, nano‐sized particles, that were colloidally stable when dispersed in 5% human serum albumin solution. Furthermore, they provided a remarkable maximum oxygen capacity, determined with a respirometer, reflecting a higher oxygen transport capacity than the competitor Perftoran®. Intravenous administration to healthy rats was well tolerated. Undesirable effects on either mean arterial blood pressure, hepatic microcirculation (determined by in vivo microscopy) or any deposit of capsules in organs, except the spleen, were not observed. Some minor, dose‐dependent effects on tissue damage (release of cellular enzymes, alterations of spleens micro‐architecture) were detected. As our promising albumin‐derived perfluorocarbon‐based nanoparticles fulfilled decisive physico‐chemical demands of an artificial oxygen carrier while lacking severe side‐effects after in vivo administration they should be advanced to functionally focused in vivo testing conditions. Graphical abstract Figure. No caption available.