An On-Demand Drug Delivery System for Control of Epileptiform Seizures.

Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal-entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans.

Encapsulation of Electrically Conductive Apparel Fabrics: Effects on Performance.

Electrically conductive fabrics are achieved by functionalizing with treatments such as graphene; however, these change conventional fabric properties and the treatments are typically not durable. Encapsulation may provide a solution for this, and the present work aims to address these challenges. Next-to-skin wool and cotton knit fabrics functionalized using graphene ink were encapsulated with three poly(dimethylsiloxane)-based products. Properties known to be critical in a next-to-skin application were investigated (fabric structure, moisture transfer, electrical conductivity, exposure to transient ambient conditions, wash, abrasion, and storage). Wool and cotton fabrics performed similarly. Electrical conductivity was conferred with the graphene treatment but decreased with encapsulation. Wetting and high humidity/low temperature resulted in an increase in electrical conductivity, while decreases in electrical conductivity were evident with wash, abrasion, and storage. Each encapsulant mitigated effects of exposures but these effects differed slightly. Moisture transfer changed with graphene and encapsulants. As key performance properties of the wool and cotton fabrics following treatment with graphene and an encapsulant differed from their initial state, use as a patch integrated as part of an upper body apparel item would be acceptable.

The Synthesis of Multifunctionalized 1,3-Oxazin-4-ones from Donor-Acceptor Cyclopropanes.

A series of electronically diverse imines were found to readily react with various donor-acceptor cyclopropyl acid chlorides, with complete regioselectivity, to form 1,3-oxazin-4-ones in moderate yields (25-48% over two steps). Select oxazinones underwent a base induced rearrangement to afford the corresponding cycloheptene-fused oxazinones in good yields (up to 70%).

Signaled drug delivery and transport across the blood-brain barrier.

We use a mathematical model to describe the delivery of a drug to a specific region of the brain. The drug is carried by liposomes that can release their cargo by application of focused ultrasound (US). Thereupon, the drug is absorbed through the endothelial cells that line the brain capillaries and form the physiologically important blood-brain barrier (BBB). We present a compartmental model of a capillary that is able to capture the complex binding and transport processes the drug undergoes in the blood plasma and at the BBB. We apply this model to the delivery of levodopa (L-dopa, used to treat Parkinson's disease) and doxorubicin (an anticancer agent). The goal is to optimize the delivery of drug while at the same time minimizing possible side effects of the US.

Expedient metal-free synthesis of 1,3-oxazinen-4-ones.

1,3-Oxazinen-4-ones are medicinally important scaffolds which have traditionally been accessed using a hetero-Diels-Alder approach or more recently using a cobalt-catalyzed three-component cycloaddition. Herein we report a novel strategy to access this scaffold which allows for the rapid and high yielding synthesis of 1,3-oxazinen-4-ones under ambient temperature and pressures with improved substrate scope.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

1-Tetra-decyl-pyridinium bromide monohydrate.

In the title compound, C(19)H(34)N(+)·Br(-)·H(2)O, the dihedral angle between the trans-planar alkyl side chain and the pyridinium ring is 52.73 (7)°. In the crystal structure, O-H⋯Br, C-H⋯Br and C-H⋯O hydrogen bonds form a network, while the hydro-phobic alkyl chains inter-digitate, forming bilayers.

Adhesive secretions of live mussels observed in situ by attenuated total reflection-infrared spectroscopy.

The chemical species involved in the adhesion of blue mussels (Mytilus galloprovincialis) and greenshell mussels (Perna canaliculus) to surfaces has been investigated using in situ attenuated total reflection infrared (ATR-IR) spectroscopy. Mussel spat ranging in size from 0.5 to 25 mm were placed in a flow cell containing a ZnSe multiple internal reflection prism and supplied with temperature-controlled seawater. Distinctively different absorption spectra were obtained when the mussels were predominantly moving across the surface or forming permanent bonds. With limited movement, the absorption spectrum was characteristic of protein with peaks near 1647 cm-1 (amide I), 1543 cm-1 (amide II), and 1235 cm-1 (amide III). When the mussels were observed to be moving across the surface of the ATR-IR crystal there was a strong broad absorption maximum around 1200-900 cm-1 (carbohydrate polymers), presumably due to the secretion of a weakly acidic mucopolysaccharide. Distinct differences in the spectra obtained from the adhesive secretions of blue or greenshell mussels were not observed. The data presented is the first reported use of IR spectroscopy to obtain in situ, real-time, chemical data on the interactions between invertebrates and substrates immersed in sea water.

Synthesis and evaluation of bifunctional nitrocatechol inhibitors of pig liver catechol-O-methyltransferase.

Bifunctional compounds were tested in vitro as potential inhibitors of pig liver catechol-O-methyltransferase (COMT) with respect to the catechol substrate 4-[(3,4-dihydroxyphenyl)azo]benzenesulfonate. The bifunctional compounds were a composite of either two nitrocatechols or one nitrocatechol and one phenol, linked by amide bonds to a spacer unit comprising two to five methylene groups. The unsymmetrical compounds N-[2-(4-hydroxybenzoylamine)ethyl]-3,4-dihydroxy-5-nitrobenzamide], N-[3-(4-hydroxybenzoyl-amine)propyl]-3,4-dihydroxy-5-nitrobenzamide] and N-[5-(4-hydroxybenzoylamine)pentyl]-3,4-dihydroxy-5-nitrobenzamide] demonstrated strong inhibitory action against COMT with K(i) values in the 100 nM range. In comparison, the monofunctional nitrocatechol analogues of these compounds had K(i) values that were significantly higher.

A colormetric assay for catechol-O-methyltransferase.

A series of catechol diazo dyes were synthesized and tested as substrates for the enzyme catechol-O-methyltransferase (COMT) with the aim of developing a sensitive HPLC assay method using visible wavelength light detection. A method was developed which allowed for the determination of the two regioisomeric methylated products of the COMT catalyzed reaction of 4-[(3,4-dihydroxyphenyl)azo]benzenesulfonate with S-adenosylmethionine (AdoMet). Separation of the assay components was achieved by reverse phase chromatography using an isocratic mobile phase. No pre-preparation of the assay samples was required.

A polar effects controlled enantioselective 1,2-chlorine atom migration via a chlorine-bridged radical intermediate.

An enantioselective 1,2-chlorine atom migration was observed in the tributyltin hydride reduction of various dihalogenated dihydrocinnamic acid derivatives. It is proposed that the reduction involves the formation of a chlorine-bridged radical intermediate, followed by hydrogen atom transfer to either the beta- or the alpha-carbon. The product distribution is affected by electron-withdrawing groups in that hydrogen atom transfer to the proximate carbon is favored. Presumably, this is due to the transition state of the hydrogen delivery step being electron rich, due to the relatively electropositive tin radical. These results demonstrate a 1,2-chlorine atom migration reaction governed by polar effects.