Effect of zymosan and poly (I:C) adjuvants on responses to microneedle immunization coated with whole inactivated influenza vaccine.

Microneedles are the micrometer size devices used for the delivery of vaccines and biotherapeutics. In order to increase the vaccine efficacy and reduce the antigen dose, there is a significant need to find some adjuvants for the microneedle vaccination. In this study, zymosan, which is the cell wall preparation of Saccharomyces cerevisiae, or poly (I:C) was coated on a microneedle with inactivated influenza virus, and then immunized into BALB/c mouse to determine the immunogenicity, protection and synergetic effect between two adjuvants. As a result, the group administered with zymosan and vaccine antigen showed significantly stronger IgG response, HI titer and IgG subtypes without any adverse effects, compared to the group immunized with the vaccine antigen alone. Also, there were enhanced cellular immune responses in the group received adjuvant with vaccine antigen. In addition, they showed superior protection and lung viral reduction against lethal viral challenge. Taken together, this study confirms that zymosan can be used as an immunostimulant for microneedle vaccination.

A novel electroporation system for efficient molecular delivery into Chlamydomonas reinhardtii with a 3-dimensional microelectrode.

Electroporation is one of the most widely used transfection methods because of its high efficiency and convenience among the various transfection methods. Previous micro-electroporation systems have some drawbacks such as limitations in height and design, time-consuming and an expensive fabrication process due to technical constraints. This study fabricates a three dimensional microelectrode using the 3D printing technique. The interdigitated microstructure consisting of poly lactic acid was injected by a 3D printer and coated with silver and aluminum with a series of dip-coatings. With the same strength of electric field (V cm(-1)), a higher efficiency for molecular delivery and a higher cellular viability are achieved with the microelectrode than with a standard cuvette. In addition, this study investigates chemicophysical changes such as Joule heating and dissolved metal during electroporation and showed the micro-electroporation system had less chemicophysical changes. It was concluded that the proposed micro-electroporation system will contribute to genetic engineering as a promising delivery tool, and this combination of 3D printing and electroporation has many potential applications for diverse designs or systems.

Piezoelectric two-dimensional nanosheets/anionic layer heterojunction for efficient direct current power generation.

Direct current (DC) piezoelectric power generator is promising for the miniaturization of a power package and self-powering of nanorobots and body-implanted devices. Hence, we report the first use of two-dimensional (2D) zinc oxide (ZnO) nanostructure and an anionic nanoclay layer to generate piezoelectric DC output power. The device, made from 2D nanosheets and an anionic nanoclay layer heterojunction, has potential to be the smallest size power package, and could be used to charge wireless nano/micro scale systems without the use of rectifier circuits to convert alternating current into DC to store the generated power. The combined effect of buckling behaviour of the ZnO nanosheets, a self-formed anionic nanoclay layer, and coupled semiconducting and piezoelectric properties of ZnO nanosheets contributes to efficient DC power generation. The networked ZnO nanosheets proved to be structurally stable under huge external mechanical loads.

Inverted organic solar cells with ZnO nanowalls prepared using wet chemical etching in a KOH solution.

We report on the photovoltaic (PV) performances of inverted organic solar cells (IOSCs) that were fabricated from PCBM:P3HT polymer with a ZnO thin film and ZnO nanowalls as electron transport and hole block layers. ZnO thin film on ITO/glass substrate was deposited using a simply aqueous solution route. ZnO nanowall structures were obtained via wet chemical etching of ZnO thin films in a KOH solution. The power conversion efficiency (PCE) of the IOSC with ZnO nanowalls was significantly improved by 44% from 1.254% to 1.811% compared to that of the IOSC with ZnO thin film. The short circuit current in IOSCs fabricated with the ZnO nanowalls was increased mainly due to the increase in the charge transport interface area, as a result of enhancement in the PCE. This work suggests a method for fabricating efficient PV devices with a larger charge transport area for future prospects.

p-Type polymer-hybridized high-performance piezoelectric nanogenerators.

Enhancing the output power of a nanogenerator is essential in applications as a sustainable power source for wireless sensors and microelectronics. We report here a novel approach that greatly enhances piezoelectric power generation by introducing a p-type polymer layer on a piezoelectric semiconducting thin film. Holes at the film surface greatly reduce the piezoelectric potential screening effect caused by free electrons in a piezoelectric semiconducting material. Furthermore, additional carriers from a conducting polymer and a shift in the Fermi level help in increasing the power output. Poly(3-hexylthiophene) (P3HT) was used as a p-type polymer on piezoelectric semiconducting zinc oxide (ZnO) thin film, and phenyl-C(61)-butyric acid methyl ester (PCBM) was added to P3HT to improve carrier transport. The ZnO/P3HT:PCBM-assembled piezoelectric power generator demonstrated 18-fold enhancement in the output voltage and tripled the current, relative to a power generator with ZnO only at a strain of 0.068%. The overall output power density exceeded 0.88 W/cm(3), and the average power conversion efficiency was up to 18%. This high power generation enabled red, green, and blue light-emitting diodes to turn on after only tens of times bending the generator. This approach offers a breakthrough in realizing a high-performance flexible piezoelectric energy harvester for self-powered electronics.

Poly(ethylene oxide/propylene oxide) copolymer thermo-reversible gelling system for the enhancement of intranasal zidovudine delivery to the brain.

The purpose of this study was to investigate the olfactory transfer of zidovudine (ZDV) after intranasal (IN) administration and to assess the effect of thermoreversible gelling system on its absorption and brain uptake. The nasal formulation was prepared by dissolving ZDV in pH 5.5 phosphate buffer solution comprising of 20% polyethylene oxide/propylene oxide (Poloxamer 407, PLX) as thermoreversible gelling agent and 0.1% n-tridecyl-ß-D-maltoside (TDM) as permeation enhancer. This formulation exhibited a sufficient stability and an optimum gelation profile at 27-30 °C. The in vitro permeation studies across the freshly excised rabbit nasal mucosa showed a 53% increase in the permeability of ZDV from the formulation. For in vivo evaluation, the drug concentrations in the plasma, cerebrospinal fluid (CSF) and six different regions of the brain tissues, i.e. olfactory bulb (OB), olfactory tract (OT), anterior, middle and posterior segments of cerebrum (CB), and cerebellum (CL) were determined by LC/MS method following IV and IN administration in rabbits at a dose of 1mg/kg. The IN administration of Poloxamer 407 and TDM based formulation showed a systemic bioavailability of 29.4% while exhibiting a 4 times slower absorption process (t(max) = 20 min) than control solution (t(max) = 5 min). The CSF and brain ZDV levels achieved after IN administration of the gelling formulation were approximately 4.7-56 times greater than those attained after IV injection. The pharmacokinetic and brain distribution studies revealed that a polar antiviral compound, ZDV could preferentially transfer into the CSF and brain tissue via an alternative pathway, possibly olfactory route after intranasal administration.

Direct nose-to-brain transfer of a growth hormone releasing neuropeptide, hexarelin after intranasal administration to rabbits.

The purpose of this study was to investigate the olfactory transfer of a growth hormone releasing neuropeptide, hexarelin to the brain tissues by comparing brain uptake levels after intranasal administration with those after intravenous administration. The hexarelin nasal formulation was prepared using an aqueous cosolvent vehicle consisting of ethanol, propylene glycol, and n-tridecyl-beta-D-maltoside as a permeation enhancer. Hexarelin was administered intravenously or intranasally to male rabbits at a dose of 1 mg/kg. Drug concentrations in the plasma, cerebrospinal fluid and six different regions of the brain, i.e., olfactory bulb (OB), olfactory tract (OT), anterior (CB1), middle (CB2), posterior (CB3) cerebrum, and cerebellum (CL) were analyzed by LC/MS method after solid phase extraction. The brain and cerebrospinal fluid levels achieved following intranasal administration were approximately 1.6 times greater than those attained after intravenous administration despite the intranasal plasma levels being significantly lower than the intravenous plasma levels. Intranasal administration resulted in significantly different spatial distribution patterns in various regions of brain with the rank order of C(OB)>C(OT)>C(CB1, CB2, CB3)>C(CL) at 10, 20, and 40 min post-dosing, whereas intravenous administration yielded nearly similar distribution patterns in the brain. The intranasal administration into one nostril (left or right) exhibited markedly greater hexarelin concentrations in olfactory bulb and olfactory tract on the treated-side of brain tissues than those on the non-treated-side of the brain hemisphere. It was demonstrated that the hydrophilic neuropeptide hexarelin was transferred via olfactory pathway to the brain hemispheres and the drug transfer via this route significantly contributed to high brain concentrations after nasal administration to rabbits.

Studies of chitosan/organic acid/Eudragit RS/RL-coated system for colonic delivery.

Prednisolone (PDS) beads were coated sequentially with (i) innermost hydrophobic layer of Eudragit RS/RL, (ii) middle drug release-triggering layer of chitosan, organic acid and Eudragit RS/RL, and (iii) outermost enteric coating layer. Continuous dissolution studies were carried out in artificial gastric fluid (pH 1.2), followed by intestinal fluid (pH 6.8), and finally in colonic fluid (pH 4 and 6) with and without beta-glucosidase. While drug release was prevented in the gastric and small-intestinal fluids, a continuous release was observed in the colonic fluid. Succinic acid provided the fastest rate of release in the colonic fluid compared to citric, tartaric or malic acid. A combined mechanism of drug release is proposed, which considers the swelling of chitosan and Eudragit RS/RL in the presence of succinic acid possibly via electrostatic interaction between the amine groups of chitosan/quaternary ammonium groups of Eudragit RS/RL and the carboxyl groups of succinic acid in aqueous medium. The results of plasma pharmacokinetic studies in Sprague-Dawley rats showed that the developed system provided a significant delay (T(max) 9.3 h) in the absorption profile of PDS compared with simple enteric-coated (T(max) 4 h) or powder (T(max) 1 h) formulation that was taken as proof for the colon-targeted delivery.

Pharmacokinetics and brain uptake of diazepam after intravenous and intranasal administration in rats and rabbits.

The purpose of this study was to investigate the plasma pharmacokinetics and brain uptake of a lipophilic benzodiazepine anticonvulsant, diazepam in New Zealand white rabbits and Sprague-Dawley rats to evaluate the possible absorption pathways after intravenous and intranasal administration. The intranasal formulation was prepared by dissolving DZ and 1% sodium glycocholate into microemulsion system composed of 15% ethyl laurate, 25% Labrasol, 37.5% Transcutol P, 12.5% ethanol, and 10% water. Diazepam was administered intravenously (1 mg/kg) or intranasally (2 mg/kg) to rats and rabbits. Drug concentrations in the plasma and six different regions of the brain tissues, i.e., olfactory bulb, olfactory tract, anterior, middle, and posterior segments of cerebrum and cerebellum were analyzed by LC/MS method after solid phase extraction. After i.n. administration, DZ was rapidly absorbed into the systemic circulation, and readily and homogeneously distributed into the different regions of brain tissues with a t(max) of 5 and 10 min in rats and rabbits, respectively. The bioavailability of DZ in rat plasma (68.4%) and brain (67.7%) were 32-47% higher than those observed in rabbit plasma (51.6%) and brain (45.9%). The AUC(brain)/AUC(plasma) ratios in rabbits after i.n. administration (3.77+/-0.17) were slightly lower than from i.v. administration (4.23+/-0.08). However, in rats the AUC(brain)/AUC(plasma) ratios after i.v. (3.03+/-0.07) and i.n. (3.00+/-0.32) administration were nearly identical. The plasma pharmacokinetic and distribution studies in the two animal models clearly showed that lipophilic DZ molecules reached the brain predominantly from the blood by crossing the blood-brain barrier after i.n. administration with no significant direct nose-to-brain transport via olfactory epithelium.