Preparation of nanoparticles by the self-organization of polymers consisting of hydrophobic and hydrophilic segments: Potential applications

AbstractThis review describes the preparation of core-corona type polymeric nanoparticles and their applications in various technological and biomedical fields. Over the past two decades, we have studied the synthesis and clinical applications of core-corona polymeric nanoparticles composed of hydrophobic polystyrene and hydrophilic macromonomers. These nanoparticles were utilized as catalyst carriers, carriers for oral peptide delivery, virus capture agents, and vaccine carriers, and so on. Moreover, based on this research, we attempted to develop novel biodegradable nanoparticles composed of hydrophobic poly(γ-glutamic acid) (γ-PGA) derivatives (γ-hPGA). Various model proteins were efficiently entrapped on/into the nanoparticles under different conditions: encapsulation, covalent immobilization, and physical adsorption. The encapsulation method showed the most promising results for protein loading. It is expected that biodegradable γ-hPGA nanoparticles can encapsulate and immobilize various biomacromolecules. Nanoparticles consisting of hydrophobic and hydrophilic segments have great potential as multifunctional carriers for pharmaceutical and biomedical applications, such as drug, protein, peptide or DNA delivery systems

Impact of ganglionated plexi ablation on high-frequency stimulation-induced changes in atrial fibrillation cycle length in the pulmonary vein

AbstractBackgroundWe assessed high-frequency stimulation (HFS)-induced changes in the atrial fibrillation (AF) cycle length (AFCL) in the pulmonary vein (PV) after ganglionated plexi (GP) ablation.MethodsTwenty-two patients undergoing catheter ablation for AF were retrospectively enrolled. Sites showing a vagal response (VR) to HFS were defined as GP-positive sites. AFCL was determined in the adjacent PV, distant PV, coronary sinus, and right atrium. Twenty cycles were counted before and after each HFS. After radiofrequency application to the GP site, HFS was repeated.ResultsAt GP-positive sites (n=57), significant shortening of the AFCL was detected in the adjacent PV (17% shortening, 165±38 to 137±27ms, p<0.001) and distant PV (4.8% shortening, p<0.001), but not in the coronary sinus (0.8% shortening, p=0.27) or right atrium (1.8% shortening, p=0.06). However, no significant shortening was observed at GP-negative sites (n=25). At 41 of the 57 sites where VR disappeared after a single radiofrequency application, no significant shortening was observed in the adjacent PV (2.1% shortening, p=0.25). At 16 of the 57 sites where VR was still present, significant shortening was observed in the adjacent PV (16% shortening, p<0.001).ConclusionsHFS of the GP has a strong influence on AFCL in the PV

Uptake of biodegradable poly(γ-glutamic acid) nanoparticles and antigen presentation by dendritic cells in vivo

AbstractPoly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs) carrying antigens have been shown to induce potent antigen-specific immune responses. However, in vivo delivery of γ-PGA NPs to dendritic cells (DCs), a key regulator of immune responses, still remains unclear. In this study, γ-PGA NPs were examined for their uptake by DCs and subsequent migration from the skin to the regional lymph nodes (LNs) in mice. After subcutaneous injection of fluorescein 5-isothiocyanate (FITC)-labeled NPs or FITC-ovalbumin (OVA)-carrying NPs (FITC-OVA-NPs), DCs migrated from the skin to the LNs and maturated, resulting in the upregulation of the costimulatory molecules CD80 and CD86 and the chemokine receptor CCR7. However, the migrated DCs were not detected in the spleen. FITC-OVA-NPs were found to be taken up by skin-derived CD103+ DCs, and the processed antigen peptides were cross-presented by the major histocompatibility complex (MHC) class I molecule of DCs. Furthermore, significant activation of antigen-specific CD8+ T cells was observed in mice immunized with OVA-carrying NPs (OVA-NPs) but not with OVA alone or OVA with an aluminum adjuvant. The antigen-specific CD8+ T cells were induced within 7 days after immunization with OVA-NPs. Thus, γ-PGA NPs carrying various antigens may have great potential as an antigen-delivery system and vaccine adjuvant in vivo

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

Rationale: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). Objectives: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. Methods: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. Results: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. Conclusions: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotic

Treating the placenta to prevent adverse effects of gestational hypoxia on fetal brain development.

Some neuropsychiatric disease, including schizophrenia, may originate during prenatal development, following periods of gestational hypoxia and placental oxidative stress. Here we investigated if gestational hypoxia promotes damaging secretions from the placenta that affect fetal development and whether a mitochondria-targeted antioxidant MitoQ might prevent this. Gestational hypoxia caused low birth-weight and changes in young adult offspring brain, mimicking those in human neuropsychiatric disease. Exposure of cultured neurons to fetal plasma or to secretions from the placenta or from model trophoblast barriers that had been exposed to altered oxygenation caused similar morphological changes. The secretions and plasma contained altered microRNAs whose targets were linked with changes in gene expression in the fetal brain and with human schizophrenia loci. Molecular and morphological changes in vivo and in vitro were prevented by a single dose of MitoQ bound to nanoparticles, which were shown to localise and prevent oxidative stress in the placenta but not in the fetus. We suggest the possibility of developing preventative treatments that target the placenta and not the fetus to reduce risk of psychiatric disease in later life

Inkjet printing of layer-by-layer assembled poly(lactide) stereocomplex with encapsulated proteins

Inkjet printing, a technique that precisely deposits liquid droplets in picoliter-volume ranges on a substrate, has received increased attention for its novelty and ability to produce functional materials. This technology is considered one of the most promising methods for the controlled deposition of different polymers. In our previous study, a poly(lactide) (PLA) stereocomplex was fabricated using inkjet printing on a substrate. The stereocomplex was formed by the layer-by-layer (LbL) stepwise deposition of poly(l-lactide) (PLLA) and poly(d-lactide) (PDLA). Multiple inkjet passes could conclusively improve the PLAs crystal structure with solvent evaporation (solidification) and dissolution of PLA. We suggested that this technique may also be applicable for fabricating polymer composites with drugs, such as peptides, proteins, and nanoparticles, which is incompatible with the PLA. Here, we report the utilization of this technique to create a PLA stereocomplex with drugs as a drug carrier/reservoir. The three components of PLLA, PDLA, and model drugs (an 8-mer peptide, ovalbumin, and protein-encapsulating nanoparticles) were alternately overprinted onto the substrate without an intermediate rinsing step. Inkjet printing was used successfully to form PLA stereocomplex composites with drugs by the LbL deposition of polymers and functioned as drug carriers/reservoirs. The sustained release of the drugs was observed from the PLLA/PDLA/drug composites. By varying the crystalline structure of PLAs-drug composites, the release kinetics of drugs could be altered and controlled efficiently. Moreover, a high drug loading content (wt %) of PLA stereocomplex composites was achieved up to 100 wt % loading, and the composites with 50 wt % of drug loading content were available for sustained-release formulation. This fabrication technique would provide a platform for creating protein/vaccine/gene delivery carriers with the desired release profiles by controlling the microphase-separated structure and drug distribution within the composites. © 2014 American Chemical Society