Polyethylenimine-functionalized cationic barley ß-glucan derivatives for macrophage RAW264.7 cell-targeted gene delivery systems.

Cationic barley ß-glucan derivatives (bGPEIs) with various polyethylenimine 2k (PEI2k) graft degrees were synthesized by periodate oxidation of backbone vicinal diols and reductive amination of PEI2k for gene delivery systems. bGPEIs could form positively charged (∼40 mV zeta-potential) and nano-sized (∼150 nm) spherical polyplexes. Cytotoxicity of bGPEIs was concentration and PEI graft degree-dependent. bGPEIs showed higher transfection efficiency and intracellular localization ability than PEI25k in RAW264.7 cell, especially in serum condition. High cellular uptake of bGPEI polyplexes at 4 °C in RAW264.7 cells suggested that bGPEIs would possess specific interaction ability with membrane receptors of RAW264.7 cells. In addition, bGPEIs could activate RAW264.7 cells, inducing the secretion of cytokine, tumor necrosis factor-α (TNF-α). Therefore, bGPEIs showed a potential for macrophage RAW264.7 cell-targeted gene delivery systems.

Fluorination effect to intermediate molecular weight polyethylenimine for gene delivery systems.

Fluorinated intermediate molecular weight polyethylenimine (FP2ks) with various fluorination degrees was synthesized by conjugation with heptafluorobutyric anhydride and the fluorination effect for gene delivery systems was examined. FP2ks could condense pDNA, forming compact, positively charged, and nano-sized spherical particles. It was thought that their decreased electrostatic interaction with pDNA would be compensated by hydrophobic interaction. The cytotoxicity of FP2ks was increased with the increase of fluorination degree, probably due to the cellular membrane disruption via hydrophobic interaction with FP2ks. The transfection efficiency of highly fluorinated FP2ks was not severely affected in serum condition, assuming their good serum-compatibility. Discrepancy between their higher cellular uptake efficiency and lower transfection efficiency than PEI25k was thought to arise from the formation of compact polyplexes followed by the decreased dissociation of pDNA. It was also suggested that multiple energy-dependent cellular uptake mechanisms and endosome buffering would mediate the transfection of FP2ks.

pH-Responsive i-motif Conjugated Hyaluronic Acid/Polyethylenimine Complexes for Drug Delivery Systems.

i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems.

Phenylboronic Acid-polymers for Biomedical Applications.

BACKGROUND: Phenylboronic acid-polymers (PBA-polymers) have attracted tremendous attention as potential stimuli-responsive materials with applications in drug-delivery depots, scaffolds for tissue engineering, HIV barriers, and biomolecule-detecting/sensing platforms. The unique aspect of PBA-polymers is their interactions with diols, which result in reversible, covalent bond formation. This very nature of reversible bonding between boronic acids and diols has been fundamental to their applications in the biomedical area. METHODS: We have searched peer-reviewed articles including reviews from Scopus, PubMed, and Google Scholar with a focus on the 1) chemistry of PBA, 2) synthesis of PBA-polymers, and 3) their biomedical applications. RESULTS: We have summarized approximately 179 papers in this review. Most of the applications described in this review are focused on the unique ability of PBA molecules to interact with diol molecules and the dynamic nature of the resulting boronate esters. The strong sensitivity of boronate ester groups towards the surrounding pH also makes these molecules stimuli-responsive. In addition, we also discuss how the re-arrangement of the dynamic boronate ester bonds renders PBA-based materials with other unique features such as self-healing and shear thinning. CONCLUSION: The presence of PBA in the polymer chain can render it with diverse functions/ relativities without changing their intrinsic properties. In this review, we discuss the development of PBA polymers with diverse functions and their biomedical applications with a specific focus on the dynamic nature of boronate ester groups.

Layered Double Hydroxide Nanomaterials Encapsulating Angelica gigas Nakai Extract for Potential Anticancer Nanomedicine.

We prepared hybrids consisting of Angelica gigas Nakai (AGN) root or flower extract and layered double hydroxide (LDH) for potential anticancer nanomedicine, as decursin species (DS) in AGN are known to have anticancer activity. Dimethylsulfoxide solvent was determined hybridization reaction media, as it has affinity to both AGN and LDH moiety. In order to develop inter-particle spaces in LDH, a reversible dehydration-rehydration, so-called reconstruction route, was applied in AGN-LDH hybridization. Quantitative analyses on AGN-LDH hybrids indicated that the content of DS was two times more concentrated in the hybrids than in extract itself. Using X-ray diffraction, FT-IR spectroscopy, scanning electron microscopy, and zeta-potential measurement, we found that AGN extract moiety was incorporated into inter-particle spaces of LDH nanoparticles during the reconstruction reaction. Time-dependent DS release from hybrids at pH 7.4 (physiological condition) and pH 4.5 (lysosomal condition) exhibited a pH-dependent release of extract-incorporated LDH hybrids. An anticancer activity test using HeLa, A549, and HEK293T cells showed that the AGN-LDH hybrid, regardless of extract type, showed enhanced anticancer activity compared with extract alone at an equivalent amount of DS, suggesting a nanomedicine effect of AGN-LDH hybrids.

Perception of and attitude toward ethical issues among Korean occupational physicians.

BACKGROUND: Occupational physicians (OPs) have complex relationships with employees, employers, and the general public. OPs may have simultaneous obligations towards third parties, which can lead to variable conflicts of interests. Among the various studies of ethical issues related to OPs, few have focused on the Korean OPs. The aim of the present survey was to investigate the ethical contexts, the practical resolutions, and the ethical principles for the Korean OPs. METHODS: An email with a self-administered questionnaire was sent to members of the Korean Society of Occupational and Environmental Medicine, comprising 150 specialists and 130 residents. The questionnaire was also distributed to 52 specialists and 46 residents who attended the annual meeting of the Korean Association of Occupational and Environmental Clinics in October 2015, and to 240 specialists by uploading the questionnaire to the online community 'oem-doctors' in February 2016. The responses to each question (perception of general ethical conflicts, recognition of various ethical codes for OPs, core professional values in ethics of occupational medicine, and a mock case study) were compared between specialists and residents by the chi-squared test and Fisher's exact test. RESULTS: Responses were received from 80 specialists and 71 residents. Most participants had experienced ethical conflicts at work and felt the need for systematic education and training. OPs suffered the most ethical conflicts in decisions regarding occupational health examination and evaluation for work relatedness. Over 60% of total participants were unaware of the ethical codes of other countries. Participants thought 'consideration of worker's health and safety' (26.0%) and 'neutrality' (24.7%) as the prominent ethical values in professionality ofoccupational medicine. In mock cases, participants chose beneficence and justice for fitness for work and confidential information acquired while on duty, and beneficence and respect for autonomy in pre-placement examinations. CONCLUSIONS: This study evaluated the current perception of and attitude toward ethical issues among the Korean OPs. These findings will facilitate the development of a code of ethics and the ethical decision-making program forthe Korean OPs.

Effects of shift work on abdominal obesity among 20-39-year-old female nurses: a 5-year retrospective longitudinal study.

BACKGROUND: This study aimed to investigate the effects of shift work on abdominal obesity among young and middle-aged female nurses during a 5-year retrospective study. METHODS: This retrospective study included female nurses (20-39 years old) who worked at a university hospital in Korea and had available health screening results from 2010-2015. Among 2,611 employees, 934 healthy 20-39-year-old female nurses were identified, and data regarding their demographic information (age and date of employment), waist circumferences (WC), and lifestyle factors (alcohol and exercise) were obtained. Abdominal obesity was defined as a WC of ≥80 cm, based on the World Health Organization's Asia-West Pacific standard in 2000. The mean WC change from baseline was analyzed using the paired t test, and the association between shift work and abdominal obesity was analyzed using the generalized estimating equation. RESULTS: Compared to all day workers (both age groups), the 20-29-year-old nurses did not exhibit significant changes in WC at each follow-up. However, among the 30-39-year-old nurses, shift workers exhibited a significant change in WC (vs. baseline) during years 4 and 5, compared to day workers. After adjusting for effective confounders and stratifying the participants according to age, the 20-29-year-old nurses exhibited an odds ratio of 3.21 (95 % confidence interval: 1.29-7.98) for shift work-associated obesity, although the odds ratio for the 30-39-year-old nurses was not statistically significant. CONCLUSION: In the study population, shift work was associated with a significant change in mean WC among 30-39-year-old nurses, and the shift work-associated risk of abdominal obesity was significant among 20-29-year-old nurses. These results indicate that shift work may influence abdominal obesity differently in 20-29-year-old and 30-39-year-old female nurses.

Agmatine-Containing Bioreducible Polymer for Gene Delivery Systems and Its Dual Degradation Behavior.

Agmatine-containing bioreducible polymer, poly(cystaminebis(acrylamide)-agmatine) (poly(CBA-AG)) was synthesized for gene delivery systems. It could form 200-300 nm sized and positively charged polyplexes with pDNA, which could release pDNA in reducing the environment due to the internal disulfide bonds cleavage. Poly(CBA-AG) also showed a spontaneous degradation behavior in aqueous condition in contrast to the backbone polymer, poly(cystaminebis(acrylamide)-diaminobutane) (poly(CBA-DAB)) lacking guanidine moieties, probably due to the self-catalyzed hydrolysis of internal amide bonds by guanidine moieties. The cytotoxicity of poly(CBA-AG) was cell-dependent but minimal. Poly(CBA-AG) exhibited highly enhanced transfection efficiency in comparison with poly(CBA-DAB) and even higher transfection efficiency than PEI25k. However, cellular uptake efficiency of the polyplexes did not show positive correlation with the transfection efficiency. Confocal microscopy observation revealed that pDNA delivered by poly(CBA-AG) was strongly accumulated in cell nuclei. These results suggested that high transfection efficiency of poly(CBA-AG) may be derived from the efficient pDNA localization in cell nuclei by guanidine moieties and that the polyplexes dissociation via self-catalyzed hydrolysis as well as disulfide bonds cleavage in cytosol also may facilitate the transfection process. Finally, poly(CBA-AG)/pJDK-apoptin polyplex showed a high anticancer activity induced by apoptosis, demonstrating a potential of poly(CBA-AG) as a gene carrier for cancer gene therapy.

Crosslinked Polypropylenimine Dendrimers With Bioreducible Linkages for Gene Delivery Systems and Their Reductive Degradation Behaviors.

Crosslinked bioreducible polypropylenimine-cystaminebisacrylamides (PPI-CBAs) were synthesized for gene delivery systems. They formed nano-sized polyplexes with high stability even in reducing condition probably due to the re-crosslinking. PPI-CBAs displayed high transfection efficiency comparable to PEI25k in serum condition. However, cytotoxicity increase, glutathione (GSH) decrease, and reactive oxygen species (ROS) increase were observed in cells with the elevation of PPI-CBAs concentration and crosslinking degree. These results suggest that the cytotoxicity of bioreducible polymers may be closely related with their structures and that reduction of GSH by degradation of re-crosslinked bioreducible polymers and the following increase of ROS may induce cytotoxicity by oxidative stress.

Anticancer drug-incorporated layered double hydroxide nanohybrids and their enhanced anticancer therapeutic efficacy in combination cancer treatment.

OBJECTIVE: Layered double hydroxide (LDH) nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. METHOD: Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML), 5-FU/LDH (FL), and (MTX + 5-FU)/LDH (MFL) nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. CONCLUSION: All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.