Poly(ε-benzyloxycarbonyl-L-lysine)-grafted branched polyethylenimine as efficient nanocarriers for indomethacin with enhanced oral bioavailability and anti-inflammatory efficacy.

Star-block copolymers PEI-g-PZLL with a branched polyethylenimine (PEI) core and multiple grafted poly(ε-benzyloxycarbonyl-L-lysine) (PZLL) peripheral chains were designed, synthesized, and evaluated as nanocarriers for indomethacin (IND). In an aqueous solution, PEI-g-PZLL self-assembled into spherical nanoparticles capable of encapsulating IND at high loading capacity and loading efficiency. Differential scanning calorimetry and X-ray diffraction measurements indicated that IND was molecularly or amorphously dispersed in the nanoparticles. Fourier transform infrared spectra revealed the presence of multiple intermolecular interactions, including hydrogen bonding, electrostatic forces, π-π stacking and hydrophobic interactions, between the block copolymer and the IND molecules. IND-loaded nanoparticles exhibited fast release under intestinal pH. Compared with raw IND, the utilization of PEI-g-PZLL as a carrier significantly enhanced the oral bioavailability of IND and improved its protective effect on renal ischemia-reperfusion injury, as evidenced by in vivo pharmacokinetic and pharmacodynamic studies. Cytotoxicity assay, histological observation and cellular uptake study suggested that PEI-g-PZLL was fairly biocompatible. All these results indicated that star-block copolymers PEI-g-PZLL could be used as efficient nanocarriers for IND and other poorly water-soluble drugs. STATEMENT OF SIGNIFICANCE: The use of polyethylenimine (PEI) as an oral drug delivery carrier is limited because it is not biodegradable and the use of higher molecular weight PEI leads to improved efficiency but also increased cytotoxicity. The design of functionalized PEIs with low cytotoxicity and high efficiency is crucial for developing a successful oral drug delivery system. In our study, poly(ε-benzyloxycarbonyl-L-lysine) (PZLL)-grafted branched PEI (PEI-g-PZLL) was reported as an oral nanocarrier for indomethacin (IND). The low cytotoxicity and biodegradability, well-defined self-assembled nano-sized polymeric micelles, high loading capacity and loading efficiency, amorphous state of the encapsulated IND, as well as the enhanced oral bioavailability of IND, makes the copolymer PEI-g-PZLL a promising nanocarrier for the oral administration of IND and possibly other poorly water-soluble drugs.

miR-362-3p targets nemo-like kinase and functions as a tumor suppressor in renal cancer cells.

MicroRNAs (miRNAs) have been demonstrated to exhibit abnormal expression patterns in various types of human cancer. The aim of the present study was to identify a novel tumor suppressor microRNA (miR) and investigate its physiological function and mechanism in renal cell carcinoma (RCC). The expression levels of miRNA (miR)­362­3p expres were measured in 47 pairs of RCC and adjacent normal tissue samples, using reverse transcription-quantitative polymerase chain reaction analysis. In addition, miR­362­3p was transfected into renal cancer cells to investigate its role in the regulation of cell proliferation, migration, invasion, apoptosis and cell cycle. Identification of the target gene of miR­362­3p was performed using luciferase reporter assays and western blot analyses. The results demonstrated that the expression levels of miR­362­3p were downregulated in the RCC tissue samples, compared with the adjacent normal tissue samples. The upregulation of miR­362­3p using a synthesized mimic suppressed the proliferation, migration and invasion of the renal cancer cells, and induced cell apoptosis and G1 phase arrest. Further experiments demonstrated that the overexpression of miR­362­3p resulted in decrease expression levels of nemo-like kinase. These results suggested that miR-362-3p functions as a tumor suppressor in RCC, and may serve as a potential molecular target in the treatment of RCC.

Controlling Ion Conductance and Channels to Achieve Synaptic-like Frequency Selectivity.

Enhancing ion conductance and controlling transport pathway in organic electrolyte could be used to modulate ionic kinetics to handle signals. In a Pt/Poly(3-hexylthiophene-2,5-diyl)/Polyethylene+LiCF3SO3/Pt hetero-junction, the electrolyte layer handled at high temperature showed nano-fiber microstructures accompanied with greatly improved salt solubility. Ions with high mobility were confined in the nano-fibrous channels leading to the semiconducting polymer layer, which is favorable for modulating dynamic doping at the semiconducting polymer/electrolyte interface by pulse frequency. Such a device realized synaptic-like frequency selectivity, i.e., depression at low frequency stimulation but potentiation at high-frequency stimulation.

Frequency selectivity in pulse responses of Pt/poly(3-hexylthiophene-2,5-diyl)/polyethylene oxide +Li+/Pt hetero-junction.

Pt/poly(3-hexylthiophene-2,5-diyl)/polyethylene oxide + Li+/Pt hetero junctions were fabricated, and their pulse responses were studied. The direct current characteristics were not symmetric in the sweeping range of ±2 V. Negative differential resistance appeared in the input range of 0 to 2 V because of de-doping (or reduction) in the side with the semiconductor layer. The device responded stably to a train of pulses with a fixed frequency. The inverse current after a pulse was related to the back-migrated ions. Importantly, the weight calculated based on the inverse current strength, was depressed during low-frequency stimulations but was potentiated during high-frequency stimulations when pulses were positive. Therefore, frequency selectivity was first observed in a semiconducting polymer/electrolyte hetero junction. Detailed analysis of the pulse response showed that the input frequency could modulate the timing of ion doping, de-doping, and re-doping at the semiconducting polymer/electrolyte interface, which then resulted in the frequency selectivity. Our study suggests that the simple redox process in semiconducting polymers can be modulated and used in signal handling or the simulation of bio-learning.