The justification of cancer nanomedicine relies on enhanced permeation (EP) and retention (R) effect and the capability of intracellular targeting due primarily to size after internalization ...(endocytosis) into the individual target cells. The EPR effect implies improved efficacy. Affinity targeting for solid tumors only occur after delivery to individual cells, which help internalization and/or retention. The design principles have been supported by animal results in numerous publications, but hardly translated. The natures of EP and R, such as frequency of large openings in tumor vasculature and their dynamics, are not understood, in particular, in clinical settings. Although various attempts to address the issues related to EP and delivery, by modifying design factors and manipulating tumor microenvironment, are being reported, they are still verified in artificial rodent tumors which do not mimic the nature of human tumor physiology/pathology in terms of transport and delivery. The clinical trials of experimental nanomedicine have experienced unexpected adverse effects with modest improvement in efficacy when compared to current frontline therapy. Future nanomedicine may require new design principles without consideration of EP and affinity targeting. A possible direction is to set new approaches to intentionally minimize adverse effects, rather than aiming at better efficacy, which can widen the therapeutic window of an anticancer drug of interest. Broadening indications and administration routes of developed therapeutic nanotechnology would benefit patients.
Display omitted
The phytohormone abscisic acid (ABA) modulates a number of processes during plant growth and development. In this study, the molecular mechanism of Arabidopsis RAV (Related to ABI3/VP1) transcription ...factor RAV1 involving ABA signaling was investigated. RAV1‐underexpressing lines were more sensitive to ABA than wild‐type plants during seed germination and early seedling development, whereas RAV1‐overexpressing lines showed strong ABA‐insensitive phenotypes. Overexpression of RAV1 repressed ABI3, ABI4, and ABI5 expression, and RAV1 bound to the ABI3, ABI4, and ABI5 promoters in vitro and in vivo, indicating that RAV1 directly down‐regulates the expression of ABI3, ABI4, and ABI5. The interruption of ABI5 function in RAV1‐U abi5 plants abolished the ABA‐hypersensitive phenotype of RAV1‐U plants, demonstrating that ABI5 is epistatic to RAV1. RAV1 interacted with SNF1‐RELATED PROTEIN KINASE SnRK2.2, SnRK2.3 and SnRK2.6 in the nucleus. In vitro kinase assays showed that SnRK2.2, SnRK2.3 and SnRK2.6 phosphorylated RAV1. Transient expression assays revealed that SnRK2.2, SnRK2.3 and SnRK2.6 reduced the RAV1‐dependent repression of ABI5, and the ABA‐insensitive phenotype of the RAV1‐overexpressing line was impaired by overexpression of SnRK2.3 in the RAV1 OE3 plants. Together, these results demonstrated that the Arabidopsis RAV1 transcription factor plays an important role in ABA signaling by modulating the expression of ABI3, ABI4, and ABI5, and that its activity is negatively affected by SnRK2s.
White spot syndrome virus (WSSV) is the causative agent of white spot syndrome (WSS), a disease that has led to severe mortality rates in cultured shrimp all over the world. The WSSV is a large, ...ellipsoid, enveloped double-stranded DNA virus with a wide host range among crustaceans. Currently, the main antiviral method is to block the receptor of the host cell membrane using recombinant viral proteins or virus antiserum. In addition to interference with the ligand-receptor binding, disrupting the structure of the virus envelope may also be a means to combat the viral infection. Carbon quantum dots (CQDs) are carbonaceous nanoparticles that have many advantageous characteristics, including small size, low cytotoxicity, cheap, and ease of production and modification. Polyamine-modified CQDs (polyamine CQDs) with strong antibacterial ability have been identified, previously. In this study, polyamine CQDs are shown to attach to the WSSV envelope and inhibit the virus infection, with a dose-dependent effect. The results also show that polyamine CQDs can upregulate several immune genes in shrimp and reduce the mortality upon WSSV infection. This is first study to identify that polyamine CQDs could against the virus. These results, indeed, provide a direction to develop effective antiviral strategies or therapeutic methods using polyamine CQDs in aquaculture.
Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in situ hydrogel formation, have recently attracted the ...attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiological conditions and maintains its integrity for a desired period of time, the process may provide various advantages over conventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility with biological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol–gel transition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule delivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol–gel transitions, particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. This review stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, and poly(ethylene glycol)/poly(d,l-lactide-co-glycolide) block copolymers.
Display omitted
► No drug can be effective against cancer until it is successfully delivered from the administration site to its site of action within the tumor. ► There are barriers to drug delivery ...at every level of drug distribution including systemic, tissue and cellular levels. ► Current delivery strategies such as receptor–ligand targeting and EPR may not be effective in clinical tumors. ► New drug carrier designs should be educated by an appreciation of the full scope of drug delivery barriers.
No chemotherapeutic drug can be effective until it is delivered to its target site. Nano-sized drug carriers are designed to transport therapeutic or diagnostic materials from the point of administration to the drug's site of action. This task requires the nanoparticle carrying the drug to complete a journey from the injection site to the site of action. The journey begins with the injection of the drug carrier into the bloodstream and continues through stages of circulation, extravasation, accumulation, distribution, endocytosis, endosomal escape, intracellular localization and – finally – action. Effective nanoparticle design should consider all of these stages to maximize drug delivery to the entire tumor and effectiveness of the treatment.
pH-sensitive polymeric micelles and nanogels have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more ...general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms by endosomal or lysosomal acidity plus endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. This review highlights recent progress of the pH-sensitive nanotechnology developed in Bae research group.
Abstract
Three-component carboacylation of simple alkenes with readily available reagents is challenging. Transition metal-catalysed intermolecular carboacylation works for alkenes with strained ring ...or directing groups. Herein, we develop a photoredox cooperative N-heterocyclic carbene/Pd-catalysed alkylacylation of simple alkenes with aldehydes and unactivated alkyl halides to provide ketones in good yields. This multicomponent coupling reaction features a wide scope of alkenes, broad functional group compatibility and free of exogenous photosensitizer or external reductant. In addition, a series of chlorinated cyclopropanes with one or two vicinal quaternary carbons is obtained when chloroform or carbon tetrachloride is used as the alkyl halide. The reaction involves the alkyl radicals from halides and the ketyl radicals from aldehydes under photoredox cooperative N-heterocyclic carbene/Pd catalysis.
Exendin-4 is a glucagon-like peptide-1 (GLP-1) receptor agonist and potent insulinotropic agent for type 2 diabetes patients; however, its therapeutic utility is limited due to the frequent ...injections required. Long-acting agonists reduce the number of injections, but they can compromise potency. In this study, chondroitin sulfate-g-glycocholic acid-coated and Exendin-4 (Ex-4)-loaded liposomes (EL-CSG) were prepared for oral administration of Ex-4. The Ex-4 loading efficiency was 77% and the loading content in the nanoparticles was 1 wt-%. In rat models, a single oral dose (200 μg/kg) of EL-CSG showed a relative oral bioavailability of 19.5%, compared with subcutaneous administration (20 μg/kg), and sustained pharmacokinetics for up to 72 h. The overall long-term pharmacodynamic effects, assessed by hemoglobin A1c (HbA1c), body weight, and blood lipid concentrations, of daily oral EL-CSG (300 μg/kg) for four weeks were equivalent to or better than daily subcutaneous injections of free Ex-4 solution (20 μg/kg).
Display omitted
A road network represents a set of road objects in a geographic area and their interconnections, and it is an essential component of intelligent transportation systems (ITS) enabling emerging new ...applications such as dynamic route guidance, driving assistance systems, and autonomous driving. As the digitization of geospatial information becomes prevalent, a number of road networks with a wide variety of characteristics may coexist. In this paper, we present an
approach to the conflation of two road networks with a large difference in the level of details and representation rules. Our area partitioning (AP) scheme partitions the geographic area using the Network Voronoi Area Diagram (NVAD) of the low-detailed road network. Next, a subgraph of the high-detailed road network corresponding to a complex intersection is extracted and aggregated into a supernode so that high precision can be achieved via 1:1 road object matching. For the unmatched road objects due to missing road objects and different representation rules, we also propose a subgraph growing (SG) scheme that sequentially inserts a new road object while keeping the consistency of its connectivity to the matched road objects by the AP scheme. From the numerical results at Yeouido, Seoul, Korea, we show that our APSG scheme can achieve an outstanding matching performance in terms of the precision, recall, and F1-score.
Many studies show that the dedicated short range communication (DSRC) band is insufficient to carry increasing wireless traffic demands in vehicular networks. The release of TV white space band by ...the Federal Communications Commission (FCC) for cognitive access provides additional bandwidth to solve the DSRC spectrum scarcity problem. However, FCC requires portable devices to use significantly lower transmitting power than fixed devices, which creates a challenging coexistence environment for portable (e.g., vehicular) and fixed (e.g., IEEE 802.22) networks. In this paper, we address the coexistence problem between a vehicular and an 802.22 network via resource allocation. We first formulate the coexistence problem as a mixed-integer nonlinear programming (MINLP) problem, to which three algorithms are developed. The first algorithm converts the MINLP into a convex program and obtains a near-optimal solution to the initial MINLP. In the other two algorithms, we first convert the MINLP into an integer programming (IP) problem. Then, we solve the linear program relaxation of the IP and obtain a fractional solution. Thereafter, two rounding algorithms are developed to round the fractional solution based on column-sparse packing and dependent rounding techniques, respectively. Finally, we compare the performance of the proposed algorithms with an optimal MINLP solver through numerical examples.
PDF
