Dynamic bursting in tumor vasculature has recently sparked interest as a novel particle transportation route for drug delivery. These bursts facilitate the transport of sub‐100 nm nanoparticles into ...tumors, though their contribution on the access of other blood‐borne particles remains unknown. To evaluate the versatility of this phenomenon, the in vivo kinetics of a variety of intravenously injected particles and their penetration in tumor xenografts and allografts are compared. Dextran, polymeric micelles, liposomes, and polymeric vesicles with diameters ranging from 32 to 302 nm are found to colocalize in virtually all vascular bursts. By mathematical modeling, the burst vent size is estimated to be 625 nm or larger, indicating the dynamic and stochastic formation of large permeation routes in tumor vasculature. Furthermore, some burst vents are found to be µm‐sized, allowing the transport of 1 µm microspheres. Moreover, antibody drugs and platelets are capable of utilizing vascular burst transportation, demonstrating the application of this phenomenon to other types of therapeutics and cellular components. These findings indicate the vast potential of vascular bursts, extending the biological and therapeutic significance of this phenomenon to a wide range of blood‐borne particles and cells.
The recent discovery of vascular bursts in tumor vasculature has sparked renewed interest in active transport of sub‐100 nm particles, highlighting the dynamic nature of its distribution. In this paper, an even broader versatility of vascular burst transport is demonstrated through the validation of a library of blood‐borne particles together with mathematical model simulation to estimate the burst vent size.
Here described is a phenylboronic acid (PBA) based glucose-responsive hydrogel operating under physiological pH and temperature, a material potentially applicable to a totally synthetic smart insulin ...delivery system to treat diabetes.
Despite tremendous complexity in glycan structure, sialic acid (SA) provides an analytically accessible index for glycosylation, owing to its uniquely anionic nature and glycan-chain terminal ...occupation. Taking advantage of boronic acid (BA) based SA-recognition chemistry, we here demonstrate a label-free, no enzymatic, potentiometric determination of fetuin, a blood-circulating glycoprotein implicated in physiological and various pathological states. A phenylboronic acid (PBA) ω-end-functionalized poly(ethylene glycol) (PEG) with an α-tethering unit bearing pendent alkyne groups was “grafted-to” a gold electrode modified with 11-azide-undecathiol by a copper-catalyzed azide–alkyne cycloaddition reaction. Using the electrode, fetuin was potentiometrically detectable with a μM-order-sensitivity that is comparable to what is found in blood-collected specimen. Our finding may have implications for developing a remarkably economic hemodiagnostic technology with ease of downsizing and mass production.
The work attempts to prepare a totally synthetic, glucose-responsive polymer gel bearing a phenylborate derivative as a sensor moiety to glucose, for future use as a self-regulated insulin delivery ...system. The molecular strategies to enable the system to be operated under physiological conditions (pH 7.4, 37 °C) are presented that involve the use of a novel phenylborate derivative {4-(1,6-dioxo-2,5-diaza-7-oxamyl) phenylboronic acid: DDOPBA} possessing an appreciably low pK a (∼7.8), the adoption of poly(N-isopropylmethacrylamide) (PNIPMAAm) for the main chain, which itself undergoes a sharp thermo-induced phase transition at its LCST around 40 °C, as well as the introduction of a carboxyl group of methacrylic acid as the third comonomer. Glucose-responsive behaviors of the obtained gels were evaluated based on the changes in the equilibrium swelling degree determined in the presence and the absence of glucose, for various pH and temperature conditions. As a consequence of the combined molecular effects, a sufficient sensitivity of the system was accomplished at physiological pH and in the temperature range close to the physiological condition such as 30 °C. Furthermore, the glucose-induced continuous volume changes of the gels were demonstrated under those conditions, which occurred in a remarkably concentration-dependent manner. In these experiments, the critical glucose concentrations to induce the gels' responses in the range of normoglycemic sugar level were observed. These observations may provide us with an excellent prospect for the use of the gel as a self-regulated, insulin-delivery system discretely switching the release at the normoglycemia.
Intracellular delivery of small interfering RNA (siRNA) is a long‐standing challenge in oligonucleotide therapeutics. Herein, adenosine triphosphate (ATP)‐responsive polyion complex micelles ...assembled from poly(ethylene glycol)‐block‐poly(l‐lysine) (PEG–PLys) bearing 4‐carboxy‐3‐fluorophenylboronic acid (FPBA) moiety in the PLys side chains (FPBA micelle) for the delivery of cholesterol‐modified siRNA (Chol‐siRNA) are described. The pKa of FPBA moiety is 7.2 and, therefore, it exists in equilibrium between negatively charged tetravalent and noncharged hydrophobic trivalent forms in physiological pH conditions. Each form cooperatively stabilizes the micelle in distinct modes, that is, a covalent ester‐linkage between charged boronate and ribose functionality at 3′ ends of Chol‐siRNA and a hydrophobic interaction between noncharged boronic acid and Chol‐siRNA. When exposed to ATP at a concentration associated with the intracellular environment, the Chol‐siRNA/boronate linkage is readily cleaved to facilitate the release of Chol‐siRNA into cytoplasm. In order to further optimize this switching capability, the effect of FPBA modification rate is studied for the resulting ATP‐responsive behavior of the micelles. As a result, the range of 23–35% in the modification rate is found suitable to maximize the gene silencing efficiency, demonstrating the potential of the FPBA‐modified micelles as ATP‐responsive smart siRNA carrier systems.
To fulfill selective release of small interfering RNA (siRNA) from nanocarriers inside cells, phenylboronate functionalities are introduced into siRNA‐loaded polyion complex micelles at an optimal modification rate. The fabricated micelles encapsulate siRNA stably in extracellular milieu, while releasing it promptly inside cells containing a high concentration of adenosine triphosphate. The intracellular siRNA release behavior is thoroughly validated using fluorescence‐based techniques.
Countless marine organisms were polluted with radioactive materials that were dispersed when the Fukushima Daiichi Nuclear Power Plant (FDNPP) was damaged in 2011 by the Great East Japan Earthquake. ...The aim of this study was to determine the degree to which marine herbivorous sea urchins, Mesocentrotus nudus, were contaminated with radiocesium because of the accident. We collected samples of sea urchins from four locations in Fukushima prefecture (at the coast and offshore from the Yotsukura and Ena stations) and investigated how the .sup.137 Cs activity concentrations changed. The biological half-life (T.sub.bio) of .sup.137 Cs in the individual sea urchins was between 121 and 157 days. The ecological half-life (T.sub.eco) of .sup.137 Cs was 181-423 days and was high in places close to the FDNPP. The T.sub.eco values in the sea urchins were longer than previously reported. The results infer that the food sources of the sea urchins around the Fukushima coast strongly influenced their uptake of .sup.137 Cs.
We collected continuous sedimentary 137Cs concentration data from a shallow fishery ground (Matsukawa-ura Lagoon, Fukushima, Japan) in 2016 using a new compact underwater NaI(Tl) scintillation ...spectrometer and a quantitative technique. 137Cs concentrations in sediments were low (approx. 40 Bq/kg DW) at the lagoon mouth and high (641.2 Bq/kg DW) at the head of the lagoon. Some areas of locally elevated 137Cs concentrations (>500 Bq/kg DW) were also found.
•A seabed radioactivity monitor (S-RAM) measured 137Cs in shallow sea sediments.•The S-RAM offers low count times (60 s) and rapid measurements.•Concentrations of 137Cs in Matsukawa-ura Lagoon were 40–641.2 Bq/kg DW.•Isolated areas of high 137Cs (>500 Bq/kg DW) were detected in the southern lagoon.
Abstract
The type IIB matrix model is a promising candidate for a nonperturbative formulation of superstring theory. As such, it is expected to explain the origin of space–time and matter at the same ...time. This has been partially demonstrated by the previous Monte Carlo studies on the Lorentzian version of the model, which suggested the emergence of (3+1)-dimensional expanding space–time. Here we investigate the same model by solving numerically the classical equation of motion, which is expected to be valid at late times since the action becomes large due to the expansion of space. Many solutions are obtained by the gradient descent method starting from random matrix configurations, assuming a quasi-direct-product structure for the (3+1)-dimensions and the extra 6 dimensions. We find that these solutions generally admit the emergence of expanding space–time and a block-diagonal structure in the extra dimensions, the latter being important for the emergence of intersecting D-branes. For solutions corresponding to D-branes with appropriate dimensionality, the Dirac operator is shown to acquire a zero mode in the limit of infinite matrix size.
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