Increased accumulation of paclitaxel and doxorubicin in proliferating capillary cells and prostate cancer cells following ultrasound exposure

Introduction

We have previously reported enhanced cytotoxic effects of both doxorubicin and antisense oligonucleotides using an optimized ultrasound regime of a single 10 s exposure in burst-mode (4 MHz, 32 W/cm²(SaTa), 50 ms burst period) in both PC3 (prostate cancer) cells and angiogenic Huvec (human umbilical cord endothelial cells). The objective of this study was to investigate the effect of ultrasound on the cellular uptake of both hydrophilic agents (rhodamine R123, doxorubicin hydrochloride and mannitol) and hydrophobic agents (rhodamine R6G and paclitaxel) using the same 4 MHz ultrasound exposure system.

Methods

PC3 cells and Huvec were incubated with solutions of radioactive or fluorescent compounds for 1 h and ultrasound was then applied to cells. Following washing and lysis of cells, the degree of drug uptake was measured using liquid scintillation counting or fluorescence spectroscopy.

Results

Ultrasound exposure resulted in the enhanced uptake of both hydrophilic and hydrophobic compounds into cells. For paclitaxel, approximately 100% increased uptake was observed when the drug was encapsulated in a nanoparticulate micellar formulation compared to approximately 50% for free drug.

Conclusions

The 4 MHz, 32 W/cm² ultrasound exposure regime (using burst-mode with 50 ms burst period) allows for the enhanced uptake of both water soluble and insoluble compounds into proliferating cancer and angiogenic cells.     

Same-single-cell analysis using the microfluidic biochip to reveal drug accumulation enhancement by an amphiphilic diblock copolymer drug formulation

Multidrug resistance (MDR) is one of the major obstacles in drug delivery, and it is usually responsible for unsuccessful cancer treatment. MDR may be overcome by using MDR inhibitors. Among different classes of these inhibitors that block drug efflux mediated by permeability-glycoprotein (P-gp), less toxic amphiphilic diblock copolymers composed of methoxypolyethyleneglycol-block-polycaprolactone (MePEG-b-PCL) have been studied extensively. The purpose of this work is to evaluate how these copolymer molecules can reduce the efflux, thereby enhancing the accumulation of P-gp substrates (e.g., daunorubicin or DNR) in MDR cells. Using conventional methods, it was found that the low-molecular-weight diblock copolymer, MePEG₁₇-b-PCL₅ (PCL5), enhanced drug accumulation in MDCKII-MDR1 cells, but the high-molecular-weight version, MePEG₁₁₄-b-PCL₂₀₀ (PCL200), did not. However, when PCL200 was mixed with PCL5 (and DNR) in order to encapsulate them to facilitate drug delivery, there was no drug enhancement effect attributable to PCL5, and the reason for this negative result was unclear. Since drug accumulation measured on different cell batches originated from single cells, we employed the same-single-cell analysis in the accumulation mode (SASCA-A) to find out the reason. A microfluidic biochip was used to select single MDR cells, and the accumulation of DNR was fluorescently measured in real time on these cells in the absence and presence of PCL5. The SASCA-A method allowed us to obtain drug accumulation information faster in comparison to conventional assays. The SASCA-A results, and subsequent curve-fitting analysis of the data, have confirmed that when PCL5 was encapsulated in PCL200 nanoparticles as soon as they were synthesized, the ability of PCL5 to enhance DNR accumulation was retained, thus suggesting PCL200 as a promising delivery system for encapsulating P-gp inhibitors, such as PCL5. Graphical Abstract

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Supersymmetric extension of the SU(3)×SU(2)×U(1) model

We describe a class of supersymmetric SU(3)×SU(2)×U(1) models where all quarks and leptons, as well as their scalar partners, get masses through one-loop radiative corrections.     

库仑加线性位基态解析解

应用新发展的单一轨迹积分方法求解库仑加线性位的基态量子波函数,得到基态能量和波函数的一般解析表达式,并讨论了解的收敛性.应用此方法讨论了重夸克偶素系统.     

Carbon isotope analysis of dissolved organic carbon in fresh and saline (NaCl) water via continuous flow cavity ring-down spectroscopy following wet chemical oxidation

This work examines the performance and limitations of a wet chemical oxidation carbon analyser interfaced with a cavity ring-down spectrometer (WCO-CRDS) in a continuous flow (CF) configuration for measuring δ¹³C of dissolved organic carbon (δ¹³C-DOC) in natural water samples. Low-chloride matrix (<5?g Cl/L) DOC solutions were analysed with as little as 2.5?mg C/L in a 9?mL aliquot with a precision of 0.5?‰. In high-chloride matrix (10–100?g Cl/L) DOC solutions, bias towards lighter δ¹³C-DOC was observed because of incomplete oxidation despite using high-concentration oxidant, extended reaction time, or post-wet chemical oxidation gas-phase combustion. However, through a combination of dilution, chloride removal, and increasing the oxidant:sample ratio, high-salinity samples with sufficient DOC (>22.5?µg C/aliquot) may be analysed. The WCO-CRDS approach requires more total carbon (µg C/aliquot) than conventional CF-isotope ratio mass spectrometer, but is nonetheless applicable to a wide range of DOC concentration and water types, including brackish water, produced water, and basinal brines.     

Designed iron carbonyls as carbon monoxide (CO) releasing molecules: rapid CO release and delivery to myoglobin in aqueous buffer, and vasorelaxation of mouse aorta

The physiological roles of CO in neurotransmission, vasorelaxation, and cytoprotective activities have raised interest in the design and syntheses of CO-releasing materials (CORMs) that could be employed to modulate such biological pathways. Three iron-based CORMs, namely, [(PaPy(3))Fe(CO)](ClO(4)) (1), [(SBPy(3))Fe(CO)](BF(4))(2) (2), and [(Tpmen)Fe(CO)](ClO(4))(2) (3), derived from designed polypyridyl ligands have been synthesized and characterized by spectroscopy and X-ray crystallography. In these three Fe(II) carbonyls, the CO is trans to a carboxamido-N (in 1), an imine-N (in 2), and a tertiary amine-N (in 3), respectively. This structural feature has been correlated to the strength of the Fe-CO bond. The CO-releasing properties of all three carbonyls have been studied in various solvents under different experimental conditions. Rapid release of CO is observed with 2 and 3 upon dissolution in both aqueous and nonaqueous media in the presence and absence of dioxygen. With 1, CO release is observed only under aerobic conditions, and the final product is an oxo-bridged diiron species while with 2 and 3, the solvent bound [(L)Fe(CO)](2+) (where L = SBPy(3) or Tpmen) results upon loss of CO under both aerobic and anaerobic conditions. The apparent rates of CO loss by these CORMs are comparable to other CORMs such as [Ru(glycine)(CO)(3)Cl] reported recently. Facile delivery of CO to reduced myoglobin has been observed with both 2 and 3. In tissue bath experiments, 2 and 3 exhibit rapid vasorelaxation of mouse aorta muscle rings. Although the relaxation effect is not inhibited by the soluble guanylate cyclase inhibitor ODQ, significant inhibition is observed with the BK(Ca) channel blocker iberiotoxin.     

Tractive performance of a tread design for improved flexibility

The tractive performance of an 18.4R38 radial-ply tractor tire with increased flexibility in the tread area was compared to that of a standard tread design. Normal soil-tire interface stresses were measured at four locations on the lug surfaces of both tires operating on Decatur clay loam and Norfolk sandy loam soils. There was a tendency for the increased flexibility in the tread area to provide a higher net traction ratio at the same tractive efficiency as the standard tread design, especially on Decatur clay loam soil. The more flexible tread design reduced the magnitude of peak normal contact stresses across the tire width, which may have implications for reducing soil compaction without compromising tractive performance. The more flexible tire reduced the average normal contact stress by approximately 15% in the sandy loam soil and 23% in the clay loam soil for the range of operating conditions investigated.     

Non-Gaussianities in New Ekpyrotic Cosmology

The new ekpyrotic model is an alternative scenario of the early Universe which relies on a phase of slow contraction before the big bang. We calculate the 3-point and 4-point correlation functions of primordial density perturbations and find a generically large non-Gaussian signal, just below the current sensitivity level of cosmic microwave background experiments. This is in contrast with slow-roll inflation, which predicts negligible non-Gaussianity. The model is also distinguishable from alternative inflationary scenarios that can yield large non-Gaussianity, such as Dirac-Born-Infeld inflation and the simplest curvatonlike models, through the shape dependence of the correlation functions. Non-Gaussianity therefore provides a distinguishing and testable prediction of New Ekpyrotic Cosmology.     

1616 supergravity coupled to matter: The low energy limit of the superstring

We analyze irreducible, N = 1 supergravity theories with 16 fermionic degrees of freedom. The lagrangians for pure $\text{16}\text{16}$ supergravity, and for $\text{16}\text{16}$ supergravity coupled to arbitrary chiral superfields are constructed. These theories are shown to have natural SU(1,1) non-compact symmetry. The low energy field theory limit of the superstring is conjectured to be of this type.