Construction of Imatinib Controlled Release Film-Forming System Based on Drug Ion-Pair and Oligomeric Ionic Liquids for the Long Local Therapy of Cutaneous Melanoma.

An imatinib controlled release film-forming system (FFS) was developed based on the drug ion-pair and newly designed oligomeric ionic liquids (OILs) for the topical therapy of cutaneous melanoma, which avoided the systemic side-effect of oral administration and maintained a long local therapy effect. The OILs significantly improved the drug release capacity about 1.5-fold, and the formability and stability of FFSs (verified by AFM/PLM). The in vivo anti-tumor efficacy studies in melanoma tumor bearing mice showed that compared with the oral capsules, the topical application of the optimized imatinib FFS significantly (p < 0.01) increased tumor inhibition rate (67.54 ± 2.72%) and the amount of apoptotic cells. As confirmed by FT-IR and NMR, the partial protonation of OILs were demonstrated to have high hydrogen bond forming capacity, thus showing low polarity and good biocompatibility. More importantly, based on 13C-NMR study, OILs demonstrated higher hydrogen bond forming capacity, and formed bridge between drug ion-pair (O-H of counter-ion) and PVA (O-H), increased the molecular mobility of PVA, thus maintaining a long drug release capacity. Therefore, an imatinib FFS was developed with good therapeutic effect and the effect of drug ion-pair and OILs on increasing the drug skin retention and controlled release of imatinib FFS for topical therapy was clarified at the molecular level, which provided a safe and effective way for the treatment of cutaneous melanoma.

Piezo-deformable mirrors for active mode matching in advanced LIGO.

The detectors of the laser interferometer gravitational-wave observatory (LIGO) are broadly limited by the quantum noise and rely on the injection of squeezed states of light to achieve their full sensitivity. Squeezing improvement is limited by mode mismatch between the elements of the squeezer and the interferometer. In the current LIGO detectors, there is no way to actively mitigate this mode mismatch. This paper presents a new deformable mirror for wavefront control that meets the active mode matching requirements of advanced LIGO. The active element is a piezo-electric transducer, which actuates on the radius of curvature of a 5 mm thick mirror via an axisymmetric flexure. The operating range of the deformable mirror is 120±8 mD in vacuum and an additional 200 mD adjustment range accessible out of vacuum. Combining the operating range and the adjustable static offset, it is possible to deform a flat mirror from -65 mD to -385 mD. The measured bandwidth of the actuator and driver electronics is 6.8 Hz. The scattering into higher-order modes is measured to be <0.2% over the nominal beam radius. These piezo-deformable mirrors meet the stringent noise and vacuum requirements of advanced LIGO and will be used for the next observing run (O4) to control the mode-matching between the squeezer and the interferometer.

The Molecular Mechanism of Propylene Glycol Monocaprylate on Skin Retention: Probing the Dual Roles on the Molecular Mobility and Collagen Connection in Roflumilast Cream.

The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett-Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 µg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10-4 mJ·m-3). More importantly, because of the good stratum corneum (SC) compatibility (∆H = - 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 µg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H = - 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.

Point Absorber Limits to Future Gravitational-Wave Detectors.

High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.

Low drug load, high retention mometasone furoate cream with polyglyceryl - 3 oleate as a chemical enhancer: Formulation development, in vivo and in vitro evaluation and molecular mechanisms.

The study aimed to create a low loading, high retention, easier to apply O/W mometasone furoate (MF) cream using a chemical enhancer (CE) approach to provide more options for patients with atopic dermatitis (AD) and to investigate molecular mechanisms of its increased release and retention. A Box-Behnken design determined the optimal formulation based on stability and in vitro skin retention. Evaluations included appearance, rheological properties, irritation, in vivo tissue distribution and pharmacodynamics. Molecular mechanisms of enhanced release were studied using high-speed centrifugation, molecular dynamics and rheology. The interaction between the CE, MF and skin was studied by tape stripping, CLSM, ATR-FTIR and SAXS. The formulation was optimized to contain 0.05% MF and used 10% polyglyceryl-3 oleate (POCC) as the CE. There was no significant difference from Elocon® cream in in vivo retention and pharmacodynamics but increased in vivo retention by 3.14-fold and in vitro release by 1.77-fold compared to the basic formulation. POCC reduced oil phase cohesive energy density, enhancing drug mobility and release. It disrupted skin lipid phases, aiding drug entry and formed hydrogen bonds, prolonging retention. This study highlights POCC as a CE in the cream, offering insights for semi-solid formulation development.

The enantioselective enhancing effect and mechanistic insights of chiral enhancers in transdermal drug delivery.

Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects, decreasing therapeutical effects. To improve the transdermal delivery efficiency of eutomer, this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers. Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers. The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer, in which the enhancement effect (ER) of L-menthol on S-enantiomer (ER = 3.23) was higher than that on R-enantiomer (ER = 1.49). According to the pharmacokinetics results, L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer (2.56 fold), and showed excellent in vitro/in vivo correlations. The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention, but the D-isomer by improving partition for better permeation. Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation. Additionally, stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects. In conclusion, enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery, rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects, increasing transdermal therapeutical efficiency.

Synthesis and bioimaging of a BODIPY-based fluorescence quenching probe for Fe3.

Iron is the main substance for maintaining life. Real-time determination of ferric ion (Fe3+) in living cells is of great significance for understanding the relationship of Fe3+ concentration changes with various physiological and pathological processes. Fluorescent probes are suitable for the detection of trace metal ions in cells due to their low toxicity and high sensitivity. In this work, a boron-dipyrromethene-based fluorescent probe (BODIPY-CL) for selective detection of Fe3+ was synthesized. The fluorescence emission of BODIPY-CL was determined at 516 nm. In a pH range of 1 to 10, the probe BODIPY-CL exhibits a quenching response to Fe3+. Meanwhile, BODIPY-CL showed a highly selective response to Fe3+ compared with 16 kinds of metal ions. The stoichiometry ratio of BODIPY-CL bound to Fe3+ was nearly 2 : 1. The fluorescence quenching response obtained by the sensor was linear with the Fe3+ concentration in the range of 0-400 µM, and the detection limit was 2.9 µM. BODIPY-CL was successfully applied to image Fe3+ in cells. This study provides a promising fluorescent imaging probe for further research on the physiological and pathological effects of Fe3+.

Synthesis of hierarchical porous zirconium dioxide and its application in the detection of sulfonamides in animal-derived food.

In order to effectively remove grease for the detection of sulfonamides, a non-toxic and low-cost hierarchical porous zirconia material was synthesized using the dual template method. The lipid impurities in an animal-derived food matrix can be absorbed by hierarchical zirconia. A ZrO2 prepolymer was synthesized by mixing amphiphilic triblock copolymer poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (P123) with tannin extract as the double template and Zr(SO4)2 as the metal source. After aging, drying and calcination at high temperature, the prepolymer transforms into a hierarchical porous structure. The synthesized materials were characterized using SEM, XRD, FT-IR, and BET. The results show that the material has an abundant pore structure and hierarchical pore structure. The adsorption conditions were optimized. The hierarchical porous ZrO2 synthesized by this method is relatively uniform, and is characterized by large specific surface area as well as high lipid impurity adsorption capacity. Through the optimization experiment of adsorption conditions, we found that hierarchical porous ZrO2 can reach the maximum adsorption capacity in 60 min under weak acidic conditions. The samples are used for actual sample testing such as HPLC of sulfadiazine (SD), sulfamethazine (SM2), sulfamethoxydiazine (SMD), sulfamethoxazole (SIZ) and sulfadimethoxine (SDM), and the recovery experiment of sulfonamides in chicken was carried out. The recoveries were 80.9-97.6% and the detection limit was 3.8-17.6 µg L-1. This work provides a new strategy for oil removal using hierarchical porous materials.