A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells.

While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 allosteric inhibitor targeting the PLK1 T-loop (a switch responsible for activation) and evaluate its effects in triple-negative breast cancer cells. A novel compound, RK-10, was developed based on an in silico model, and its effects on specificity, viability, migration, and cell cycle regulation in MCF-10A and MDA-MB 231 cells were evaluated. When MDA-MB 231 cells were treated with 0−50 µg/mL RK-10, phospho-PLK1 (Thr-210) was decreased in cells cultured adherently and cells cultured as mammospheres. RK-10 significantly inhibited viability after 24 h; however, by 48 h, 25−50 µM RK-10 caused >50% reduction. RK-10 attenuated wound healing by up to 99.7% and caused S and G2/M cell cycle arrest, which was associated with increased p21 expression. We developed a novel allosteric inhibitor which mediates anti-proliferative and anti-migratory properties through targeting phospho-PLK1 (Thr-210) in mammospheres and causing S phase and G2/M cell cycle arrest. Further development of PLK1 allosteric inhibitors may be a promising approach for TNBC treatment.

Influence of temperature on the thirty-day chemical stability of extemporaneously prepared dexamethasone paste.

Dexamethasone, a high-potency synthetic glucocorticoid, is often used to treat various immunological and inflammatory conditions. Commercial preparations of dexamethasone facilitate administration to human patients. Veterinary use of dexamethasone may be complicated by the unavailability of commercial dosage forms. As such, compounded preparations containing dexamethasone, such as a topical paste, are used in veterinary medicine. The purpose of this study was to determine the 30-day stability of compounded dexamethasone 2 mg/mL paste when incubated in temperatures which may mimic storage conditions during any given season. Samples were incubated at room temperature, -20 degrees C, 4 degrees C, 40 degrees C, and 80 degrees C for 30 days. Samples were subsequently analyzed using a stability-indicating high-performance liquid chromatography method on a reverse phase column. Our data suggests that the chemical stability of dexamethasone, the active pharmaceutical ingredient, is well within the guidelines set forth in United States Pharmacopeia Chapter <795> (90% to 110% stated potency) for all tested temperatures, with the exception of 80 degrees C (approximately 176 degrees F).

Interfacially assembled carbohydrate nanocapsules: a hydrophilic macromolecule delivery platform.

A prospective approach was used to synthesize carbohydrate nanocapsules with a macromolecule payload and suitable interfacial properties for in vivo systemic circulation. Spatially directed carbohydrate assembly and polymerization resulted in structured hydrophilic vesicles with diameters of 200-300 nm. Mononucleated dispersions with monodisperse distributions were demonstrated in aqueous vehicles. The effects of pH, buffer capacity and reaction time on the molar degree of substitution of terephthaloyl chloride, trimesoyl chloride, and diethylmalonyl chloride were evaluated. The delivery of a test protein, lysozyme showed continuous release for 7 days. Immobilization of lysozyme caused by co-polymerization was 20% based on asymptotic recovery of released lysozyme. A theoretical shell thickness of 9.5 nm was estimated from a relative core volume of 80% and the average vesicle size.