A Novel Docetaxel-Biotin Chemical Conjugate for Prostate Cancer Treatment

A novel conjugate of docetaxel and biotin (designated as IDD-1010) was designed and chemically synthesized via an ester linkage at position 2’ carbon in docetaxel. The synthesized pure IDD-1010 exhibits a potent anti-cancer activity in in vitro and in vivo studies. At 10 nM, IDD-1010 has induced increased apoptosis and mitotic arrest of PC3-Luc prostate cancer cells, causing aneuploidy and cell death at higher concentrations. Toxicology studies indicate that the maximal tolerated dose (MTD) of IDD-1010 is 150 mg/kg in mice; equivalent to about 12.2 mg/kg of body weight, or to about an 850 mg dose for a patient weighing 70 kg. The MTD-treated mice exhibited weight gain similar to that of the control group, with no gross pathological signs at 14 days post-dosing. At a lower dose, IDD-1010 treatment did not lead to any significant weight loss in mice, although decreased the tumor volume stemming from injecting cancer cells into the dorsal loop of mouse prostate, and it was found to be more potent than Paclitaxel (reference drug). Similarly, IDD-1010 treatment significantly reduced tumor weight and thereby increased the percentage of mice survival as compared to reference drug-treated and control groups. To summarize, the described experiments using IDD-1010, as compared to the reference drug, strongly suggest a potential treatment utility with a wider therapeutic window for prostate cancer. Henceforth, clinical research on such a novel drug candidate would be greatly worthwhile.     

Determination of the transplacental transfer of paclitaxel and antipyrine by high performance liquid chromatography coupled with photodiode array detector

Ex vivo placental perfusion experiments are important in understanding the quantity and mechanisms of xenobiotic transport to the fetus during pregnancy. Our study demonstrates that paclitaxel and antipyrine concentrations in placental perfusion medium containing physiological concentrations of human serum albumin during pregnancy (30?mg/mL) can be quantified by RP-HPLC and UV detection. A liquid-liquid extraction method was developed for the quantification of paclitaxel and celecoxib (internal standard) from perfusion medium. Antipyrine, which is a necessary marker in placental perfusions for determining the validity of experiments and calculating the clearance index of xenobiotics, was also analyzed by HPLC and UV detection. Antipyrine concentrations were determined by HPLC after precipitating the perfusion medium in acetonitrile and separating the precipitated proteins by centrifugation. Concentrations were fitted to linear regressions with R² values approaching 1. Lower limits of detection for paclitaxel and antipyrine were 100?ng/mL and 200?ng/mL, respectively. Both methods demonstrated high intra-day and inter-day precision and trueness. Additionally, the use of these methods was demonstrated in a placental perfusion experiment using Taxol^® (paclitaxel dissolved in Cremophor-EL). The fetal transfer rate of Taxol was 6.6% after 1 hour.     

Quantitative analysis of docetaxel in human plasma using liquid chromatography coupled with tandem mass spectrometry

An assay for the quantitative determination of docetaxel in human plasma is described. Docetaxel was extracted from the matrix using liquid-liquid extraction with ter-butylmethylether, followed by high-performance liquid chromatographic analysis using an alkaline eluent. Paclitaxel was used as internal standard. Positive ionization electrospray tandem mass spectrometry was performed for selective and sensitive detection. The method was validated according to the FDA guidelines on bioanalytical method validation. The validated range for docetaxel was from 0.25--1000 ng/mL using 200 microL plasma aliquots. The method requires only a limited volume (200 microL) of human plasma and the method can be applied in studies requiring a low lower limit of quantitation of 0.25 ng/mL. The assay was applied successfully in several clinical and pharmacological studies with docetaxel.     

A novel micellar PEGylated hyperbranched polyester as a prospective drug delivery system for paclitaxel

A hyperbranched aliphatic polyester has been functionalized with PEG chains to afford a novel water-soluble BH40-PEG polymer which exhibits unimolecular micellar properties, and is therefore appropriate for application as a drug-delivery system. The solubility of the anticancer drug paclitaxel was enhanced by a factor of 35, 110, 230, and 355 in aqueous solutions of BH40-PEG of 10, 30, 60, and 90 mg x mL(-1), respectively. More than 50% of the drug is released at a steady rate and release is almost complete within 10 h. The toxicity of BH40-PEG was assessed in vitro with A549 human lung carcinoma cells and found to be nontoxic for 3 h incubation up to a 1.75 mg x mL(-1) concentration while LD50 was 3.5 mg x mL(-1). Finally, it was efficiently internalized in cells, primarily in the absence of foetal bovine serum, while confocal microscopy revealed the preferential localization of the compound in cell nuclei. [Figure: see text].     

Preparation of Catechin Nanoemulsion from Oolong Tea Leaf Waste and Its Inhibition of Prostate Cancer Cells DU-145 and Tumors in Mice

Anti-cancer activity of catechin nanoemulsions prepared from Oolong tea leaf waste was studied on prostate cancer cells DU-145 and DU-145-induced tumors in mice. Catechin nanoemulsions composed of lecithin, Tween-80 and water in an appropriate proportion was prepared with high stability, particle size of 11.3 nm, zeta potential of −67.2 mV and encapsulation efficiency of 83.4%. Catechin nanoemulsions were more effective than extracts in inhibiting DU-145 cell growth, with the IC₅₀ being 13.52 and 214.6 μg/mL, respectively, after 48 h incubation. Furthermore, both catechin nanoemulsions and extracts could raise caspase-8, caspase-9 and caspase-3 activities for DU-145 cell apoptosis, arresting the cell cycle at S and G2/M phases. Compared to control, catechin nanoemulsion at 20 μg/mL and paclitaxel at 10 μg/mL were the most effective in reducing tumor volume by 41.3% and 52.5% and tumor weight by 77.5% and 90.6% in mice, respectively, through a decrease in EGF and VEGF levels in serum.     

脱氢枞酸酯键合硅胶色谱固定相的制备及应用

A dehydroabietic acid glycidyl methacrylate ester (DAGME)-bonded silica stationary phase (Sil-DAGME) was fabricated in this paper. The DAGME was firstly prepared using dehydroabietic acid and glycidyl methacrylate via a ring-opening addition reaction, and then grafted onto the surface of a thiol-functionalized spherical silica by click reaction to obtain the Sil-DAGME. The successful immobilization of DAGME on the silica was confirmed through series of characterizations including Fourier-transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA)and elemental analysis (EA). The chromatographic performance and retention mechanisms of Sil-DAGME were validated using a variety of compounds including alkylbenzenes, Tanaka standard test mixtures, polycyclic aromatic hydrocarbons, phenols and flavonoids. Meanwhile, the Sil-DAG⁃ME exhibits multiple interactions, including hydrophobic, π-π and hydrogen bonding interaction between the stationary phase and the analytes during the separation process due to the co-existing of benzene ring, carbonyl group, hydroxyl group and hydrophobic rigid tricyclic hydrophenanthrene skeleton in the DAGME on the silica surface. Based on synergistic action of multiple retention mechanisms, the probe molecules metioned above achieved ideal resolution and flexible selectivity in separation. In addition, the Sil-DAGME not only exhibited good stability, repeatability and reproducibility with the run-to-run relative standard deviations (RSDs) of 0. 050%-0. 19% (n = 10), the daytoday RSDs of 0. 25%-1. 0% (n = 7), and the column-to-column RSDs of 0. 78%-2. 1% (n = 3) for the retention time, but also showed an excellent separation ability for Yew tree bark extract. In short, the application of dehydroabietic acid in chromatographic separation materials not only provided a new approach for the separation and detection of paclitaxel, but also presented a reference for the design stationary phase using natural product rosin as functional ligand. © 2023, China Association for Instrumental Analysis. All rights reserved.     

Synthesis of 14-Bromo and 14-Hydroxy Baccatin III Derviatives

Numerous efforts towards synthesis of anticancer drug paclitaxel (Taxol(r), 1a) with improved activities led to the modification at 13-phenylisoserine side chain and different positions of its core structure-baccatin III 1c1. At the same time, the activities of searching new taxoids for starting materials of new semi-synthetic paclitaxel analogs from Taxus spp. plant have not ever been stopped. Among these taxoids, 14?-hydroxy-10-deacetylbaccatin III 22 and 13-acetyl-9-dihydrobaccatin III …     

In vitro evaluation of antiproliferative effect of ethyl gallate against human oral squamous carcinoma cell line KB

Although some polyphenols are known to possess anticancer activity against different cancer cell lines through induction of apoptosis, the mode of antiproliferative effect of ethyl gallate against human oral squamous carcinoma cell line KB was not studied until now. Therefore, the antiproliferative effect of ethyl gallate was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in comparison with the reference drug paclitaxel. Generation of reactive oxygen species, mitochondrial membrane potential loss, DNA damage and apoptosis were determined using 2,7-diacetyldichlorofluorescein fluorescence, uptake of rhodamine-123 by mitochondria, comet assay and acridine orange/ethidium bromide dual-dye staining method. Both ethyl gallate and paclitaxel exhibited cytotoxicity in a dose-dependent manner. The 50% inhibitory concentration for ethyl gallate was 30 and 20 μg/mL for paclitaxel. A volume of 50 μg/mL of ethyl gallate was found to be significantly effective (P < 0.05) in controlling the cancer cell proliferation leading to acute apoptosis.