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paul142857

铜虫 (小有名气)

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注册: 2015-03-03
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专业: 高分子科学

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The H-460 human lung carcinoma cell line was adapted for solid tumor growth by serial trocar passage in BALB/c nu/nu mice. Tumors were minced into 1 to 3 mm square fragments using sterile techniques. Tumor pieces were implanted subcutaneously in the axillary region by trocer. Xenograft mice bearing tumors were treated with Nanoxel-PM™, Taxotere® at 13 mg/kg and saline as a control intravenously on days 0, 1, 2 from the day of randomization. All mice
in each treatment group had tumors of similar size (100–300 mm3) at the start of treatment (day 0). Tumor growth and body weight of mice were monitored up to 2–3 times per week for the duration of the study. Tumor measurement was performed using calipers to measure the tumor volume in 2 dimensions, at the longest and widest points. Anti-cancer effect of the test articles was expressed as decrease in tumor volume re ected by tumor growth delay.

Safety and tolerability of Nanaoxel-PM were assessed in several toxicity studies in rats, mice, and beagle dogs. The SD rats and Balb/c mice were allocated to 7 treatment groups, comprising 5 males, by means of a strati ed randomization procedure based on bodyweight. Rats were dosed at a dose volume of 5 mL/kg by a single intravenous infusion into a lateral tail vein for 30 min with Nanoxel-PM™ (7, 10,13 mg/kg), Taxotere® (7, 10, 13 mg/kg) or saline (control group). And mice were dosed by a 3 daily intravenous bolus injection (10 mL/kg) into tail vein with Nanoxel-PM™ (10, 13, 15 mg/kg), Taxotere® (10, 13, 15 mg/kg) or saline (control group). Bodyweight for each study animal was recorded (GF-2000, A&D Balance, Japan) and rat blood samples were obtained for hematology (white blood cell (WBC) counts) before dosing and 2–3 times per week after dosing for 3 weeks. The beagle dog study was based on intravenous administration of drugs (Nanoxel-PM™ and Taxotere®

in 3 ascending doses (0.25 → 0.5 → 0.75 mg/kg) for total 4 doses at 2-week intervals with the last dose (0.75 mg/kg) given as a cross-over design. The drugs (Nanoxel-PM™ and Taxotere®, n = 4) and saline (control, n = 2) were administered to male beagle dogs (7.5–9.0 kg) via the right cephalic vein over 30 min at a dose volume of 1.5 mL/kg. All treatment animals received pre-medication with dexamethasone as described in pharmacokinetic study in beagle dogs. Clinical signs, food consumption, and body weight were recorded. Blood samples were obtained for hematology (predose, 4 and 7 days after each dose, prior to necropsy), blood chemistry (predose and prior to necropsy), docetaxel pharmacokinetics (as described in pharmaco-kinetics) and histamine levels (15, 30 min after start of the infusion and 5, 15, 30 min after the end of infusion). Plasma histamine concentration was analyzed using a Histamine ELISA kit (IBL, Hamburg, Germany) with quanti cation range of 0.35–150 ng/mL. The maximum tolerated dose (MTD) was estimated as the highestdose that results in less than 20% of weight loss and dose not cause lethality. If weight loss was not a good predictor of tolerability, the dose where no animals needed to be terminated due to toxicity was used.

All data were expressed as means ± standard deviation (S.D.). An unpaired, two-tailed Student's t test or Mann–Whitney rank sum test was used to determine the signicance of differences between two group means. A p value <0.05 was considered to be statistically signicant.

The copolymer carrier system used in Nanoxel-PM™, mPEG-PDLLA, allows intravenous delivery of docetaxel without the presence of polysorbate 80. The diblock copolymers self-assemble in water into spherical micelles that consist of two spherical concentrical regions, a densely packed core consisting of hydropho-bic blocks and a shell consisting of a dense brush of poly (ethylene glycol). Hydrophobic drug substance may be physically incorporat-ed within the core of the polymeric micelle by hydrophobic interactions. The polymeric micelles prepared using mPEG 2K-PDLLA 1.8K typically have a diameter in the range of 10–50 nm and usually consist of 50–100 of block copolymers. The average diameter of the Nanoxel-PM™ was 25.4 nm and the particle size of all samples exhibited a narrow size distribution and monodis-perse unimodal pattern (Fig. 1A). The SEM photograph showed that the particles have regular spherical shape with a mono-disperse distribution (Fig. 1B). When reconstituted with saline for injection, the solutions of 0.1–2.0 mg/mL in docetaxel concentration were found to be physically stable for over 6 h at room temperature without showing any precipitation.