Synthesis, Anticancer Activity, and Molecular Docking of New 1,2,3-Triazole Linked Tetrahydrocurcumin Derivatives.

Cancer is one of the deadliest diseases to humanity. There is significant progress in treating this disease, but developing some drugs that can fight this disease remains a challenge in the field of medical research. Thirteen new 1,2,3-triazole linked tetrahydrocurcumin derivatives were synthesized by click reaction, including a 1,3-dipolar cycloaddition reaction of tetrahydrocurcumin baring mono-alkyne with azides in good yields, and their in vitro anticancer activity against four cancer cell lines, including human cervical carcinoma (HeLa), human lung adenocarcinoma (A549), human hepatoma carcinoma (HepG2), and human colon carcinoma (HCT-116) were investigated using MTT(3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetraz-olium bromide) assay. The newly synthesized compounds had their structures identified using NMR HRMS and IR techniques. Some of prepared compounds, including compounds 4g and 4k, showed potent cytotoxic activity against four cancer cell lines compared to the positive control of cisplatin and tetrahydrocurcumin. Compound 4g exhibited anticancer activity with a IC50 value of 1.09 ± 0.17 µM against human colon carcinoma HCT-116 and 45.16 ± 0.92 µM against A549 cell lines compared to the positive controls of tetrahydrocurcumin and cisplatin. Moreover, further biological examination in HCT-116 cells showed that compound 4g can arrest the cell cycle at the G1 phase. A docking study revealed that the potential mechanism by which 4g exerts its anti-colon cancer effect may be through inhabiting the binding of APC-Asef. Compound 4g can be used as a promising lead for further exploration of potential anticancer agents.

Dual targetable drug delivery system based on cell membrane camouflaged liposome for enhanced tumor targeting and improved anti-tumor efficiency.

Receptor and ligand binding mediated targeted drug delivery systems (DDS) sometimes fail to target to tumor sites, and cancer cell membrane (CCM) coating can overcome the dilemma of immune clearance and nonspecific binding of DDS in vivo. In order to enhance the targeting ability and improve the anti-tumor effect, a dual targeting DDS was established based on U87MG CCM mediated homologous targeting and cyclic peptide RGD mediated active targeting. The DDS was prepared by coating RGD doped CCM onto doxorubicin (DOX) loaded liposomes. The homologous and active dual targeting ability endowed the DDS (RGD-CCM-LP-DOX) exhibited superior cancer cell affinity, improved tissue distribution and enhanced anti-tumor effects. In vivo pharmacodynamic studies revealed that RGD-CCM-LP-DOX exhibited superior therapeutic effect compared with homologous targeting CCM-LP-DOX and non-targetable LP-DOX injection. H&E staining, Ki 67 staining and TUNEL staining confirmed that RGD-CCM-LP-DOX not only increased anti-tumor efficacy, but also reduced tissue toxicity by changing the distribution in vivo. The experimental results showed that the RGD doped CCM camouflaged liposome DDS is a better choice for chemotherapeutics delivery.

Cancer cell membrane coated PLGA nanoparticles as biomimetic drug delivery system for improved cancer therapy.

Based on the immune escape and homologous adhesion ability of cancer cells, a drug delivery system (DDS) could overcome the dilemma of immune clearance and non-specific binding by coating the cancer cell membrane (CCM). In this study, a biomimetic DDS based on CCM and poly lactic acid-glycolic acid (PLGA) nanoparticles was successfully constructed for tumor active and homologous targeting therapy. The doped CCM on the surface of the nanoparticle enabled the DDS to achieve immune escape and had an affinity for tumor tissues. The cellular uptake and in vivo distribution tests showed a superior cellular affinity of CCM coated PLGA nanoparticles (CCMNPs) than that of PLGA nanoparticles (PLGANPs). All of those results proved that CCMNPs endowed with drug-loaded nanoparticles had the abilities of immune escape and homologous targeting through the biological functional proteins retained on the coated CCM. In addition, the tumor inhibition rate of CCMNPs in tumor-bearing nude mice was 1.3 and 2.0-fold compared to PLGANPs and PTX injection, which showed the capacity to efficiently and accurately deliver drugs to cancer sites improved the therapeutic effect of tumor and achieved accurately targeted therapy.

Fatigue Reliability Analysis of a Compressor Disk Based on Probability Cumulative Damage Criterion.

The reliability of aero engine has a direct impact on the flight safety of the whole plane. With the continuous improvement of performance requirements of aero engines, the related fatigue and reliability problems also appear. For the fatigue failure characteristics of the typical component (compressor disk) in an aero engine, the fatigue reliability of its multi-site damage structure in service is analyzed by using probability cumulative damage criterion in this paper. The probability distribution definitions of life, damage and damage threshold are discussed and the relationship among them is also introduced by the new proposed criterion. Meanwhile, a method to determine the probability distribution of cumulative damage threshold and probability life prediction is carried out, based on which a hierarchical index system of statistical analysis and reliability modeling principle on the system level is further constructed for compressor disk. At the end of the paper, a certain cruise of fighter plane is analyzed to verify the validity of the new model. Emphasizing the difference between the compressor disk and traditional component, the new reliability analysis model developed in this study is basically reasonable for most of the load histories for the compressor disk, other than the traditional one, especially for the changeable and complex cruise missions.

Comparative Evaluation of Raw and Ripe Fruits of Forsythia suspensa by HPLC-ESI-MS/MS Analysis and Anti-Microbial Assay.

A multi-component quantification fingerprint based on high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry technique has been established for the comparative analysis of raw and ripe fruits of Forsythia suspensa originated from different provinces. Eighteen bioactive constituents including three phenylethanoid glycosides derivatives, six phenolic acids, three flavonoids, four phenylpropanoids, one fatty acid and one terpenoid were identified and quantified. Total contents of phenylethanoid glycosides, phenylpropanoids and flavonoids from raw samples were found much higher than those from ripe samples, while total content of phenolic acids showed a contrary tendency. Moreover, the anti-microbial activities were comparatively assayed for the first time using five different bacterial strains. Results revealed a positive relationship between contents of total phenolic and anti-microbial activity. The results obtained in the present study may provide useful information for future utilization of F. suspensa.

Tissue distribution of borneol-modified ganciclovir-loaded solid lipid nanoparticles in mice after intravenous administration.

The main purpose of this research was to prepare borneol-modified and non-borneol ganciclovir-loaded solid lipid nanoparticles (SLNs) to study whether borneol could enhance the transport of ganciclovir (GCV) incorporated in SLN to the brain in mice after their intravenous administration. Ganciclovir injection (GCV-inj) was selected as a control. The SLNs were prepared using a modified microemulsion method. Pharmacokinetic and biodistribution studies were conducted in kunming mice after intravenous administration of GCV-inj, GCV solid lipid nanoparticles without borneol (GCV-SLN), and three types of GCV solid lipid nanoparticles containing different ratios of borneol (GCVb-SLN). It was found that, in plasma, the area under the concentration-time curve (AUC 0 ∼ t) for GCVb-SLN and GCV-SLN was greater than that for the GCV-inj. In the brain, the AUC 0 ∼ t of GCVb-SLN was significantly increased compared with that of a GCV-inj and GCV-SLN. In the other mouse tissues, the peak concentration of GCV achieved was always lower after the injection of any of the four types of SLN than after the commercial injection. These results indicate that GCV-SLN modified with borneol enhances the transport of ganciclovir to the brain. Therefore, SLN modified with borneol is a potential delivery system for transporting drugs to the central nervous system (CNS).

Effect of diallyl trisulfide on the pharmacokinetics of dipyridamole in rats.

This study was aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic used to inhibit platelet thromboxane formation, on the pharmacokinetics of dipyridamole. Pharmacokinetic parameters of dipyridamole were determined in rats following intragastric (80 mg/kg suspension or 40 mg/kg solution) or intravenous (3 mg/kg) administration of dipyridamole with coadministration (20 mg/kg) and long-term pretreatment of DATS (10 or 20 mg/kg/day for 15 consecutive days). In addition, everted gut sac models were used to assess transepithelial transport of dipyridamole and the effect of DATS on the intestinal absorption of dipyridamole. After coadministration and long-term pretreatment of DATS, significantly lower Cmax and AUC(0-24 h) were observed for intragastric administration of dipyridamole, whereas little change was noted after intravenous dipyridamole administration. After adding DATS (10 and 50 µg/mL) in the everted gut sacs, absorption of dipyridamole was remarkably decreased in the ileum and jejunum (p < 0.01). In conclusion, DATS reduced the oral exposure of dipyridamole in rats likely by the modification of the dissolution rate and intestinal absorption of dipyridamole, indicating that combined use of DATS or DATS-containing supplements with dipyridamole may require caution as low plasma concentrations of dipyridamole may lead to a subtherapeutic effect of this agent.

Pharmacokinetics of carbamazepine polymorphs and dihydrate in rats, related to dogs and humans.

Species differences in the oral pharmacokinetics and absolute bioavailability (F ( abs )) of carbamazepine polymorphs (form I and form III) and dihydrate were studied. The pharmacokinetics of each form was investigated in rats following a single oral/intravenous administration of 10 mg/kg and an oral dose of 80 mg/kg, which were compared with the published data obtained from dogs and humans. No significant differences were found in their C (max), T (max), AUC(0-∞) and F ( abs ) among the forms at the low dose. However, significant differences were observed at the high dose. The Fabs of each form was markedly reduced with increasing of doses in species (e.g. F ( abs ) in rats ranged from > 82% to 38.4%-56.0%). At a comparable dose, the C (max), and AUC(0-∞) of rats and humans were about 3-10 times higher than in dogs. The absorption rate of form III in rats exhibited a similar trend to that in humans, and was far higher in dogs. A multi-peak phenomenon in plasma curves was observed in rats and humans, but not in dogs. In conclusion, rats appear to be a better predictor of carbamazepine polymorphs absorbed in humans, and form III may be more suitable as a pharmaceutical crystal.

Effect of diallyl trisulfide on the pharmacokinetics of nifedipine in rats.

This study aimed to evaluate the effect of diallyl trisulfide (DATS), a major component derived from garlic, on the pharmacokinetics of nifedipine. Pharmacokinetic parameters of nifedipine were determined in rats following an oral gavage (3 mg/kg) or intravenous administration (0.75 mg/kg) of nifedipine with co-administration of DATS (20 mg/kg) and long-term pretreatment of DATS (20 mg/kg/d for 15 consecutive days). Compared to the control groups, higher C(max) and AUC(0-24 h) were observed for oral gavage of nifedipine after short-term and long-term pretreatment of DATS, whereas those for intravenous nifedipine were little changed. The oral bioavailabilities of nifedipine were remarkably enhanced via the concomitant use of DATS. In conclusion, DATS increased the oral exposure of nifedipine in rats likely by the modification of intestinal metabolism of nifedipine, indicating that combined use of DATS or DATS-containing supplement with nifedipine may require caution because high plasma concentrations may lead to an undesired toxicity of this agent. Practical Application: Patients suffering from cardiovascular disease should take caution in combined use of DATS or DATS-rich garlic supplement with nifedipine because long-term treatment of DATS could lead high plasma concentrations of nifedipine.

Wax-matrix tablet for time-dependent colon-specific delivery system of sophora flavescens Aiton: preparation and in vivo evaluation.

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37 degrees C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.