Assessment of Mononuclear/Dinuclear copper acylhydrazone complexes for lung cancer treatment.

Non-platinum metal-based complexes have good potential for cancer treatment. Here, we designed and synthesized five hydrazone copper(II) complexes, [Cu2(HL)2Cl2] 1A, [Cu2(HL)2(NO3)H2O]·NO3 2A, [Cu2(HL)2Br2] 3A, [Cu(L)pyridine] 1B and [Cu(HL)(pyridine)Br] 3B, and evaluated their anti-lung cancer activities. MTT experiments revealed that these copper(II) complexes exhibit higher anticancer activity than cisplatin. Mechanism studies revealed that complex 3A induced G1 phase cell cycle arrest, and induced cell apoptosis via reactive oxygen species (ROS)-mediated mitochondrial dysfunction. Scratch wound healing assay was also performed, revealing that complex 3A have good anti-cell migration activity. Hemolysis assays showed good blood biocompatibility of complex 3A. Furthermore, complex 3A can significantly inhibit the proliferation of A549 3D tumor spheroid. An in vivo anticancer study showed that complex 3A could delays the growth of A549 tumor xenografts with lower systemic toxicity. These results highlight the great possibility of developing highly active copper complexes as anti-lung cancer agents.

Preparation, characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin.

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA-SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA-PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA-PEG6000 (1:3) SD and NA-suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA-PEG6000 (1:3) SD (Cmax = 0.645 ± 0.262 µg/ml, AUC0-t = 0.471 ± 0.084 µg/ml h) were higher than that of NA-suspension (Cmax = 0.328 ± 0.183 µg/ml, AUC0-t = 0.361 ± 0.093 µg/ml h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.

Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel.

Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of ß-butyrolactone (ß-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)2 as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T1/2 (4-fold) and higher AUCtumor (19-fold), but Cmax was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.

[Chemical Constituents from Young Fruits of Citrus maxima cv. Shatian].

OBJECTIVE: To investigate the chemical constituents from the young fruits of Citrus maxima cv. Shatian. METHODS: The chemical constituents were isolated and purified by silica gel column chromatography and recrystallization, and their structures were identified on the basis of physicochemical properties and spectral analysis. RESULTS: Seven compounds were isolated and identified as naringenin (I), marmin (II), naringin (III), ß-sitosterol (IV) 5,7-dihydroxylcoumarin (V) 1, 3,5-trihydroxyhenzene (VI) and xanthotoxol (VII). CONCLUSION: Except compound III, all compounds are isolated from the young fruits of Citrus maxima cv. Shatian for the first time.

Synthesis, characterization, biodegradability and biocompatibility of a temperature-sensitive PBLA-PEG-PBLA hydrogel as protein delivery system with low critical gelation concentration.

Temperature-sensitive hydrogels were designed using a series of A-B-A triblock copolymers consisting of poly (ethylene glycol) (PEG) with different molecular weights as the hydrophilic block B and poly (ß-butyrolactone-co-lactic acid)(PBLA) with varying block lengths and composition as the hydrophobic block A. The triblock copolymers were synthesized by ring-opening polymerization (ROP) of ß-BL and LA in bulk using PEG as an initiator and Sn(Oct)2 as the catalyst. Their chemical structure and molecular characteristics were determined by NMR, GPC and DSC, and the relationship between structure and phase behaviors in aqueous solutions was investigated as well. It was found that the phase behaviors in aqueous solutions including critical micelle concentration (CMC), sol-gel-sedimentation phase transition temperature, gel window width and critical gelation concentration (CGC) are largely dependent on the molecular weight and block length ratio of PEG/PBLA. Most importantly, they show a very low CGC ranging from 4 to 8 wt% because of the introduction of ß-BL. Furthermore, the biodegradability and biocompatibility of the hydrogels were evaluated. Finally, lysozyme as a model protein was used to evaluate the ability to deliver protein drugs in a sustained release manner and biologically active form. All results demonstrated that the temperature-sensitive in situ forming hydrogel has a promising potential as sustained delivery system for protein drugs.

Isolation, characterization and bioactivities of the polysaccharides from Dicliptera chinensis (L.) Juss.

The polysaccharides of Dicliptera chinensis (L.) Juss. (DCP-1 and DCP-2) were extracted and isolated using the methods of water extract-ethanol precipitate and sephadex column chromatography and characterized by gel permeation chromatography (GPC), Fourier transform infrared spectrometry (FT-IR) and gas chromatography (GC), respectively. The antioxidant activity of DCPs was evaluated by scavenging activity of DPPH, hydroxyl, superoxide anion and ABTS radical. Moreover, the anti-aging activity of DCP-2 was investigated using an aging model-induced by D-galactose (D-gal) in mice. The results show that the weight average molecular weight (Mw) of DCP-2 was 2 273Da with a narrow polydispersity index of 1.01, and it was a heteropolysaccharide and consisted of glucose, galactose, arabinose, rhamnose and mannose with a molar ratio of 3.20:2.54:1.69:1.58:1.00. DCP-2 had stronger antioxidant activity against DPPH, hydroxyl, superoxide anion and ABTS radical, while DCP-1 had hardly any antioxidant activity and DCP had weaker antioxidant activity. Furthermore, DCP-2 can enhance antioxidant capacity and had anti-aging activity against D-gal induced aging mice. These results proposed that DCP-2 might be developed as a potential functional food with the activity of anti-aging.

Hepatoprotective effects of Dicliptera chinensis polysaccharides on dimethylnitrosamine-induced hepatic fibrosis rats and its underlying mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dicliptera chinensis is a traditional herbal medicine used anciently in China for hepatopathy treatment, especially in south areas. Our several studies have demonstrated that dicliptera chinensis polysaccharides (DCP), which has a markedly protective effects on chemistry-induced models of acute liver injury in rats. In this study, we further investigated the potentially hepatoprotective effect of dicliptera chinensis polysaccharides (DCP) on hepatic fibrosis (HF) rats induced by dimethylnitrosamine (DMN). MATERIAL AND METHODS: The 96 rats were randomly divided into six groups (n=16, per group), the normal control group intragastrically administrated normal saline, model control group intraperitoneally injected with 0.5% DMN solution at 1.6mL per kg (three times a week); colchicine intragastrically administrated group (0.2mgkg(-)(1)d(-1))+DMN-treated rats; DCP intragastrically administrated groups (100mgkg(-)(1)d(-)(1), 200mgkg(-1)d(-1), 300mgkg(-1)d(-1))+DMN-treated rats. At the end of 8 weeks, all rats were sacrificed. RESULTS: Pathological examination showed that high and medium doses of DCP presented remarkable effect in ameliorating hepatic fibrosis, alleviate the inflammation, necrosis and reduced collagen deposits. DCP effectively improved the liver function, as revealed in being lowered sero-enzyme levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) while increased albumin (ALB), and being reduced sero-concentrations of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in the HF rats. Additionally, the contents of hyaluronic acid (HA), collagen type Ⅳ (Ⅳ-C), type III precollagen (PCIII) and laminin (LN) in the hepatic tissue of HF rats were markedly decreased, whereas the expressions of transforming growth factor-ß l (TGF-ß l), collagen type I (Col- I), metal protease-1 (TIMP-1), nuclear factor-kappa B (NF-κB) expression in the hepatic tissue were notably down-regulated. CONCLUSION: DCP exerts effectively antagonistic activity on DMN-caused hepatotoxicity in HF rats, which the anti-fibrotic mechanisms are associated with regulating functionally serous enzymes, improving metabolic function and inhibiting inflammatory reaction in liver tissue.

[Preliminary study on the alpha-glucosidase inhibitor from Glycyrrhiza uralensis Fisch].

OBJECTIVE: To extract and isolate alpha-glucosidase inhibitor from Glycyrrhiza uralensis Fisch. METHODS: The aqueous extract of Glycyrrhiza uralensis Fisch. was extracted by petroleum, ethyl acetate and n-butanol. In addition, the inhibitory activity against alpha-glucosidase of every fraction was determined and the inhibitory kinetics of ethyl acetate fraction was investigated. RESULTS: The inhibitory activities of four fractions were 68.93%, 83.2%, 32.17% and 10.79% respectively. Compared with the aqueous extract (69.77%), the inhibitory activity of ethyl acetate fraction was higher. Ethyl acetate fraction was shown to be a fast-binding, dose-dependent and competitive model with a Ki value of 34 microg/ml. CONCLUSION: It is hoped to obtain good alpha-glucosidase inhibitors by separating ethyl acetate fraction of aqueous extract of Glycyrrhiza uralensis Fisch further.

[Study on the chemical constituent from Buddleja purdomii].

OBJECTIVE: To study the chemical constituents from Buddleja purdomii W. W. Smith. METHODS: The constituents were isolated and purified by various chromatographic methods and structurally identified by spectral analysis. RESULTS: 4 compounds were identified as vanillin (I), vanillic acid (II), acteoside (III), acteoside isomer (IV). CONCLUSION: All these compounds were obtained from this plant for the first time.

Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery.

In order to limit the adverse reactions caused by polysorbate 80 in Taxotere(®), a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO) with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.