Animals ; Dexamethasone ; administration & dosage ; metabolism ; pharmacokinetics ; Drug Administration Routes ; Ear, Middle ; Guinea Pigs ; Nanoparticles ; administration & dosage

The purpose of this study was to prepare the nobiletin-loaded nanoemulsions (NOB-NE) and study its in vivo distribution in mice. The characteristics and stability of the unloaded and drug-loaded nanoemulsions were investigated. The size, apparent viscosity and pH value of NOB-NE were respectively (15.5 +/- 2.9) nm, (3.10 +/- 0.33) mPa x s and 6.56 +/- 0.05, which were all higher than those of unloaded nanoemulsions. The zeta potential of unloaded and drug-loaded nanoemulsions carried negative charge. The NOB-NE after diluted by 5% glucose solution was stable in 8 h, and there was no significant difference in the size, content and diluted stability of its preconcentrate in long-term storage. The concentration of nobiletin in plasma and tissues was determined by HPLC after intravenous administration of NOB-NE. Based on AUC(0-t), MRT and C(max), the nanoemulsions delivered more nobiletin into the brain and kidney compared to those of nobiletin solution. The brain and kidney targeting efficiency was improved. In addition, the results fitting using SAAM II software show that the higher drug concentration of the NOB-NE in the brain might be owed to the quicker transport rate from the blood to the brain, and that in the kidney relate to the probable accumulation effect. These results indicate that the in vivo distribution of NOB-NE with consistent quality in mice could be changed and its brain and kidney targeting absorption capability was enhanced comparing with nobiletin solution.
Animals ; Drug Stability ; Emulsions ; Female ; Flavones ; administration & dosage ; pharmacokinetics ; Male ; Mice ; Nanoparticles ; administration & dosage ; Tissue Distribution

Various geometric shapes and structures self-assembled of amphiphilic lipids when present in an aqueous environment, as active delivery vehicles, are becoming one of focuses of drug delivery system. Lipid-based cubic liquid crystalline nanoparticles (or Cubosomes) consisting of "honeycombed (cavernous)" structure spontaneously formed when a certain concentration of amphiphilic lipids dispersed in aqueous solution has curved bicontinuous lipid bilayer in three dimensions, separating two congruent networks of water channels. Its unique structure consists of internal double water channels and large interfacial areas, which reveal great flexibility in encapsulation efficiency of various polarities and amount of drugs, and has variegated range of drugs encapsulated. As a drug delivery vehicle, high drug payloads, stabilization of peptides or proteins and simple preparation process are also its advantages. The ability of cubic phase to incorporate and control release of drugs of varying size and polar characteristics, and biodegradability of lipids make it an interesting drug delivery system for various routes of administration, including oral, topical (or mucosal) and intravenous administrations, with extensive application in a multitude of dosage forms. Furthermore, a number of different proteins in cubic phase appear to retain their native conformation and bioactivity, and are protected against chemical and physical inactivation. In this paper, investigations of lipid-based cubic liquid crystalline nanoparticles are reviewed and summarized, with a hope to provide a reference for its in-depth study. At the end, the authors made a development prospect of this novel excellent candidate for active ingredients delivery vehicle.
Drug Carriers ; chemistry ; Drug Delivery Systems ; methods ; Lipids ; administration & dosage ; chemistry ; Liquid Crystals ; chemistry ; Nanoparticles

OBJECTIVE: To explore the effects and related mechanisms of oral exposure titanium dioxide nanoparticles (TiO₂ NPs) for 90 days on the intestinal and the gut microbiota of rats, through fecal metabolomics. METHODS: Twelve 4-week-old clean-grade Sprague Dawley (SD) rats were randomly de-vided into 2 groups by body weight, treated with TiO₂ NPs at dose of 0 or 50 mg/kg body weight everyday respectively for 90 days. The solution of each infection was freshly prepared and shocked fully by ultrasonic. Characterization of the particle size, crystal form, purity, and specific surface area of TiO₂ NPs was conducted. And the fresh feces of the rats were collected on the 90th day. After lyophilized and hydrophilic phase extraction, ultra performance liquid chromatography-Q-exactive orbitrap-high-resolution mass spectrometry system (UPLC-QEMS) was utilized for non-targeted determination of fecal meta-bolites. The metabolites were identified and labeled through Compound Discoverer 3.0 software, and used for subsequent metabolomics analysis. Bioinformatics analysis was carried out including unsupervised principal component analysis and supervised orthogonal projection to latent structure discriminant analysis for the differential metabolites between the two groups. The differential metabolites were followed-up for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: Compared with the control group, the body weight of the rats was significantly reduced (P<0.05) in the treatment group. A total of 22 metabolites in fecal metabolomics showed significant changes. Among them, xanthine, 1-methyladenine, 3-hydroxypyridine, methionine sulfoxide, pyridoxine, 1,5-isoquinolinediol, N-acetylornithine, N-acetyl-D-galactosamine, L-citrulline, L-methionine, leucine, DL-tryptophan, L-ornithine, 4-methyl-5-thiazoleethanol, and L-glutamic acid totaled 15 metabolites increased significantly. N-acetylhistamine, D-pipecolinic acid, imidazolelactic acid, L-valine, 2,3,4,6-tetramethylpyrazine, caprolactam, and histamine totaled 7 metabolites decreased significantly. N-acetylhistamine, L-valine and methionine sulfoxide were changed more than 16 times. Analysis of KEGG pathway revealed that the two metabolic pathways arginine biosynthesis and aminoacyl-tRNA biosynthesis were significantly changed (false discover rate < 0.05, pathway impact > 0.1). CONCLUSION Oral exposure to TiO₂ NPs for 90 days could disrupt the metabolism of the intestine and gut microbiota, causing significant changes in metabolites and metabolic pathways which were related to inflammatory response, oxidative stress, glucose homeostasis, blood system and amino acid homeostasis in rat feces. It is suggested that the toxic effect of TiO₂ NPs on rats may be closely related to intestinal and gut microbiota metabolism.
Administration, Oral ; Animals ; Feces ; Metabolome ; Metal Nanoparticles ; Rats ; Rats, Sprague-Dawley ; Titanium

Administration, Oral ; Animals ; Mice ; Nanoparticles ; toxicity ; Particle Size ; Titanium ; toxicity ; Toxicity Tests, Acute

Liposomes and nanoparticles have been used as drug carriers to increase solubility, prolong drug duration in vivo, target drug delivery, reduce toxicity and combat multi-drug resistance. With major advances in the preparation techniques, preparation material, and surface modifiers in recent years, liposomes and nanoparticles delivery systems have achieved success in fields including cancer therapy, overcoming biological barriers, and biological drugs and vaccine carriage.
Drug Carriers ; Drug Delivery Systems ; methods ; Humans ; Liposomes ; Nanoparticles ; Vaccines ; administration & dosage ; chemistry

OBJECTIVE1H magnetic resonance (1H MR) spectroscopic technique in combination with pattern recognition technique were applied to analyze toxic effects of rats which were intratracheally instilled with titanium dioxide nanoparticles (nano-TiO2) as well as to detect the target organs and biomarkers associated with the toxic effects.

METHODSTwenty-four SD male rats were divided into 4 groups randomly which were high dose group (40 mg/kg nano-TiO2), moderate dose group (4 mg/kg nano-TiO2), low dose group (0.4 mg/kg nano-TiO2) and control group (0.9% NaCl solution) respectively, there were six rats per group. All rats were exposed to the object by single intratracheally instilling at a volume of 0.1 ml/100 g. After one week observation, 1H MR spectra of plasma were measured and analyzed by principal component analysis. Histopathologic examination for tissues such as heart, lung, liver, and kidney were performed simultaneously.

RESULTSThe relative content of lactate [(37.86+/-2.58)x10(-3)], citrate [(2.21+/-0.45)x10(-3)], choline [(7.74+/-0.76)x10(-3)] and creatine [(4.17+/-1.15)x10(-3)] in high dose group were significantly decreased as compared with those [(52.07+/-5.12)x10(-3), (3.01+/-0.21)x10(-3), (9.28+/-0.78)x10(-3), (8.59+/-2.64)x10(-3)] in control group (t values were -6.024, -3.177, -3.374, -4.215 respectively, P<0.05), however the relative content of glucose [(19.41+/-1.72)x10(-3)] was significantly increased compared with that [(14.45+/-2.45)x10(-3)] in control group (t value was 2.802, P<0.05). The relative content of lactate [(44.39+/-5.09)x10(-3)] and creatine [(3.67+/-0.76)x10(-3)] in moderate group was significantly decreased compared with those [(52.07+/-5.12)x10(-3), (8.59+/-2.64)x10(-3)] in control group (t values were -3.254, -4.694 respectively, P<0.05). The relative content of pyruvate [(3.84+/-0.70)x10(-3)] was significantly increased in low dose group as compared with that [(3.13+/-0.46)x10(-3)] in control group (t value was 2.787, P<0.05), however the relative content of creatine [(8.10+/-0.72)x10(-3)] was significantly decreased compared with that [(9.28+/-0.78)x10(-3)] in control group (t value was -2.602, P<0.05). No significant difference was found between other experimental groups and control group. No visible damage was found in histopathologic examination.

CONCLUSIONLung, liver, kidney and heart were the target organs of rats which were intratracheally instilling titanium dioxide nanoparticles. Lactate, pyruvate, glucose, citrate, choline and creatine can be presumed as the biomarkers when searching the target organs of the toxic effects.

Animals ; Male ; Metal Nanoparticles ; Plasma ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Titanium ; administration & dosage ; toxicity

Nanocrystal suspensions drug delivery system is used to solve the delivery difficulty of poorly soluble drug. However, the physical stability of liquid nanocrystal suspensions is very bad. Solid nanocrystal delivery system as a novel technology, can improve the thermokinetics stability of nanocrystal suspensions and have good clinical compliance, which can achieve stabilization of nanocrystal suspension systems as an ideal delivery system. In this paper, we reviewed the research progress of nanotechnology and solidification technology of solid nanocrystal suspension delivery system, which will give the new mirrors and thoughts on the development of solid nanocrystal delivery system.
Drug Delivery Systems ; Nanoparticles ; Nanotechnology ; methods ; Pharmaceutical Preparations ; administration & dosage ; chemistry

This study was aimed to explore the potential therapy of Gambogic acid (GA) combined with magnetic nanoparticle of Fe3O4 (Fe3O4-MNP) on leukemia. The proliferation of U937 cells and the cytotoxicity were evaluated by MTT assay. Cell apoptosis was observed and analyzed by microscopy and flow cytometry respectively. The expressions of gene and protein were detected by quantitative real-time polymerase chain reaction and Western blot respectively. The results showed that GA enhanced the cytotoxicity for U937 cells in dose- and time-dependent manners. The Fe3O4-MNP itself had not cytotoxicity, but could enhance the inhibitory effect of GA on proliferation of U937 cells. The apoptotic rate of U937 cells induced by combination of GA with Fe3O4-MNP was higher than that by GA alone. The typical apoptotic features of cells treated with GA and Fe3O4-MNP were observed. The expression levels of caspase-3 and bax after co-treatment of GA and Fe3O4-MNP were higher than that exposed to GA or Fe3O4-MNP alone, but the expressions of bcl-2, NF-kappaB and survivin were down-regulated. It is concluded that Fe3O4-MNP can promote GA-induced apoptosis in U937 cells, and the combination of GA with Fe3O4-MNP may be a safer and less toxic new therapy for leukemia.
Apoptosis ; drug effects ; Humans ; Iron Compounds ; administration & dosage ; pharmacology ; Magnetics ; Nanoparticles ; U937 Cells ; Xanthones ; pharmacology

OBJECTIVETo evaluate the targeted distribution of cis-platin magnetic nanoparticles (CDDP-MNP) in normal mice.

METHODSThirty-two normal mice were randomly assigned into 4 equal groups. External magnetic field of 4100-4200 Gs was established in the unilateral kidney area of each mouse, and CDDP-MNP was administered via the tail vein, with the external magnetic field maintained in groups A, B, C, and D for 30 min and 1, 2 and 4 h after the injection, respectively. A flame atomic absorption spectrometer (AAS) was used to detect CDDP concentration in the mouse kidney tissues. Magnetic resonance imaging (MRI), Prussian blue staining, and transmission electron microscopy (TEM) were used to detect the distribution of the magnetic nanoparticles in vivo.

RESULTSIn groups A, B and C, the concentrations of CDDP in the targeted kidney tissues increased significantly in comparison with those in non-targeted kidney. The signal intensity of the targeted kidney tissue was lower than that of the non-targeted kidney on T2-weighted MR images. TEM and Prussian blue staining demonstrated MNP distribution in the lumens and endothelial cells of the blood capillary in the kidney tissue.

CONCLUSIONCDDP-MNP allows targeted distribution induced by external magnetic field in normal mice after intravenous injection.

Animals ; Cisplatin ; administration & dosage ; pharmacokinetics ; Drug Delivery Systems ; Female ; Magnetics ; Male ; Mice ; Nanoparticles ; administration & dosage ; Random Allocation ; Tissue Distribution