To evaluate the effects of Hydroxypropyl methylcellulose acetate succinate(HPMCAS MF) on absorption of silybin(SLB) from supersaturable self-nanoemulsifying drug delivery system which was pre-prepared at the early stage experiment. The cell toxicity of self-emulsifying preparation was evaluated by the MTT method, and the in vitro membrane permeability and absorption promoting effect of the self-emulsifying preparation were evaluated by establishing a Caco-2 cell monolayer model. The in vivo and in vitro supersaturation correlation was evaluated via the blood concentration of SLB. The results of MTT showed that the concentration of the preparation below 2 mg·mL~(-1)(C_(SLB) 100 μg·mL~(-1)) was not toxic to Caco-2 cells, and the addition of polymer had no significant effect on Caco-2 cells viability. As compared with the solution group, the transport results showed that the P_(app)(AP→BL) of the self-emulsifying preparation had a very significant increase; the transport rate of silybin can be reduced by polymer in 0-30 min; however, there was no difference in supersaturated transport between supersaturated SLB self-nanoemulsion drug delivery system(SLB-SSNEDDS) and SLB self-nanoemulsion drug delivery system(SLB-SNEDDS) within 2 hours. As compared with SLB suspension, pharmacokinetic parameters showed that the blood concentration of both SLB-SNEDDS and SLB-SSNEDDS groups were significantly increased, and C_(max) was 5.25 times and 9.69 times respectively of that in SLB suspension group, with a relative bioavailability of 578.45% and 1 139.44% respectively. C_(max) and relative bioavailability of SLB-SSNEDDS were 1.85 times and 197% of those of SLB-SNEDDS, respectively. Therefore, on the one hand, SSNEDDS can increase the solubility of SLB in gastrointestinal tract by maintaining stability of SLB supersaturation state; on the other hand, the osmotic transport process of SLB was regulated through the composition of its preparations, and both of them could jointly promote the transport and absorption of SLB to improve the oral bioavailability of SLB.
Administration, Oral ; Biological Availability ; Caco-2 Cells ; Drug Delivery Systems ; Emulsions ; Humans ; Methylcellulose/analogs & derivatives* ; Nanoparticles ; Particle Size ; Silybin ; Solubility

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

Using three-dimensional printing to produce antibacterial wound dressing is a new topic that will change the production style of wound dressing industry. Combining with post-3D-printed process, a desktop fused deposition molding equipment can be used to produce wound dressing containing polyvinyl alcohol, alginate and chitosan. The wound dressing produced by FDM has good aspects of absorbency, moisture vapour transmission rate and mechanical property. After loaded with antibacterial agent iodine and silver nano particle, the antibacterial activity rate increases to 99% and it is suitable to use as antibacterial wound dressing. This method affects the production of wound dressing to a more cost-effective way, and provides a possible individualized treatment for patient in the future.
Alginates ; chemistry ; Anti-Bacterial Agents ; administration & dosage ; Bacteria ; drug effects ; Bandages ; economics ; standards ; Chitosan ; chemistry ; Humans ; Iodine ; administration & dosage ; pharmacology ; Nanoparticles ; administration & dosage ; Polyvinyl Alcohol ; chemistry ; Printing, Three-Dimensional ; Silver ; administration & dosage ; pharmacology ; Wound Healing

Zinc oxide quantum dots (ZnO QDs) were synthesized by gel-sol method and employed as the transdermal aloesin (Alo) carriers. ZnO QDs were surface-functionalized with amino using aminopropyltriethoxysilane (APTES). Alo was covalently bonded on the surface of ZnO QDs via N,N'-carbonyldiimidazole to obtain Alo NPs, which were characterized by transmission electron microscope (TEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analyzer (TGA). TEM images showed that ZnO QDs were analogously sphere and monodisperse with a reasonably narrow size distribution, of which was around 4 nm. The size of Alo NPs increased to around 8 nm due to the surface modification. The intense bands at around 3 400 cm and 1 200 cm in the FTIR spectrum of Alo NPs from the vibration of -OH indicated the linkage of Alo on the surface of ZnO QDs. The results of TGA analysis showed that the mass ratio of ZnO QDs and Alo were 39.27% and 35.14%, respectively. The penetration of Alo NPs was much higher than raw Alo according to the passive penetration experiments with Franz-type diffusion cells instrument using full-thickness cavy skin, which manifested the improvement of the penetration for Alo delivered by ZnO QDs. The pH-controlled drug release behavior was investigated. At pH 7.4, only a small amount of Alo (1.45% ± 0.21%) had been released after 2 h. In contrast, as incubation at pH 5.0 of which pH was similar to endosomal environment, Alo was released very fast (87.63% ± 0.46% in 2 h) from Alo NPs, confirming that Alo NPs could response to the pH and realize the intracellular drug release. The inhibitory effect of Alo NPs on tyrosinase was in a dose dependent manner. When the concentration of Alo NPs was 12.5 μg/mL, the inhibition rate was up to 40.32% ± 1.57%. All the results show that the Alo NPs hold a great potential in transdermal tyrosinase inhibition.
Administration, Cutaneous ; Animals ; Chromones ; administration & dosage ; Drug Delivery Systems ; Glucosides ; administration & dosage ; Guinea Pigs ; Monophenol Monooxygenase ; metabolism ; Nanoparticles ; Quantum Dots ; Zinc Oxide

Although intravesical instillation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the most successful cancer immunotherapy for superficial bladder cancer, the serious side effects are frequently arisen by using live mycobacteria. To allow less toxic and more potent immunotherapeutic agents following intravesical BCG treatment for superficial bladder cancer, noninfectious immunotherapeutic drug instead of live BCG would be highly desirable. Recently, immune-enhancing adjuvants are considered an effective vaccine immunotherapy for cancer, providing enhanced antitumor effects and boosted immunity. The BCG-cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate as a noninfectious immunotherapeutic drug instead of live BCG against bladder cancer. However, the most limited application for anticancer therapy, it is difficult to formulate a water-soluble BCG-CWS due to the aggregation of BCG-CWS in both aqueous and nonaqueous solvents. To overcome the insolubility and improve the internalization of BCG-CWS into bladder cancer cells, it should be developed the lipid nanoparticulation of BCG-CWS, resulting in improved dispensability, stability, and small size. In addition, powerful technology of delivery systems should be applied to enhance the internalization of BCG-CWS, such as encapsulated into lipid nanoparticles using novel packaging methods. Here, we describe the progress in research on effects of BCG-CWS for cancer immunotherapy, development of lipid-based solvent, and packaging method using nanoparticles with drug delivery system.
Administration, Intravesical ; Bacillus ; Cell Wall Skeleton ; Drug Delivery Systems ; Immunotherapy ; Methods ; Mycobacterium bovis ; Nanoparticles ; Product Packaging ; Skeleton ; Solvents ; Urinary Bladder Neoplasms ; Urinary Bladder

OBJECTIVETo investigate the subchronic oral toxicity of silica nanoparticles (NPs) and silica microparticles (MPs) in rats and to compare the difference in toxicity between two particle sizes.

METHODSSprague-Dawley rats were randomly divided into seven groups: the control group; the silica NPs low-, middle-, and high-dose groups; and the silica MPs low-, middle-, and high-dose groups [166.7, 500, and 1,500 mg/(kg•bw•day)]. All rats were gavaged daily for 90 days, and deionized water was administered to the control group. Clinical observations were made daily, and body weights and food consumption were determined weekly. Blood samples were collected on day 91 for measurement of hematology and clinical biochemistry. Animals were euthanized for necropsy, and selected organs were weighed and fixed for histological examination. The tissue distribution of silicon in the blood, liver, kidneys, and testis were determined.

RESULTSThere were no toxicologically significant changes in mortality, clinical signs, body weight, food consumption, necropsy findings, and organ weights. Differences between the silica groups and the control group in some hematological and clinical biochemical values and histopathological findings were not considered treatment related. The tissue distribution of silicon was comparable across all groups.

CONCLUSIONOur study demonstrated that neither silica NPs nor silica MPs induced toxicological effects after subchronic oral exposure in rats.

Administration, Oral ; Animals ; Dose-Response Relationship, Drug ; Female ; Male ; Nanoparticles ; toxicity ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Silicon Dioxide ; toxicity ; Toxicity Tests, Subchronic

The present study was designed to improve storage stability and oral bioavailability of Ganneng dropping pills (GNDP) by transforming lignans of Herpetospermum caudigerum (HL) composed of herpetrione (HPE) and herpetin (HPN) into nanosuspension (HL-NS), the main active ingredient of GNDP, HL-NS was prepared by high pressure homogenization and lyophilized to transform into solid nanoparticles (HL nanoparticles), and then the formulated HL nanoparticles were perfused into matrix to obtain NS-GNDP by melting method. For a period of 3 months, the content uniformity, storage stability and pharmacokinetics test in vivo of NS-GNDP were evaluated and compared with regular GNDP at room temperature. The results demonstrated that uniformity of dosage units of NS-GNDP was acceptable according to the criteria of Chinese Pharmacopoeia 2015J. Physical stability of NS-GNDP was investigated systemically using photon correlation spectroscopy (PCS), zeta potential measurement, and scanning electron microscopy (SEM). There was a slight increase in particles and PI of HL-NS re-dispersed from NS-GNDP after storage for 3 months, compared with new formulated NS-GNDP, which indicated a good redispersibility of the NS-GNDP containing HL-NS after storage. Besides, chemical stability of NS-GNDP was studied and the results revealed that HPE and HPN degradation was less when compared with that of GNDP, providing more than 99% of drug residue after storage for 3 months. In the dissolution test in vitro, NS-GNDP remarkably exhibited an increased dissolution velocity compared with GNDP and no distinct dissolution difference existed within 3 months. The pharmacokinetic study showed that HPE and HPN in NS-GNDP exhibited a significant increase in AUC, C and decrease in T when compared with regular GNDP. These results indicated that NS-GNDP possessed superiority with improved storage stability and increased dissolution rate and oral bioavailability.
Animals ; Benzofurans ; chemistry ; Biological Availability ; Cucurbitaceae ; chemistry ; Drug Carriers ; chemistry ; Drug Compounding ; Drug Stability ; Freeze Drying ; Furans ; chemistry ; Humans ; Lignans ; administration & dosage ; chemistry ; isolation & purification ; pharmacokinetics ; Male ; Nanoparticles ; administration & dosage ; chemistry ; Particle Size ; Plant Extracts ; chemistry ; isolation & purification ; Rats ; Rats, Sprague-Dawley ; Solubility

The effect of surface charges on the cellular uptake rate and drug release profile of tetrandrine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TPNs) was studied. Stabilizer-free nanoprecipitation method was used in this study for the synthesis of TPNs. A typical layer-by-layer approach was applied for multi-coating particles' surface with use of poly(styrene sulfonate) sodium salt (PSS) as anionic layer and poly(allylamine hydrochloride) (PAH) as cationic layer. The modified TPNs were characterized by different physicochemical techniques such as Zeta sizer, scanning electron microscopy and transmission electron microscopy. The drug loading efficiency, release profile and cellular uptake rate were evaluated by high performance liquid chromatography and confocal laser scanning microscopy, respectively. The resultant PSS/PAH/PSS/PAH/TPNs (4 layers) exhibited spherical-shaped morphology with the average size of 160.3±5.165 nm and zeta potential of-57.8 mV. The encapsulation efficiency and drug loading efficiency were 57.88% and 1.73%, respectively. Multi-layer coating of polymeric materials with different charges on particles' surface could dramatically influence the drug release profile of TPNs (4 layers vs. 3 layers). In addition, variable layers of surface coating could also greatly affect the cellular uptake rate of TPNs in A549 cells within 8 h. Overall, by coating particles' surface with those different charged polymers, precise control of drug release as well as cellular uptake rate can be achieved simultaneously. Thus, this approach provides a new strategy for controllable drug delivery.
Antineoplastic Agents, Phytogenic ; administration & dosage ; chemistry ; Benzylisoquinolines ; administration & dosage ; chemistry ; Cell Line, Tumor ; Drug Liberation ; Humans ; Lactic Acid ; chemistry ; Nanoparticles ; adverse effects ; chemistry ; metabolism ; Polyamines ; chemistry ; Polyglycolic Acid ; chemistry ; Polystyrenes ; chemistry ; Static Electricity

The study aimed to examine the applicability of carbon nanoparticles as a tracer for lymph node mapping and the related factors of lymph node and No.8p subgroup metastasis in patients with gastric cancer. Clinical data of 50 patients with gastric cancer, who had not received treatment preoperatively and underwent gastrectomy in Department of Gastrointestinal Surgery, Wuhan Union Hospital, between October 2014 and August 2015, were retrospectively analyzed. These patients were found to have no distant metastasis preoperatively. Thirty-five out of 50 patients were subjected to lymphatic mapping technique using carbon nanoparticles as the tracer, and the rest 15 cases did not experience the lymphatic mapping and served as controls. The sensitivity, specificity, false positive rate and false negative rate were calculated according to the number of lymph nodes, and the staining and metastasis condition of lymph nodes. The diagnostic value of carbon nanoparticles on metastatic lymph nodes was evaluated. The relationship between the metastasis of lymph nodes or subgroup No.8p lymph nodes and clinicopathologic features was analyzed by χ-test or Fisher's exact test. All patients underwent D2 surgery (lymph node dissection including all the group 1 and group 2 nodes) plus the dissection of the subgroup No.8p lymph nodes. It was found that the average number of harvested lymph nodes in lymphatic mapping technique group (45.7±14.5) was greater than that in control group (39.2±11.7), but the difference was not significantly different (P=0.138>0.05). The success rate, the accuracy, sensitivity, specificity and false negative rate was 97%, 57%, 28%, 62% and 72% respectively. The metastasis of lymph nodes was correlated to the depth of cancer invasion (T stage) (P=0.004<0.05), and the metastasis of No.8p lymph nodes was correlated to the extent of lymph node involvement (N stage) (P=0.007<0.05). Six cases had lymph node metastasis in subgroup No.8p, and their TNM stages and clinical stages were as follows: T1N2M0 IIA, T3N3M0 IIIB, T4aN3M0 IIIC, T4aN3M0 IIIC, T4aN3M0 IIIC, and T4bN3M0 IIIC. In conclusion, our study indicated that carbon nanoparticles failed to show good selectivity for metastatic lymph nodes; the result of lymphatic mapping does not achieve a satisfactory performance; the incidence of lymph node metastasis may increase, accompanying with the increase of the depth of cancer invasion; No.8p lymph node metastasis tends to occur for gastric carcinoma patients with the extent of lymph node metastasis over N2 stage.
Adolescent ; Adult ; Aged ; Carbon ; Carcinoma ; diagnostic imaging ; pathology ; surgery ; Female ; Humans ; Lymph Nodes ; diagnostic imaging ; pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Nanoparticles ; administration & dosage ; adverse effects ; chemistry ; Sensitivity and Specificity ; Stomach Neoplasms ; diagnostic imaging ; pathology ; surgery

OBJECTIVETo compare the effect of bone regeneration with two different ratios of nano-hydroxyapatite(nHA)/collagen(Col) (nHAC) after tooth extraction in canine.

METHODSTwo kinds of nHAC grafts were prepared with different nHA/collagen ratio of 3∶7 and 5∶5. Eighteen male healthy adult dogs had been randomly divided into three groups. Immediately after extraction of the mandibular second premolars, each kind of nHAC was implanted into extraction sockets as follow: Group A, nHA/Col=3∶7(12 sites); Group B, nHA/Col=5∶5(12 sites); Group C, blank control group(12 sites). The bone repairing abilities of the two grafts such as vertical distance of alveolar, CT values, general observation, histological observation, trabecular volume fraction and porosity were separately analyzed at 1st, 3rd and 6th month, respectively (each group had 4 sites in different time periods).

RESULTSnHAC were absorbed gradually after they were implanted into alveolar bone defect and were replaced by new bone. The vertical distance of alveolar bone in Group A([15.76±0.28] mm) was significant higher than that in Group B([14.88±0.36] mm), and CT values of Group A([879±31] HU) were higher than those in Group B([718±29] HU) (P<0.05). The trabecular bone volume percentage of Group A([22.2±0.4]%) was higher than that in Group B([20.3±0.4]%), and the bone porosity of Group A([23.6±0.9]%) was lower than that in Group B([27.6±0.6]%) (P<0.05). In addition, the vertical distance, CT values and the trabecular bone volume percentage of Group C was lower than those in Group A and B, but the bone porosity of Group C was higher.

CONCLUSIONSThe nHAC with nHA/collagen ratio of 3∶7 could better promote bone regeneration than nHAC with the nHA/collagen ratio of 5∶5 did.

Animals ; Bone Regeneration ; Collagen ; administration & dosage ; pharmacokinetics ; Dogs ; Durapatite ; administration & dosage ; pharmacokinetics ; Male ; Nanoparticles ; Random Allocation ; Tissue Engineering ; Tooth Extraction