Carbon nanoparticles suspension injection for the delivery of doxorubicin: Comparable efficacy and reduced toxicity.

Drug delivery systems for doxorubicin (DOX) have attracted tremendous interest nowadays for the improved efficacy and/or reduced toxicity. Due to the aromatic structures and hydrophobic domains, carbon nanoparticle suspension injection (CNSI), a clinical applied reagent for lymph node mapping, strongly adsorbs DOX and holds great potential in cancer therapy. Herein, we evaluated the therapeutic effects of CNSI-DOX to establish its delivery applications for cancer drugs. CNSI adsorbed DOX from solution quickly after the mixing, and the release of DOX from CNSI followed a pH-dependent way. CNSI-DOX and free DOX had nearly identical inhibitive effects on cancer cells, while the vehicle CNSI was nontoxic. CNSI-DOX largely prolonged the life span of ascites tumor bearing mice after the intraperitoneally injection and the ascites weights showed significant decreases. CNSI-DOX also inhibited the growth of subcutaneous xenografts following the same administration route. The therapeutic efficacy of CNSI-DOX was similar to that of free DOX in ascites tumor model, but slightly lower in subcutaneous xenografts model. The advantage of using CNSI was majorly reflected by the reduced toxicity of DOX according to the bodyweight changes, serum biochemical indicators and histopathological observations. The LD50 (median lethal dose) value of CNSI-DOX was 43.8 mg/kg bodyweight, nearly three times of that of free DOX (15.2 mg/kg bodyweight). Our results suggested that CNSI might be used for DOX delivery through "off label" use to benefit the patients immediately.

Bioaccumulation and Toxicity of Carbon Nanoparticles Suspension Injection in Intravenously Exposed Mice.

Carbon nanoparticles suspension injection (CNSI) has been widely used in tumor drainage lymph node mapping, and its new applications in drug delivery, photothermal therapy, and so on have been extensively investigated. To develop new clinical applications, the toxicity of CNSI after intravenous exposure should be thoroughly investigated to ensure its safe use. Herein, we studied the bioaccumulation of CNSI in reticuloendothelial system (RES) organs and the corresponding toxicity to mice. After the intravenous injection of CNSI, no abnormal behavior of mice was observed during the 28-day observation period. The body weight increases were similar among the exposed groups and the control group. The parameters of hematology and serum biochemistry remained nearly unchanged, with very few of them showing significant changes. The low toxicity of CNSI was also reflected by the unchanged histopathological characteristics of these organs. The injection of CNSI did not induce higher apoptosis levels either. The slight oxidative stress was observed in RES organs at high dosages at day 7 post-exposure. The implication to the clinical applications and toxicological evaluations of carbon nanomaterials is discussed.

[Preparation and evaluation of pharmacodynamic of the pectin-doxorubicin conjugate nanosuspensions].

This study was conducted to produce pectin-doxorubicin conjugate（PDC） nanosuspensions by high-pressure homogenization, and investigating the physico-chemical properties, the cumulative release rate in vitro and in vivo, and the anti-tumor activity. The major production parameters such as pressure, cycle numbers and types of stabilizers on the mean particle size and polydispersity index（PI） of PDC nanosuspensions were investigated. The cumulative release rate in phosphate buffer saline（PBS） at pH 5.1 or 7.0 were studied. The concentration of doxorubicin（DOX） in plasma of rabbit were recorded after intraperitoneal injection of PDC nanosuspensions(DOX was equivalent to 10 mg·kg-1) or DOX (10 mg·kg-1). We established an animal model of the nude mice with SKOV3 cell, and injected the PDC nanosuspensions(DOX was equivalent to 10, 5, 2.5 mg·kg-1) in the first day, and observed the growth state of nude mice. The particle size of PDC nanosuspensions was 118.8 ± 6.93 nm, PI was 0.14 ± 0.03, as well as the zeta potential was -27.2 ± 0.36 m V. It shows that no drug release was found in PBS at p H 7.4. About 40% cumulative release was determined in PBS at 5.1 after 30 h. The concentration of DOX in plasma of PDC group was 60 ng·mL-1, and was lower than that of DOX group. Compared with control group, high-dose-group decreased the weight of nude mice's ascites tumor and burrknot. PDC nanosuspensions can inhibit the growth of SKOV3 cell line in nude mice.In summary, PDC nanosuspensions are target-specific drugs with high efficiency and low toxicity in the ascites cancer model.

The chromosomal protein HMGN2 mediates the LPS-induced expression of ß-defensins in mice.

Human ß-defensin-2 (HBD-2), an antimicrobial peptide produced by epithelial cells, plays an important role in the body's innate and adaptive immunity. High-mobility group N2 (HMGN2), a member of the HMG superfamily, binds to chromatin to modulate gene transcription. Previously, we have shown that HMGN2 acts as a positive modulator of the signal transduction cascade in the process of inducible human ß-defensin expression. In our current study, we found that down-regulation of HMGN2 reduces the expression level of murine ß-defensin-3 and -4 (mBD-3 and mBD-4), but not mBD-1 upon LPS stimulation in various tissues of pregnant ICR mice, as well as in embryonic and neonatal lungs and livers at different developmental time points. In the control group, murine HMGN2 expression decreased, while mBD-1 and mBD-4 expression increased slightly during development. In the LPS-treated groups, murine HMGN2 and mBD-1 expression did not change significantly, whereas mBD-3 and mBD-4 expression significantly increased in maternal, embryonic, and neonatal tissues, especially the mBD-3 expression. HMGN2 shRNA interference led to decreased mBD-3 and mBD-4 expression, while mBD-1 expression did not significantly change. These results demonstrate that HMGN2 is a component of the LPS-induced mouse ß-defensin response.

Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis

High mobility group chromosomal protein B1 (HMGB1) and N2 (HMGN2), two members of High mobility group (HMG) family, play important role in inflammation. The purposes of this study were to investigate the expression of HMGB1 and HMGN2 in periodontistis. The expression of HMGB1 and HMGN2 mRNA in gingival tissues and gingival crevicular fluid (GCF) in chronic periodontitis (CP), generalized aggressive periodontitis (G-AgP) patients and healthy subjects was detected by real-time PCR. The protein level of HMGB1 and HMGN2 in peri-implant crevicular fluid (PICF), peri-implant crevicular fluid of peri-implantitis (PI-PICF) and normal patients was determined by Western blotting. Furthermore, IL-1â, IL-6, IL-8, TNF-á and HMGB1 levels in GCF, PI-PICF and healthy-PICF samples from different groups were determined by ELISA. HMGN2 expression was increased in inflamed gingival tissues and GCF from CP and G-ApG groups compared to control group. HMGB1 expression was the highest in the gingival tissues and GCF from CP patients and was accompanied by increased concentrations of IL-1â, IL-6, IL-8 proinflammaory cytokines. To our knowledge, this is the first study reporting that the expression of HMGB1 and HMGN2 was increased in the gingival tissues and GCF in CP and G-AgP and the PICF in PICF. Our data suggest that HMGB1 may be a potential target for the therapy of periodontitis and PI.

Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis.

BACKGROUND AND OBJECTIVE: High mobility group chromosomal protein B1 (HMGB1) and N2 (HMGN2), two members of high mobility group (HMG) family, play important role in inflammation. The purpose of this study was to investigate the expression of HMGB1 and HMGN2 in periodontistis. MATERIALS AND METHODS: The expression of HMGB1 and HMGN2 mRNA in gingival tissues and gingival crevicular fluid (GCF) in chronic periodontitis (CP), generalised aggressive periodontitis (G-AgP) patients and healthy subjects was detected by real-time PCR. The protein level of HMGB1 and HMGN2 in peri-implant crevicular fluid (PICF), peri-implant crevicular fluid of peri-implantitis (PI-PICF) and normal patients was determined by Western blotting. Furthermore, IL-1ß, IL-6, IL-8, TNF-α and HMGB1 levels in GCF, PI-PICF and healthy-PICF samples from different groups were determined by ELISA. RESULTS: HMGN2 expression was increased in inflamed gingival tissues and GCF from CP and G-ApG groups compared to control group. HMGB1 expression was the highest in the gingival tissues and GCF from CP patients and was accompanied by increased concentrations of IL-1ß, IL-6, IL-8 proinflammaory cytokines. CONCLUSION: To our knowledge, this is the first study reporting that the expression of HMGB1 and HMGN2 was increased in the gingival tissues and GCF in CP and G-AgP and the PICF in PICF. Our data suggest that HMGB1 may be a potential target for the therapy of periodontitis and PI.

Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis.

High mobility group chromosomal protein B1 (HMGB1) and N2 (HMGN2), two members of High mobility group (HMG) family, play important role in inflammation. The purposes of this study were to investigate the expression of HMGB1 and HMGN2 in periodontistis. The expression of HMGB1 and HMGN2 mRNA in gingival tissues and gingival crevicular fluid (GCF) in chronic periodontitis (CP), generalized aggressive periodontitis (G-AgP) patients and healthy subjects was detected by real-time PCR. The protein level of HMGB1 and HMGN2 in peri-implant crevicular fluid (PICF), peri-implant crevicular fluid of peri-implantitis (PI-PICF) and normal patients was determined by Western blotting. Furthermore, IL-1ß, IL-6, IL-8, TNF-α and HMGB1 levels in GCF, PI-PICF and healthy -PICF samples from different groups were determined by ELISA. HMGN2 expression was increased in inflamed gingival tissues and GCF from CP and G-ApG groups compared to control group. HMGB1 expression was the highest in the gingival tissues and GCF from CP patients and was accompanied by increased concentrations of IL-1ß, IL-6, IL-8 proinflammaory cytokines. To our knowledge, this is the first study reporting that the expression of HMGB1 and HMGN2 was increased in the gingival tissues and GCF in CP and G-AgP and the PICF in PICF. Our data suggest that HMGB1 may be a potential target for the therapy of periodontitis and PI.

Synthesis, characterization, and in vitro and in vivo evaluation of a novel pectin-adriamycin conjugate.

Adriamycin (ADM) has been widely used in the treatment of many types of solid malignant tumor. However, cardiotoxicity, multidrug resistance and a short half-life in vivo are significant problems that limit its clinical application. To resolve these problems, a novel pectin-adriamycin conjugate (PAC) was synthesized by attaching ADM to low-methoxylated pectin via an amide linkage. The ADM content and weight-average molecular weight (Mw) of PAC were greater than 25% (w/w) and 50,360 g/mol, respectively. PAC was highly stable in plasma, but 33.2% of ADM was released from PAC after incubation for 30 h with lysosomes derived from rat liver. PAC was distributed uniformly in the cytoplasm of most A549 cells and accumulated in the nucleus of a few A549 cells after incubation for 30 h. At concentrations equivalent to 0.125-1.000 microg of ADM/mL, PAC did not inhibit the growth of either A594 or B16 cells to the same extent as free ADM or a mixture of ADM and pectin. Interestingly, at all concentrations, PAC inhibited the growth of 2780cp cells in vitro significantly more effectively than ADM or the mixture of ADM and pectin. The anticancer effect of PAC in vivo was evaluated with C57BL/6 mice bearing pulmonary metastases of B16 cells. Compared with ADM and the mixture of ADM and pectin, PAC suppressed tumor growth significantly and prolonged the mean survival time of the B16-inoculated mice. PAC has great potential for development as a tumor targeting polymer-drug.

[Preparation and dissolution in vitro of esomeprazole zinc solid dispersion].

OBJECTIVE: To prepare esomeprazole zinc solid dispersion (EZSD) to improve its dissolution in vitro. METHODS: EZ solid dispersions were prepared by solvent method using PVP K30 and PEG 6000 as carriers. The in vitro dissolution of the EZ solid dispersions enteric capsules was analyzed. The existence status of EZ in the carrier was determined by differential scanning calorimeter (DSC). RESULTS: The dissolution of EZ increased first and then decreased with the increase of the ratio of carries. The dissolution of the solid dispersions with PEG 6000 as carrier was faster than that with PVP K30 as carrier. The EZ was amorphously dispersed in the solid dispersion. CONCLUSION: The in vitro dissolution rate of EZ is significantly improved by the solid dispersion.