Co-Delivery of Paclitaxel by a Capsaicin Prodrug Micelle Facilitating for Combination Therapy on Breast Cancer.

Poor anticancer ability, serious adverse reaction, and drug resistance against paclitaxel (PTX) have limited its clinical applications. When a mouse breast carcinoma cell line (4T1) was treated with both PTX and capsaicin (CAP), there was a synergistic anti-proliferative effect demonstrated with a combination index of 0.28. Therefore, a novel polyethylene glycol-derivatized CAP (PEG-Fmoc-CAP2) polymeric prodrug micellar carrier was developed and further encapsulated with PTX for antitumor combination treatment. The PEG-Fmoc-CAP2 polymeric micelles co-delivered with PTX achieved a 62.3% fraction of apoptotic cells in comparison to 45.4% fraction of apoptotic cells to that upon treatment with PTX alone. Comparable CAP amounts were found in the cell lysate treatment with PEG-Fmoc-CAP2-conjugated micelles to that of free CAP-treated 4T1 cells after 12 h treatment. Pharmacokinetic and biodistribution studies showed that the micelles possessed much longer circulation time in blood and preferential tumor tissue accumulation compared to the Taxol solution. Importantly, PTX/CAP-loaded micelles exhibited superior in vivo antitumor activity on the inhibition rate of tumor growth than other treatments (70.5% tumor growth reduction in PTX/CAP micelle-treated mice vs 57.8, 43.3, and 23.8% of tumor growth inhibition rate in PTX/PEG-Fmoc-OA2 micelles, Taxol, and PEG-Fmoc-CAP2 micelle-treated mice, respectively). Thus, the dual-functional PEG-Fmoc-CAP2 polymeric prodrug micelles are a promising co-delivery nanosystem for achieving synergistic antitumor efficacy of PTX and CAP.

Two New Preyssler-Type Polyoxometalate-Based Coordination Polymers and Their Application in Horseradish Peroxidase Immobilization.

Enzyme immobilization is of increasing importance for biocatalysis, for which good supports are critical. Herein, two new Preyssler-type polyoxometalate (POM)-based coordination polymers, namely, {[Cu(H2 biim)2 ][{Cu(H2 biim)2 (µ-H2 O)}2 Cu(H2 biim)(H2 O)2 ]H[({Cu(H2 biim)(H2 O)2 }0.5 )2 ((µ-C3 HN2 Cl2 ){Cu(H2 biim)}2 ){Z(H2 O)P5 W30 O110 }]⋅x H2 O}n (1: Z=Na, x=9; 2: Z=Ag, x=10; H2 biim=2,2'-biimidazole) were designed and synthesized. Compounds 1 and 2 exhibit the same skeletons, which contain multiple CuII complex fragments and penta-supported {ZP5 W30 } (Z=Na, Ag) clusters. They were first employed to immobilize horseradish peroxidase (HRP). Results show that compounds 1 and 2 are good supports for HRP immobilization, and exhibit higher enzyme loading, lower loading times, and excellent reusability. The immobilized HRP (HRP/1 or HRP/2) was further applied to detect H2 O2 , and good sensitivity, wide linear range, low detection limit, and fast response were achieved. This work shows that POM-based hybrid materials are a new kind of promising support for enzyme immobilization.

[Identification of salivary biomarkers in breast cancer patients with thick white or thick yellow tongue fur using isobaric tags for relative and absolute quantitative proteomics].

OBJECTIVE: To explore the presence of informative protein biomarkers in the salivary proteome of breast cancer patients with thick white or thick yellow tongue fur. METHODS: Salivia samples were collected from 20 breast cancer patients with thick white or yellow tongue fur and 10 healthy controls. The samples were profiled by using isobaric tags for relative and absolute quantitation (iTRAQ) technology coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The analyzed map and data were assessed with Mascott 2.2 and Scaffold software. Ratio of proteins between groups of less than 0.6 or more than 1.5 could confirm that there was difference between groups. RESULTS: A total of 464 proteins were identified and 125 proteins met strict quantitative criteria. There were 9 proteins associated with breast cancer, expression levels of which were up- or down-regulated more than 1.5 folds compared with healthy people. There were 16 proteins associated with tongue coating, of which 10 proteins expressed in breast cancer patients with thick white fur were lower than in patients with thick yellow fur, and the expressions of the other 6 proteins were increased. CONCLUSION: This study demonstrates that iTRAQ combined with LC-MS/MS quantitative proteomics is a powerful tool for biomarker discovery and the identification of proteins associated with breast cancer and tongue coating.

[Clinical effects of ridge augmentation with the half-columnar shaped mandibular bone block for the placement of dental implants].

OBJECTIVE: To evaluate the treatment effects of the half-columnar shaped mandibular block bone onlay grafting technique for augmentation of the resorbed maxillary anterior alveolar ridge after single tooth missing. METHODS: A total of 15 sites of 14 patients received ridge augmentation surgeries. The recipient sites were prepared with trephines, the half-columnar shaped bone blocks were harvested from the ramus and external oblique ridges with trephines according to diameters of the recipient sites. The bone blocks were placed as lateral onlay grafts on recipient beds and secured by means of titanium screws. Particulate bone was added and absorbable membranes were used to stabilize and protect the grafts. After a mean interval of 4.5 months of healing the flaps were re-opened, the screws were removed and non-submerged implants were placed. The width and height of the alveolar ridges were recorded. After 3 months, implant-supported crowns were provided to the patients. One year later, the peri-impant condition and the marginal bone resorption on the proximal sites were observed. RESULTS: Mean lateral augmentation obtained at the time of bone grafting was (3.8 + or - 0.8) mm, 5 out of 15 sites exhibited a mean of 3 mm of vertical augmentation. The mean healing time was 4.5 months, the mean percentage of horizontal and vertical bone resorption in the mean time were 8% and 7% respectively. No major complications were recorded at donor sites. No implant was lost during the study period. Clinical parameters and probing depth (< or = 4 mm) demonstrated the presence of a healthy peri-implant mucosa after 1 year of prosthetic reconstruction. The clinical and radiographic bone observations showed no more than 1.2 mm of resorption after bone graft and implant placement. CONCLUSION: The half-columnar shaped mandibular bone graft (from the ramus and external oblique ridge) is a promising technique for bone augmentation in localized alveolar ridge defects after single tooth missing. This procedure offers easy access, good bone quantity for localized repair, low morbidity, decreased complaints of postoperative sensory disturbances or discomfort, minimal graft resorption, and a shorter healing time as compared with other methods for bone repair.

pH and Glutathione Synergistically Triggered Release and Self-Assembly of Au Nanospheres for Tumor Theranostics.

Theranostic agents based on near-infrared absorption which integrate both imaging and therapeutic functions have attracted considerable attention. However, because of the interference signal, indiscriminate treatment usually causes side effects on normal tissues during tumor treatment. To address this limitation, we propose a new synergistically triggered mechanism, release and self-assembly of Au nanospheres, for tumor theranostics based on the synergistic effect of H+ and glutathione on the tumor microenvironment. In vitro experiments reveal that Au nanospheres release from Au@ZIF-8 at a high concentration of H+ or glutathione. Importantly, Au aggregation only appears in the synergistic effect of glutathione and lower pH and exhibits strong coupling plasmonic resonance absorption in the near-infrared region and can be used as the theranostics agent. This statement was further verified by biological transmission electron microscopy and in vivo imaging. Au@ZIF-8 is stable and produces no photoacoustic signal in normal tissue; in contrast, in the presence of overexpressed glutathione and H+, Au nanospheres release from Au@ZIF-8, assemble to aggregates, and exhibit a strong signal at the tumor site for imaging and efficient photothermal therapy. This work provides a new strategy for designing theranostic agents with sequentially responsive steps to avoid interference diagnosis signals from normal tissues and reduce damage to normal tissue during treatment.

Glycyrrhetinic acid-conjugated polymeric prodrug micelles co-delivered with doxorubicin as combination therapy treatment for liver cancer.

Significant synergy of doxorubicin (DOX) and glycyrrhizic acid (GA) in inhibiting the proliferation of cancer cells was demonstrated in the human hepatocellular carcinoma cell line, HepG2. A novel polymeric prodrug micellar carrier based on polyethylene glycol-derivatized GA (PEG-Fmoc-GA), was developed for co-delivery of DOX as a combined anti-cancer treatment. The PEG-Fmoc-GA polymeric prodrug micelles achieved a more effective synergistic action on cell proliferation inhibition and apoptosis induction, when co-delivered with DOX, which can be attributed to the dual effect of the cleaved GA and loaded DOX. PEG-Fmoc-GA conjugated micelles significantly facilitated the intracellular uptake of DOX by HepG2 cells, when compared to a DOX solution alone. In addition, DOX encapsulated in PEG-Fmoc-GA micelles displayed longer blood circulation time, larger drug concentration area under the curve, decreased volume distribution and clearance than DOX solution. Biodistribution studies showed that DOX/PEG-Fmoc-GA micelles were preferentially accumulated at the tumor site. Importantly, DOX/PEG-Fmoc-GA micelles demonstrated a more pronounced therapeutic efficacy in vivo compared with DOX alone with respect to both tumor growth inhibition and overall survival in a HepG2 xenograft model. Thus, PEG-Fmoc-GA polymeric prodrug micelles represent a promising dual-function co-delivery system to achieve anti-cancer synergistic activity of DOX and GA.

Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene.

CCL19 [chemokine (C-C motif) ligand 19; also known as MIP-3beta (macrophage inflammatory protein-3beta) or ELC (Epstein-Barr-virus-induced molecule 1 ligand chemokine)], one of the immunostimulatory cytokines, chemoattracts both DCs (dendritic cells) and T-lymphocytes. Adenoviral vector is one of the most used gene delivery vectors for cancer therapy because of its high gene-transfection efficiency. However, its wider application is limited, owing to immune responses that reduce transgene expression and decrease the efficacy of repeated administration. We constructed the recombinant replication deficient adenoviral vectors containing the CCL19 gene (Ad-CCL19) and combined them with PEG-PE [poly(ethylene glycol)-phosphatidylethanolamine]-modified cationic liposomes (Ad-CCL19/PEG-PE) for immunotherapy against murine fibrosarcoma. Although there were hardly any therapeutic differences between Ad-CCL19- and Ad-CCL19/PEG-PE-treated mice that were observed at the second administration, the final results demonstrated that Ad-CCL19/PEG-PE-treated mice survived much longer. The antitumour efficacy may be related to the high level of CCL19 after the final administration and lasting expression of IFN-gamma (interferon-gamma) and IL-12 (interleukin-12) in the Ad-CCL19/PEG-PE-treated group, which were measured by reverse-transcription PCR and ELISA. The results demonstrated that PEG-PE-cationic-liposome-conjugated adenovirus could prolong the expression of the therapeutic gene in vivo and may enhance the antitumour efficacy.

The biological activity of cationic liposomes in drug delivery and toxicity test in animal models.

In the study we made use of DOTAP (1,2-dioleoyl-3-trimethylammonium), DOPE (1,2-dioleoyl-snglycero-3-phosphoethanolamine) and PEG-PE (polyethylene glycol- polyethylene) to make cationic PEG-liposomes by ultrasonic dispersion method. The plasmid pGPU6 combined with cationic PEG-liposomes or Liopofectamin 2000 was used to transfect PC3 cells to judge the transfection efficiency. HE staining showed that the pGUP6-shAurora B plasmid/liposomes complex could significantly inhibit tumor growth in mice tumor model. The results indicated that there was no remarkable difference between the homemade liposomes and Lipofectamin 2000 after transfection, with transfection efficiency over 80%. And the homemade liposomes also had high transfection efficiency in vivo. No significant side effects were observed on weight, coat condition, behavior or appetite and the life span of mice treated with pGPU6-shAurora B were extended. Beyond that, there were no differences in mortality or in pathological changes to the heart, liver, spleen, lungs and kidneys among all the mice.

[Research on population structure and distribution characteristic of indigenous microorganism in post-polymer-flooding oil reservoir].

Denaturing gradient gel electrophoresis (DGGE) method and principal component analysis (PCA) method were used to analyze the structures of microorganism population in injection wells and production wells of a post-polymer-flooding oil reservoir in Daqing oil field. The results showed that the dominant species in injection wellhead were aerobic bacteria Pseudomonas and Acinenobacter. Facultative anaerobic bacteria Enterbacter was the dominant bacteria in near area of injection wells. Bacteria detected in production wells included Thauera, Clostridia, Pseudomonas, Petrobacter and some uncultured bacteria. Methanosaeta turned out to be the only archaea detected in injection wells, which was an aceticlastic methane-producing archaeon. Archaea detected in production wells consisted of Methanomicrobium, Methanospirillum and Methanobacterium. In general, aerobic bacteria, facultative anaerobe, and strictly anaerobic bacteria distributed successively from injection wells to production wells in this block. The dominant populations of archaea were different between injection wells and production wells, while were influenced by different environments and microbial metabolism products.

Preparation, characterization, and in vitro cytotoxicity study of cationic PCL-pluronic-PCL (PCFC) nanoparticles for gene delivery.

In this article, poly(epsilon-caprolactone)-pluronic-poly(epsilon-caprolactone) (PCFC) copolymer was synthesized by ring-opening polymerization and characterized by 1H-NMR and GPC. Cationic PCFC nanoparticles were prepared at one-step by modified emulsion solvent evaporation method using cetyltrimethylammonium bromide as the stabilizer. The cytotoxicity of PCFC nanoparticles was studied here with and without serum. The obtained cationic PCFC nanoparticles were employed to condense and adsorb DNA onto its surface. And it could protect plasmid GFP (pGFP) from enzymatic degradation and acidic degradation in a certain period. Release behavior of pGFP from the pGFP/PCFC nanoparticles complex was also studied in vitro. The obtained cationic PCEC nanoparticles might have great potential application in DNA delivery.

One-step preparation of poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) nanoparticles for plasmid DNA delivery.

In this article, a kind of biodegradable poly(epsilon-caprolactone)-Poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) copolymer was synthesized by ring-opening polymerization method. The PCEC nanoparticles were prepared at one-step by modified emulsion solvent evaporation method using CTAB as stabilizer. With increase in PCEC concentration, the particle size increased obviously, but zeta potential only increased slightly. The obtained cationic PCEC nanoparticle was employed to condense and adsorb DNA onto its surface. Plasmid GFP (pGFP) was used as model plasmid to evaluate the loading capacity of cationic PCEC nanoparticles in this work. The DNA/nanoparticles weight ratio at 1:16 induced almost neutral zeta potential of DNA-nanoparticles complex. At this time, the size of complex became abnormally large which implied aggregates formed. So DNA-nanoparticles weight ratio should be chosen carefully. The cationic PCEC nanoparticles had the capacity of condensing plasmid DNA into complex when the DNA/nanoparticles weight ratio was lower than 1:8, which was evidenced by gel retardation assay. In vitro release behavior of DNA/nanoparticle complexes was also studied here. The obtained cationic PCEC nanoparticles might have great potential application in DNA delivery.