A large and pedunculated inflammatory pseudotumor with pseudosarcomatous change of the cecum mimicking a malignant polyp: a case report and literature review.

Inflammatory pseudotumor (IPT) is a rare benign tumor of unknown etiology that can occur in almost any organ system. It has neoplastic features such as local recurrence, invasive growth, and vascular invasion, leading to the possibility of malignant sarcomatous changes. The clinical presentations of colonic IPT may include abdominal pain, anemia, a palpable mass, and intestinal obstruction. A few cases of colonic IPT have been reported, but colonic IPT with pedunculated morphology is very rare. Furthermore, since it can mimic malignant polyps, understanding the endoscopic findings of colonic IPT is important for proper treatment. Herein, we present a case of colonic IPT with pseudosarcomatous changes, presenting as a large polyp, mimicking a malignant polyp in the cecum, along with a literature review.

Self-Organized Nanoparticles of Caffeic Acid Conjugated Polysaccharide and Its Anticancer Activity.

Caffeic acid-conjugated chitosan (ChitoCFA) and carboxymethyl dextran-b-poly(ethylene gycol) (CMD-PEG) copolymer were synthesized to fabricate self-organized nanoparticles. Nanoparticles were formed through ion-complex formation between ChitoCFA and CMD-PEG. Nanoparticles have small sizes ranged about 80 nm~300 nm with spherical shapes. Doxorubicin (DOX) was incorporated into the nanoparticles of ChitoCFA/CMD complexes. Particle sizes were increased according to the contents of drug. At drug release experiment, DOX was continuously released over 96 h. Anticancer acticity of nanoparticles were assessed with DOX-resistant CT26 cells. CT26 cells treated with DOX-incorporated nanoparticles revealed strong fluorescence intensity while free DOX revealed weak fluorescence intensity, indicating that DOX-loaded nanoparticles of ChitoCFA/CMD are promising vehicle for anticancer drug targeting.

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery.

BACKGROUND: Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting. METHODS: Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure. RESULTS: The synthesized DendGDP was confirmed with (1)H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity. CONCLUSION: DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting.

Nano-Aggregates of Doxorubicin-Conjugated Methoxy Poly(ethylene glycol)-b-Carboxymethyl Dextran Copolymer.

Block copolymer composed of carboxymethyl dextran (CMDex) and methoxy poly(ethylene glycol) (MPEG) (abbreviated as CMDexPEG) was synthesized and doxorubicin (DOX) was conjugated with carboxyl groups of CMDexPEG. DOX-conjugated CMDexPEG block copolymer formed nanoparticles in water with sizes less than 100 nm. DOX-conjugated nanoparticles enhanced DOX delivery to the DOX-resistant CT26 cells and showed higher anticancer activity in vitro. DOX-conjugated nanoparticles inhibited growth of CT26 solid tumor at tumor-bearing mouse model study. In near infrared (NIR)-dye study, nanoparticles were retained in the tumor tissues for a longer period.

Smart Nanoparticles Based on Hyaluronic Acid for Redox-Responsive and CD44 Receptor-Mediated Targeting of Tumor.

BACKGROUND: Since aggressive cancer cells highly express the CD44 receptor compared to normal cells, hyaluronic acid (HA) can be used for CD44 targeting molecule. Since glutathione (GSH) level is normally elevated in the intracellular compartment and in the tumor cell, the fact that disulfide bond can be cleaved by GSH is widely used for intracellular drug delivery. METHODS: HA was connected with poly(DL-lactide-co-glycolide) (PLGA) using disulfide linkage, and then a diblock copolymer (HAssLG) was prepared. Doxorubicin (DOX)-loaded HAssLG nanoparticles were prepared by dialysis procedures. RESULTS AND DISCUSSION: DOX-loaded HAssLG nanoparticles have spherical shapes with small particle size of less than 300 nm. In fluorescence measurement, DOX was dose-dependently liberated from nanoparticles by the addition of GSH. DOX release rate from HAssLG nanoparticles was increased by the addition of GSH. To confirm CD44 receptor-mediated endocytosis of nanoparticles, CD44-positive MDA-MB231 cells were employed and fluorescence intensity was strong when nanoparticles were treated to tumor cells. However, fluorescence intensity was significantly decreased through blocking of the CD44 receptor by pretreatment of cells with free HA. Fluorescence intensity of cells was increased again when GSH was added, indicating that HAssLG nanoparticles have CD44 receptor targetability and potential of redox-responsive drug delivery. For animal imaging study, CD44-positive MDA-MB231 cells and CD44-negative NIH3T3 cells were simultaneously implanted into the right flank and left flank of mice, respectively. Fluorescence intensity was significantly stronger at tumor mass of MDA-MB231 cells than solid mass of NIH3T3 cells, indicating that HAssLG nanoparticles were specifically delivered to tumor cells. CONCLUSIONS: The results indicated that HAssLG nanoparticles have specificity against the CD44 receptor and can be used for anticancer drug targeting. We recommend HAssLG nanoparticles as a promising vehicle for cancer drug targeting.

Folic-acid-conjugated pullulan/poly(DL-lactide-co-glycolide) graft copolymer nanoparticles for folate-receptor-mediated drug delivery.

BACKGROUND: Nanoparticles have been extensively investigated for targeted delivery of anticancer drugs. Since the folate receptor is universally over-expressed on the tumor cell membrane, folic acid is often used to modify the fate of nanoparticles in biologicals. METHODS: To fabricate targetable nanoparticles, folic acid was conjugated to a pullulan backbone and poly(DL-lactide-co-glycolide) (PLGA) (abbreviated as FAPuLG) was conjugated. KB cells and NIH3T3-cell-bearing mice were prepared to prove folate receptor targeting of FAPuLG nanoparticles. RESULTS AND DISCUSSION: Nanoparticles of FAPuLG copolymer that self-assembled in water were small with diameters <200 nm. Doxorubicin (DOX) as a model drug was incorporated into the FAPuLG nanoparticles that were used to treat folate receptor over-expressing KB human carcinoma cells. Fluorescence microscopy revealed that DOX-incorporated FAPuLG nanoparticles induced strong red fluorescence in the KB cells in the absence of folic acid. However, fluorescence intensity was decreased by blocking folate receptors. Antitumor activity of FAPuLG nanoparticles against KB cells in vitro was also decreased by blocking folate receptors. In animal study using near-infrared dye-conjugated FAPuLG nanoparticles, fluorescence intensity was significantly higher at KB solid tumor than that of NIH3T3. CONCLUSIONS: The results indicate that FAPuLG nanoparticles can target the folate receptor of tumor cells. FAPuLG nanoparticles are a promising candidate for active targeting of anticancer agents.

Analysis of cariogenic bacteria in saliva of cancer patients.

This study examined salivary flow and salivary pH and the prevalence and levels of cariogenic bacteria in the saliva of oncological patients and healthy controls. Quantitative real-time polymerase chain reaction was used to assess the levels of microbes including Streptococcus mutans, Streptococcus sobrinus, Lactobacillus salivarius, and Lactobacillus acidophilus in the saliva of 41 patients with a solid tumor (SO), 30 patients with a hematologic malignancy (HE), and 40 healthy controls. Salivary flow and pH were lower in oncological patients than in controls. The frequencies of all four cariogenic bacteria were highest in the SO group. S. mutans and L. salivarius were the most commonly detected in all three study groups. Mean numbers of S. sobrinus and L. salivarius in the SO group were significantly higher than in controls (p<0.05). There were no significant differences between patients and controls with respect to mean numbers of S. mutans and L. acidophilus in saliva. However, the proportions of S. mutans, S. sobrinus, and L. salivarius versus total bacteria in the SO group were significantly higher than in controls. Within patients, both mean numbers and the proportions of S. mutans and S. sobrinus were significantly different (p<0.05). In summary, significant differences were found in salivary pH values and the levels of S. mutans, S. sobrinus, and L. salivarius between SO patients and healthy controls.

Caffeic acid-conjugated chitosan derivatives and their anti-tumor activity.

In this study, we synthesized caffeic acid (CFA)-conjugated chitosan (ChitoCFA) as an anti-cancer compound. CFA was conjugated to the amine groups of chitosan (ChitoCFA) and its chemical composition was confirmed using (1)H nuclear magnetic resonance spectra, which indicates that specific peaks of CFA was observed at ChitoCFA conjugates. The anti-cancer effects of CFA and ChitoCFA were studied using CT26 colorectal carcinoma cells. In this cytotoxicity study, CFA and ChitoCFA revealed a dose-dependent decrease of cell viability while chitosan had lower cytotoxicity against tumor cells. CFA and ChitoCFA also proved an anti-proliferative effect against tumor cells. In comparison with CFA, ChitoCFA may accelerate an apoptosis of tumor cells. Furthermore, ChitoCFA demonstrated good anti-invasive efficacy at Matrigel(®) invasion assay against tumor cells. We suggest that ChitoCFA is a promising candidate as an anti-cancer compound.

Inhibitory effect of chlorophyllin on the Propionibacterium acnes-induced chemokine expression.

Chlorophyllin (CHL), a chlorophyll-derivative, exhibits several beneficial properties, including antibacterial, antioxidant, and anticancer activities. However, its antibacterial and anti-inflammatory activities against Propionibacterium acnes have not been described. The antibacterial activity of this compound was evaluated in vitro using the broth microdilution method. CHL had an inhibitory effect on the growth of P. acnes (MIC = 100 µM). In a real-time reverse transcription-polymerase chain reaction and an enzyme-linked immunosorbent assay, CHL significantly decreased interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production in a dose-dependent manner, decreasing both mRNA and protein levels for these chemokines in THP-1 cells indicating the anti-inflammatory effects of it. To investigate the molecular mechanisms underlying the anti-inflammatory properties of CHL in THP-1 cells stimulated by P. acnes, we used western blotting to analyze the effect of CHL on activation of the nuclear factor (NF)-κB. CHL inhibited P. acnes-induced IL-8 and MCP-1 production via blockade of NF-κB activation in THP-1 cells. Therefore, based on these results, we suggest that CHL is a useful agent to control the growth of P. acnes involved in acne inflammation and prevent acne.

Paclitaxel-incorporated nanoparticles of hydrophobized polysaccharide and their antitumor activity.

The aim of this study was to characterize paclitaxel-incorporated polysaccharide nanoparticles and evaluate their antitumor activity in vitro and in vivo. Pullulan was hydrophobically modified using acetic anhydride to make the paclitaxel-incorporated nanoparticles. Pullulan acetate (PA) was used to encapsulate paclitaxel using the nanoprecipitation method. The particles had spherical shapes under electron microscopy with sizes <100 nm. The sizes of paclitaxel-incorporated nanoparticles increased to >100 nm, and higher drug feeding induced higher particle size and drug content. Initial drug burst release was observed until 2 days and then the drug was continuously released over 1 week. Intrinsic cytotoxicity of empty PA nanoparticles was tested with RAW264.7 macrophage cells for biocompatibilty. The viability of RAW264.7 cells was >93% at all concentrations of empty PA nanoparticles, indicating that the PA nanoparticles are not acutely cytotoxic to normal human cells. The nanoparticles showed lower antitumor activity in vitro against HCT116 human colon carcinoma cells than that of paclitaxel itself, indicating the sustained release properties of nanoparticles. An in vivo study using HCT116 human colon carcinoma-bearing mice showed that paclitaxel-incorporated PA nanoparticles reduced tumor growth more than that of paclitaxel itself. These results indicate that PA paclitaxel-incorporated nanoparticles are a promising candidate for antitumor drug delivery.

Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma.

The aim of this study was to evaluate the antitumor effect of combinatorial targeted therapy with paclitaxel and all-trans retinoic acid (ATRA) nanoparticles in vitro. Paclitaxel-incorporated pullulan acetate (PA) nanoparticles were prepared by the nanoprecipitation-solvent evaporation method. ATRA-incorporated nanoparticles were prepared by dialysis using a methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) copolymer. Particle sizes of paclitaxel-incorporated nanoparticles and ATRA-incorporated nanoparticles were about 160 nm and 60 nm, respectively. Nanoparticles were reconstituted in various aqueous media such as deionized water, phosphate-buffered saline, and fetal bovine serum-supplemented cell culture media. The combination of paclitaxel + ATRA (10 + 10 µg/mL) delivered by nanoparticles showed a synergistic antiproliferative effect against CT26 cells that was not observed with other combinations. Furthermore, the activity of MMP-2, a key enzyme in tumor cell invasion, was significantly decreased in cells treated with the combination of paclitaxel and ATRA while other combinations and single agents did not significantly affect its activity. A matrigel assay supported these results, indicating that paclitaxel/ATRA combination nanoparticles are effective for the inhibition of the invasion of tumor cells. The results of the present study suggest that combination treatment with paclitaxel and ATRA could be an effective treatment for the inhibition of tumor cell proliferation and invasion, and that nanoparticles are promising candidates for antitumor drug delivery.

Chemokines gene expression of RAW 264.7 cells by Actinobacillus actinomycetemcomitans lipopolysaccharide using microarray and RT-PCR analysis.

Actinobacillus actinoinycetemcomitans (A. actinomycetem-comitans) is an important pathogen casuing aggressive periodontitis. The present study was designed to investigate the chemokines expression regulated by A. actinomycetemcomitans lipopolysaccharide (LPS). Chemokines genes expression profiling was performed in Raw 264.7 cells by analyses of microarray and reverse transcription-polymerase chain reaction (RT-PCR). Microarray results showed that the induction of monocyte chemoattractant protein-1alpha (MCP-1alpha) and macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, MIP-1gamma, regulated upon activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-2 (MIP-2), and interferon-gamma inducible protein 10 (IP 10) by A. actinomycetemcomitans LPS was increased to 12.5, 1.53, 9.09, 17.3, 2.82, 16.1, and 18.1 folds at 18 h, respectively. To check these chemokines expression by A. actinomycetemcomitans LPS, we examined gene expressions by RT-PCR, and found that the expression of MIP-1beta, MIP-1gamma, RANTES, MIP-2, and IP 10 was increased 107.1, 93.6, 106.8, 86.5, and 162.0 folds at 18 h, respectively. These results indicate that A. actinomycetemcomitans LPS stimulates the several chemokines expressions (MIP-1alpha, MIP-1beta, MIP-1gamma, RANTES, MIP-2, and IP 10) in Raw 264.7 cells.

Effects of methyl gallate and gallic acid on the production of inflammatory mediators interleukin-6 and interleukin-8 by oral epithelial cells stimulated with Fusobacterium nucleatum.

Interactions between periodontal bacteria and human oral epithelial cells can lead to the activation and expression of a variety of inflammatory mediators in epithelial cells. Fusobacterium nucleatum is a filamentous human pathogen that is strongly associated with periodontal diseases. This study examined the effects of methyl gallate (MG) and gallic acid (GA) on the production of inflammatory mediators, interleukin (IL)-6 and IL-8, by oral epithelial cells stimulated by F. nucleatum. In a real-time reverse transcription-polymerase chain reaction and an enzyme-linked immunosorbent assay, live F. nucleatum induced high levels of gene expression and protein release of IL-6 and IL-8. The effects of MG and GA were examined by treating KB oral epithelial cells with MG and GA and stimulating them with F. nucleatum. MG and GA inhibited significantly the increases in the IL-6 and IL-8 gene and protein levels in a dose-dependent manner. These Compounds also inhibited the growth of F. nucleatum. No visible effects of MG and GA on the adhesion and invasion of KB cells by F. nucleatum were observed. In conclusion, both MG and GA inhibit IL-6 and IL-8 production from F. nucleatum-activated KB cells.

Inhibitory effect of methyl gallate and gallic acid on oral bacteria.

This study examined the ability of methyl gallate (MG) and gallic acid (GA), the main compounds of gallo-tannins in Galla Rhois, to inhibit the proliferation of oral bacterial and the in vitro formation of Streptococcus mutans biofilms. The antimicrobial activities of these compounds were evaluated in vitro using the broth microdilution method and a beaker-wire test. Both MG and GA had inhibitory effects on the growth of cariogenic (MIC<8 mg/ml) and periodontopathic bacteria (MIC=1 mg/ml). Moreover, these compounds significantly inhibited the in vitro formation of S. mutans biofilms (MG, 1 mg/ml; GA, 4 mg/ml; P<0.05). MG was more effective in inhibiting bacterial growth and the formation of S. mutans biofilm than GA. In conclusion, MG and GA can inhibit the growth of oral pathogens and S. mutans biofilm formation, and may be used to prevent the formation of oral biofilms.

Adriamycin release from self-assembling nanospheres of poly(DL-lactide-co-glycolide)-grafted pullulan.

Poly(DL-lactide-co-glycolide)-graft pullulan (PuLG) was synthesized to produce a hydrophobically modified polysaccharide. Specific pullulan and poly(DL-lactide-co-glycolide) (PLGA) (abbreviated as PuLG) appeared in the peaks of the PuLG spectra on (1)H NMR spectroscopy, suggesting that PLGA was successively grafted to the pullulan backbone. PuLG nanospheres have a round shape with a particle size of about 75-150 nm. From the fluorescence excitation spectra in a fluorescence probe study, the critical association concentration (CAC) values were determined to be 0.017 g/l for PuLG-1, 0.0054 g/l for PuLG-2, and 0.0047 g/l for PuLG-3. The drug contents of the PuLG nanospheres were approximately 20-30% (w/w). As the drug contents of PuLG nanospheres increased, the drug release rate from nanospheres decreased. The drug release rate from PuLG nanospheres was delayed as the molecular weight of PuLG increased. PuLG copolymer with higher graft ratio of PLGA showed slower degradation rate rather than that with lower graft ratio. Since degradation rate of PuLG was taken over 1 month, drug release was governed by diffusion mechanism rather than degradation mechanism.

Coaggregation ability of Weissella cibaria isolates with Fusobacterium nucleatum and their adhesiveness to epithelial cells.

In the present study, we evaluated the ability of Weissella cibaria isolated from the oral cavity to coaggregate with Fusobacterium nucleatum, and the adhesiveness of these strains to epithelial cells. W. cibaria efficiently coaggregated with F. nucleatum, and adhered to epithelial cells. We tested the effects of various factors on the coaggregation. The coaggregation and adhesiveness of W. cibaria disappeared upon exposure to pronase or LiCl, suggesting that proteinaceous components on the surface of W. cibaria mediated the coaggregation and adhesiveness. In conclusion, W. cibaria may serve as a potential probiotic with the ability to establish an oral flora protecting against oral pathogens.