Zenghui Teng

Intestinal Absorption and First-Pass Metabolism of Polyphenol Compounds in Rat and Their Transport Dynamics in Caco-2 Cells

Background Polyphenols, a group of complex naturally occurring compounds, are widely distributed throughout the plant kingdom and are therefore readily consumed by humans. The relationship between their chemical structure and intestinal absorption, transport, and first-pass metabolism remains unresolved, however. Methods Here, we investigated the intestinal absorption and first-pass metabolism of four polyphenol compounds, apigenin, resveratrol, emodin and chrysophanol, using the in vitro Caco-2 cell monolayer model system and in situ intestinal perfusion and in vivo pharmacokinetic studies in rats, so as to better understand the relationship between the chemical structure and biological fate of the dietary polyphenols. Conclusion After oral administration, emodin and chrysophanol exhibited different absorptive and metabolic behaviours compared to apigenin and resveratrol. The differences in their chemical structures presumably resulted in differing affinities for drug-metabolizing enzymes, such as glucuronidase and sulphatase, and transporters, such as MRP2, SGLT1, and P-glycoprotein, which are found in intestinal epithelial cells.

Dose-Dependent Absorption and Metabolism of trans-Polydatin in rats

There is considerable evidence that stilbenes provide health benefits. trans-Polydatin is one of the major stilbenoid compounds in red wine. The purpose of this study is to investigate the dose-dependent absorption and metabolism of trans-polydatin in rats. trans-Polydatin was administered to rats by gavage at three different doses (50, 100, and 300 mg x kg(-1)). Blood samples were then collected at different time points. In situ perfusion of rat small intestine and liver was used to investigate the first-pass metabolism of trans-polydatin. trans-Polydatin and its metabolites were detected by LC-MS/MS. trans-Polydatin and its metabolites resveratrol, glucuronidated resveratrol, and glucuronidated trans-polydatin were detected in plasma within 10 min following oral administration of trans-polydatin; in situ perfusion of the rat small intestine and liver with trans-polydatin yielded the same result. The AUC(0-infinity) of trans-polydatin and its metabolites increased in a dose dependent manner following oral administration of trans-polydatin. This indicates that in the rats, trans-polydatin is absorbed in a dose-dependent manner and undergoes extensive first-pass deglycosylation and glucuronidation. Orally administered trans-polydatin, therefore, is metabolized primarily to resveratrol in the small intestine and liver, where it is further metabolized to the glucuronidated resveratrol.

In Vitro and In Vivo Antitumor Activity of a Novel pH-Activated Polymeric Drug Delivery System for Doxorubicin

Background Conventional chemotherapy agent such as doxorubicin (DOX) is of limited clinical use because of its inherently low selectivity, which can lead to systemic toxicity in normal healthy tissue. Methods A pH stimuli-sensitive conjugate based on polyethylene glycol (PEG) with covalently attachment doxorubicin via hydrazone bond (PEG-hyd-DOX) was prepared for tumor targeting delivery system. While PEG-DOX conjugates via amid bond (PEG-ami-DOX) was synthesized as control. Results The synthetic conjugates were confirmed by proton nuclear magnetic resonance (NMR) spectroscopy, the release profile of DOX from PEG-hyd-DOX was acid-liable for the hydrazone linkage between DOX and PEG, led to different intracellular uptake route; intracellular accumulation of PEG-hyd-DOX was higher than PEG-ami-DOX due to its pH-triggered profile, and thereby more cytotoxicity against MCF-7, MDA-MB-231 (breast cancer models) and HepG2 (hepatocellular carcinoma model) cell lines. Following the in vitro results, we xenografted MDA-MB-231 cell onto SCID mice, PEG-hyd-DOX showed stronger antitumor efficacy than free DOX and was tumor-targeting. Conclusions Results from these in vivo experiments were consistent with our in vitro results; suggested this pH-triggered PEG-hyd-DOX conjugate could target DOX to tumor tissues and release free drugs by acidic tumor environment, which would be potent in antitumor drug delivery.

Conjugation with α-linolenic acid improves cancer cell uptake and cytotoxicity of doxorubicin

The synthetic DOX-LNA conjugate was characterized by proton nuclear magnetic resonance and mass spectrometry. In addition, the purity of the conjugate was analyzed by reverse-phase high-performance liquid chromatography. The cellular uptake, intracellular distribution, and cytotoxicity of DOX-LNA were assessed by flow cytometry, fluorescence microscopy, liquid chromatography/electrospray ionization tandem mass spectrometry, and the tetrazolium dye assay using the in vitro cell models. The DOX-LNA conjugate showed substantially higher tumor-specific cytotoxicity compared with DOX.

Synthesis of a New pH-Sensitive Folate-Doxorubicin Conjugate and its Antitumor Activity In Vitro

Folate-aminocaproic acid-doxorubicin (FA-AMA-DOX) was synthesized and characterized by H NMR spectroscopy and mass spectrometry. Cytotoxicity and cellular uptake experiments were performed in KB and HepG2 cells, which express folic acid receptor, and the cell line A549, which does not express folic acid receptor. Cytotoxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cellular uptake was monitored using fluorescence microscopy. The amount of DOX released from FA-AMA-DOX was much greater at pH 5.0 than that at pH 6.5 or 7.4. The cytotoxicity of FA-AMA-DOX toward KB and HepG2 cells was greater than that of DOX or AMA-DOX at the same concentrations, and cytotoxicity could be attenuated by FA in a dose-dependent manner. On the contrary, the cytotoxicity of FA-AMA-DOX and AMA-DOX toward A549 cells was lower than that of DOX at the same concentration, and cytotoxicity could not be reduced by FA. Compared with FA-AMA, FA-AMA-DOX increased the intracellular accumulation of DOX in KB cells. These results suggested that FA-AMA-DOX have suitable attributes for the active targeting of folate-receptor-positive tumor cells and for releasing the chemotherapeutic agent, DOX, in situ; it therefore has potential as a novel cancer therapeutic.

A new natural angelica polysaccharide based colon‐specific drug delivery system

Colon-specific drug delivery systems are clinically necessary to treat colon diseases locally while minimizing systemic side effects. In this study, we extracted angelica polysaccharide from fresh roots of Angelica sinensis Diels and analyzed the monosaccharide components. With succinate as a cross-linker and angelica polysaccharide as a drug carrier, a dexamethasone-polysaccharide conjugate was synthesized. The amount of dexamethasone (Dex) loaded in the dexamethasone-polysaccharide conjugate was 14.13/100 mg. The newly synthesized dexamethasone-polysaccharide conjugate was found to greatly reduce systemic absorption of Dex and effectively deliver Dex to the large intestine. When dexamethasone-polysaccharide conjugate was used to treat TNBS-induced ulcerative colitis in rats by gavage, the ulcerative area of the colon and the colonic myeloperoxidase (MPO) activity was reduced in a dose-dependent manner. There was no effects on spleen weight, thymus weight, or peripheral blood lymphocyte count (0.25 micromol kg(-1) day(-1)). These results indicate that the dexamethasone-polysaccharide conjugate has a therapeutic effect on TNBS-induced ulcerative colitis in rats, while simultaneously reducing the systemic immunosuppression caused by Dex. Thus, the angelica polysaccharide was a promising colon-specific drug carrier, and the new dexamethasone-polysaccharide conjugate may yield a potential drug for the treatment of human inflammatory bowel disease.

Co-transfection of dendritic cells with AFP and IL-2 genes enhances the induction of tumor antigen-specific antitumor immunity

Dendritic cells (DCs) are highly efficient, specialized antigen-presenting cells and DCs transfected with tumor-related antigens are regarded as promising vaccines in cancer immunotherapy. The aim of the present study was to investigate whether DCs co-transfected with the α-fetoprotein (AFP) and human interleukin-2 (IL-2) genes were able to induce stronger therapeutic antitumor immunity in transfected DCs. In this study, DCs from hepatocellular carcinoma (HCC) patients were co-transfected with the IL-2 gene and/or the AFP gene. The reverse transcription-PCR (RT-PCR) data revealed that the DCs transfected with the adenovirus AdAFP/IL-2 expressed AFP and IL-2. The DCs co-transfected with IL-2 and AFP (AFP/IL-2-DCs) enhanced the cytotoxicities of cytotoxic T lymphocytes (CTLs) and increased the production of IL-2 and interferon-γ significantly compared with their AFP-DC, green fluorescent protein (GFP)-DC, DC or phosphate-buffered saline (PBS) counterparts. In vivo data suggested that immunization with AFP-DCs enhances antigen-specific antitumor efficacy more potently than immunization with IL-2-DCs or AFP-DCs. These findings provide a potential strategy to improve the efficacy of DC-based tumor vaccines.

High Performance Liquid Chromatography—Tandem Mass Spectrometric Determination of Resveratrol and Its Metabolites in Rat Tissues

In this study, we established a rapid, sensitive, and specific liquid chromatography method coupled with electrospray ionization–tandem mass spectrometry to evaluate the disposition of resveratrol and its metabolites in rat tissues following oral administration. Here, we validate this method and show that it is useful for quantifying tissue concentrations of resveratrol and its metabolites with acceptable specificity, linearity, lower limits of quantification, precision, accuracy, and recovery. The present study demonstrates that the major distribution of the trans-resveratrol and its metabolites in investigated tissues, which suggests that there is a specified range of target organs for cancer chemoprevention by polyphenols.

In Vivo Anti-Tumor Activity of a New Doxorubicin Conjugate via α-Linolenic Acid

The conventional chemotherapy agent, doxorubicin, is of limited clinical use because of its systemic toxicity toward normal healthy tissue. A new doxorubicin conjugate with α-linolenic acid showed good anti-tumor activity with lower toxicity than free doxorubicin and exhibited an active tumor-targeting profile due to the introduction of α-linolenic acid which might be an effective tumor-targeting moiety for the modification of chemotherapeutics.

pH-Triggered Surface Charge Reversed Nanoparticle with Active Targeting To Enhance the Antitumor Activity of Doxorubicin

PLGA nanoparticles are widely used in tumor targeting drug delivery systems. However, the naked PLGA nanoparticles (NNPs) not only have low drug loading but also can be rapidly removed from blood circulation by the immune system. The aim of this study was to prepare pH-triggered surface charge reversed lipid hybrid PLGA nanoparticles (LNPs) to enhance drug loading and drug delivery efficiency. CHO-Arg-His-OMe and FA-PEG-DSPE were synthesized to modify PLGA nanoparticles to prepare LNPs. The drug loading and encapsulation rate of LNPs were greatly improved as compared with NNPs. In pH 7.4 medium, doxorubicin (DOX)-loaded LNPs showed negative charge and released DOX slowly. In pH 5.0 medium, DOX-loaded LNPs exhibited positive charge and released DOX quickly. DOX-loaded LNPs delivered more DOX to the nucleus of KB cells and MBA-MD-231/ADR cells than did free DOX. In addition, DOX-loaded LNPs significantly inhibited the proliferation of KB cells and MBA-MD-231/ADR cells. Compared with free DOX, the same dose of the DOX-loaded LNPs delivered more DOX to tumor tissue. Thus, DOX-loaded LNPs significantly inhibited the growth of tumor in tumor-bearing nude mice and obviously reduced the systemic toxicity of DOX. In conclusion, pH-triggered surface charge reversed DOX-loaded LNPs significantly enhanced the antitumor activity of DOX in vitro and in vivo. DOX-loaded LNPs had great potential in tumor targeted chemotherapy.