Shuang Zhou

Review: Bismuth complexes: synthesis and applications in biomedicine

A variety of bismuth complexes have been extensively explored in biomedical applications. The well-known low toxicity and environmental friendliness of bismuth salts make them valuable for large-scale synthesis of various bismuth-based complexes, which become more significant as active pharmaceutical ingredients of medical products. Bismuth complexes have been widely and preferably used in biomedicine with satisfactory therapeutic effect, which is highlighted in this review. However, their synthesis methods have been scarcely summarized. The classification of the main synthesis methods of bismuth complexes has been done here, followed by updates of the relevant advances concerning applications in biomedicine such as therapeutic effect on gastrointestinal diseases, antimicrobial, and anticancer activities, and the description of the side effect and biotoxicity resulting from long-term use of bismuth as well. Bismuth containing metal–organic frameworks, newly developed bismuth-based materials, are also discussed here, becoming a hot research topic recently. An outlook for future study on the potential use of bismuth complexes in biomedicine is provided in the end. This paper reviews the synthesis and biomedical applications of bismuth complexes with unusually low toxicity and excellent clinical performances, summarizes their main synthesis methods, and biomedical applications as drugs for the therapeutic treatment of gastrointestinal disease, Helicobacter pylori infection, and various cancers; especially, describes the development of bismuth-based MOFs in the drug delivery and potential application in cancer treatment.

Local expression of secondary lymphoid tissue chemokine delivered by adeno-associated virus within the tumor bed stimulates strong anti-liver tumor immunity

ABSTRACT Development of an effective antitumor immune response depends on the appropriate interaction of effector and target cells. Thus, the expression of chemokines within the tumor may induce a more potent antitumor immune response. Secondary lymphoid tissue chemokine (SLC) is known to play a critical role in establishing a functional microenvironment in secondary lymphoid tissues. Its capacity to attract dendritic cells (DCs) and colocalize them with T cells makes it a good therapeutic candidate against cancer. In this study, we used SLC as a treatment for tumors established from a murine hepatocellular carcinoma model. SLC was encoded by recombinant adeno-associated virus (rAAV), a system chosen for the low host immunity and high efficiency of transduction, enabling long-term expression of the gene of interest. As a result, rAAV-SLC induced a significant delay of tumor progression, which was paralleled by a profound infiltration of DCs and activated CD4+ T cells and CD8+ T cells (CD3+ CD69+ cells) into the tumor site. In addition, rAAV-SLC treatment was also found to reduce tumor growth in nude mice, most likely due to inhibition of neoangiogenesis. In conclusion, local expression of SLC by rAAV represents a promising approach to induce immune-mediated regression of malignant tumors.

CCR7 Expression and Intratumoral FOXP3+ Regulatory T Cells are Correlated with Overall Survival and Lymph Node Metastasis in Gastric Cancer

The aim of this study was to investigate the prognostic value of chemokine receptor CCR7 expression and intratumoral FOXP3+ regulatory T cells (Tregs) in gastric cancer. CCR7+ tumor cells and FOXP3+ Tregs were assessed by immunohistochemistry in tissue microarrays containing gastric cancer from 133 patients. Prognostic effects of low or high CCR7 and FOXP3 expression were evaluated by Cox regression and Kaplan-Meier analysis, as well as the correlation between CCR7 positive score and intratumoral FOXP3+ cell number in a longitudinal assessment. The analysis showed that the high expression levels of CCR7 and FOXP3 were detected in 69.9% and 65.4% of cases, respectively. High CCR7 expression in gastric cancer cells was significantly associated with poor overall survival (OS) (P = 0.010) and lymph node metastasis (P = 0.009), and was an independent factor for worse OS (P = 0.023) by multivariate analysis. High numbers of intratumoral FOXP3+ Tregs significantly correlated with shorter OS (P = 0.021) and lymph node metastasis (P = 0.024), and was also an independent factor for adverse OS (P = 0.035). Furthermore, there was a significantly positive correlation between CCR7 positive score and intratumoral FOXP3+ cell number (r = 0.949, P<0.001). These results revealed that CCR7 expression in gastric cancer cells and intratumoral FOXP3+ Tregs could be considered as a co-indicator of clinical prognosis of gastric cancer.

Depletion of CD4+ CD25+ regulatory T cells promotes CCL21-mediated antitumor immunity.

CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4+ CD25+ Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4+, CD8+ T cells and CD11c+ DCs within the tumor, coincident with marked induction of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.

Overexpression of suppressor of cytokine signaling 1 in islet grafts results in anti-apoptotic effects and prolongs graft survival

AIMS A significant portion of islet grafts are destroyed by apoptosis and fail to become functional after transplantation. Strategies that enhance islet resistance to apoptosis may prevent graft loss. The aim of this study was to investigate whether overexpression of suppressor of cytokine signaling 1 (SOCS1) in islet grafts could achieve an anti-apoptotic effect and prolong graft survival. MAIN METHODS We used a chimeric adenovirus vector (Ad5F35) to enhance SOCS1 expression in isolated rat islets, and assessed its protective action against TNF-alpha-induced apoptosis. After transplanting SOCS1-overexpressing islets into allogeneic recipients with streptozotocin-induced diabetes, graft survival and in situ apoptosis were analyzed using immunohistochemistry. KEY FINDINGS The isolated rat islets infected with Ad5F35-SOCS1 showed significantly higher SOCS1 expression than Ad5F35-EGFP and mock infected islets. The Ad5F35 transfection and SOCS1 overexpression on islets did not affect their insulin secretory function. After treatment with rat TNF-alpha and cycloheximide in vitro, Ad5F35-SOCS1 infected islets exhibited a lower apoptotic ratio than controls (Ad5F35-EGFP and mock infected islets). The diabetic recipients transplanted with Ad5F35-SOCS1 infected islets displayed longer time of normoglycemia than recipients transplanted with mock infected islets. Furthermore, histological analysis indicated that the infected grafts with local overexpression of SOCS1 showed decreased apoptosis in the early post-transplant period. SIGNIFICANCE These results demonstrate that overexpression of SOCS1 in islet grafts prior to transplantation can significantly protect them from apoptotic loss and prolong their survival. This approach might find a clinical counterpart.

Combination of SLC administration and Tregs depletion is an attractive strategy for targeting hepatocellular carcinoma

BackgroundSecondary lymphoid tissue chemokine (SLC) is a key CC chemokine for chemotaxis of immune cells and has been an attractive candidate for anti-tumor treatments. However, among the immune cells recruited by SLC to tumors, the CD25+ Foxp3+ regulatory T cells (Tregs) compromise the anti-tumor effects. In this study, we proposed the combination therapy of intratumoral co-administration of SLC and anti-CD25 monoclonal antibodies (mAbs). We hypothesized that the intratumoral injections of SLC and depletion of Tregs would have stronger inhibition effects on the progression of hepatocellular carcinoma (HCC) in mice.MethodsC57BL/6 mice were inoculated subcutaneously with the murine HCC cell line, and mice with visible tumors were treated intratumorally with SLC, SLC plus anti-CD25 mAbs or the control antibodies. The percentages of Tregs, effector CD8+ T cells and CD4+ T cells were checked in the tumors, lymph nodes, spleen and liver at regular intervals. The levels of intratumoral IL-12, IFN-γ, IL-10 and TGF-β1 were evaluated. The final anti-tumor effects were measured by the tumor volume and weight as well as the intratumoral activity of MMP2 and MMP9. Bone-marrow-derived dendritic cells were used to explore the mechanisms of maturation induced by SLC in vitro.ResultsOur experiments showed the combination therapy significantly decreased the frequency of Tregs, and increased CD8+ T cells and CD4+ T cells at tumor sites. These alterations were accompanied by an increased level of IL-12 and IFN-γ, and decreased level of IL-10 and TGF-β1. Unexpectedly, we observed a significantly decreased percentage of Tregs, and increased CD8+ T cells and CD4+ T cells in the lymph nodes, spleen and liver after the combination therapy. The growth and invasiveness of HCC was also maximally inhibited in the combination therapy compared with the SLC alone. Furthermore, we confirmed SLC induced the maturation of DCs via NF-κB p65 and this maturation would benefit the combination therapy.ConclusionsOur data demonstrated that intratumoral co-administration of SLC and anti-CD25 mAbs was an effective treatment for HCC, which was correlated with the altered tumor microenvironment and systemically optimized percentages of Tregs, CD8+ T cells and CD4+ T cells in peripheral immune organs.

Combination Therapy of VEGF-Trap and Gemcitabine Results in Improved Anti-Tumor Efficacy in a Mouse Lung Cancer Model

Background Angiogenesis is essential for the growth and metastasis of cancer. Although anti-angiogenic agents, particularly vascular endothelial growth factor (VEGF) inhibitors, have exhibited single-agent activity, there is considerable interest in combining these novel drugs with conventional chemotherapy reagents to achieve an optimal clinical efficacy. The objective of this study was to evaluate the benefits of the combination therapy of vascular endothelial growth factor trap (VEGF-Trap) with gemcitabine in a lung tumor model. Methods A luciferase-expressing Lewis lung carcinoma (LLC) model was established in C57BL/6J mice and tumor-bearing mice were randomized into control, VEGF-Trap, gemcitabine and VEGF-Trap/gemcitabine combination groups. Tumor growth and animal survival were monitored. Tumor microvessel density and cell proliferation were evaluated by CD31 and Ki-67 immunohistochemical analysis. TUNEL assay was performed to detect apoptotic cells. The protein levels of Cyclin D1, Pro-Caspase-3, Bcl-2, MMP2 and MMP9 in tumor extracts were examined by western blot. Results VEGF-Trap in combination with gemcitabine showed significantly enhanced inhibition of tumor growth and prolonged mouse survival compared to the VEGF-Trap or gemcitabine monotherapy. The VEGF-Trap/gemcitabine combination therapy not only potently inhibited tumor angiogenesis and cell proliferation, but also increased cellular apoptosis within tumor tissues. In addition, the combination treatment markedly down-regulated the expression of proliferation, anti-apoptosis and invasion related proteins. Conclusion Combination therapy using VEGF-Trap and gemcitabine resulted in improved anti-tumor efficacy in a lung cancer model and VEGF-Trap/gemcitabine combination might represent a promising strategy in the treatment of human lung cancer.

Potent anticancer activity of a new bismuth (III) complex against human lung cancer cells

The aim of this work is experimental study of an interesting bismuth(III) complex derived from pentadentate 2,6-pyridinedicarboxaldehyde bis(4N-methylthiosemicarbazone), [BiL(NO3)2]NO3 {L=2,6-pyridinedicarboxaldehyde bis(4N-methylthiosemicarbazone)}. A series of in vitro biological studies indicate that the newly prepared [BiL(NO3)2]NO3 greatly suppressed colony formation, migration and significantly induced apoptosis of human lung cancer cells A549 and H460, but did not obviously decrease the cell viability of non-cancerous human lung fibroblast (HLF) cell line, showing much higher anticancer activities than its parent ligands, especially with half maximum inhibitory concentration (IC50) <3.5μM. Moreover, in vivo study provides enough evidence that the treatment with [BiL(NO3)2]NO3 effectively inhibited A549 xenograft tumor growth on tumor-bearing mice (10mgkg-1, tumor volume reduced by 97.92% and tumor weight lightened by 94.44% compared to control) and did not indicate harmful effect on mouse weight and liver. These results suggest that the coordination of free ligand with Bi(III) might be an interesting and potent strategy in the discovery of new anticancer drug candidates.

SLC/CCR7 Stimulates the Proliferation of BMDCs by the pNF-κB p65 Pathway

The chemokine receptor CCR7 is highly expressed in dendritic cells (DCs), T cells, and other immune effector cells. One of the high‐affinity ligand that can bind to CCR7 is the secondary lymphoid tissue chemokine (SLC). The SLC/CCR7 axis plays an important role in the immune system by inducing the chemotaxis and migration of immune effector cells. In this study, we examined the effect of SLC at different concentrations (0, 50, 100, 200, 300, and 400 ng/mL) on the proliferation of bone‐marrow‐derived dendritic cells (BMDCs). ELC (CCL19), another high‐affinity ligand for CCR7, was used as the control at the same time. We found that SLC directly stimulated the proliferation of BMDCs and enhanced the antigen‐presenting function and CCR7 expression. Western blot analysis showed that pNF‐κBp65 was involved in this mechanism. We also found that the NF‐κB inhibitor PDTC could specifically block the proliferation and CCR7 expression of BMDCs induced by SLC or ELC (200 ng/mL). The results suggested that there were cross‐talk signals between the chemotaxis and proliferation of BMDCs involving the SLC/CCR7 axis. Anat Rec, 2010.

Adsorptive Stripping Determination Of Trace Nickel Using Bismuth Modified Mesoporous Carbon Composite Electrode

Novel bismuth nanoparticle-modified mesoporous carbon (MPC) was successfully prepared on a glassy carbon electrode (Bi@MPC/GCE) for the adsorptive stripping voltammetric determination of nickel by complexing with dimethylglyoxime (DMG). The presence of MPC obviously improved the properties of Bi particles like the electron transfer ability, particle size and hydrophicility, important parameters to achieve preferable analytical performances of Bi@MPC/GCE toward Ni(II). The best electrochemical behaviors of Bi@MPC/GCE was obtained for the stripping determination of Ni(II), compared with electrodes individually modified with Bi and MPC. The synergic effect between metallic Bi and ordered MPC (forming a 3D array like Bi microelectrodes) made major contribution to such improved electrochemical properties of Bi@MPC/GCE for Ni(II) sensing. The good linear analytical curve was achieved in a Ni(II) concentration range from 0.1μM to 5.0μM with a correlation coefficient of 0.9995. The detection limit and sensitivity were calculated to be 1.2nM (S∕N=3) and 1410μAmM−1cm−2, respectively. The new method was successfully applied to Ni(II) determination in soybean samples with recoveries higher than 99% and proved to be a simple, efficient alternative for Ni(II) monitoring in real samples.