Magnetic nanoparticles based cancer therapy: current status and applications.

Nanotechnology holds a promising potential for developing biomedical nanoplatforms in cancer therapy. The magnetic nanoparticles, which integrate uniquely appealing features of magnetic manipulation, nanoscale heat generator, localized magnetic field and enzyme-mimics, prompt the development and application of magnetic nanoparticles-based cancer medicine. Considerable success has been achieved in improving the magnetic resonance imaging (MRI) sensitivity, and the therapeutic function of the magnetic nanoparticles should be given adequate attention. This work reviews the current status and applications of magnetic nanoparticles based cancer therapy. The advantages of magnetic nanoparticles that may contribute to improved therapeutics efficacy of clinic cancer treatment are highlighted here.

Molecular magnetic resonance probe targeting VEGF165: preparation and in vitro and in vivo evaluation.

A new method for imaging the tumor human vascular endothelial growth factor 165 (VEGF 165) is presented. A magnetic resonance imaging (MRI) probe was prepared by crosslinking ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles to the aptamer for tumor vascular endothelial growth factor 165 (VEGF165-aptamer). The molecular probe was evaluated for its in vitro and in vivo activities toward VEGF165. Enzyme-linked immunosorbent assay showed that the VEGF165-aptamer-USPIO nanoparticles conjugate specifically binds to VEGF165 in vitro. A cell proliferation test showed that VEGF165-aptamer-USPIO seems to block the proliferation of human umbilical vein endothelial cells induced by free VEGF165, suggesting that VEGF165 is an effective target of this molecular probe. In xenograft mice carrying liver cancer that expresses VEGF165, T2-weighted imaging of the tumor displayed marked negative enhancement 3 h after the intravenous administration of VEGF165-aptamer-USPIO. The enhancement disappeared 6 h after administration of the probe. These results suggest the targeted imaging effect of VEGF165-aptamer-USPIO probe in vivo for VEGF165-expressing tumors. This is the first report of a targeted MRI molecular probe based on USPIO and VEGF165-aptamer.

[Recent advances in curcumin and its derivatives for treatment of liver diseases].

Curcumin is a principal polyphenolic curcuminoid extracted from turmeric rhizome, which has been used for treating inflammation of joints, ulcers, jaundice and other disorders in Asian traditional medicine. In recent years, many studies have indicated that curcumin plays important roles in treatment of liver diseases. Curcumin attenuates liver injury and non-alcoholic fatty liver disease by lowering the release of inflammation cytokines, minimizing oxidative stress, enhancing the sensitivity of insulin and altering lipid metabolism. Curcumin shows potent anti-fibrosis activity, contributing to inhibit the activation of hepatic stellate cells and reduce the deposition of extracellular matrix by its regulation of PPAR-γ, NF-ΚB and TGF-ß signaling pathways. Moreover, curcumin exhibits anti-cancer effect by inducing G2/M phase cell cycle arrest and apoptosis in several hepatoma cell lines. However, poor water solubility and low bioavailability of curcumin limit its clinical applications. To overcome its limited systemic bioavailability, many new approaches have been explored to deliver curcumin effectively. This article focuses on advances in the effects of curcumin and its derivatives for treatment of liver injury, non-alcoholic fatty liver disease, liver fibrosis and hepatocarcinoma.

Enhanced immunity against hepatoma induced by dendritic cells pulsed with Hsp70-H22 peptide complexes and CD40L.

PURPOSE: Dendritic cell (DC)-based cancer vaccines have become an attractive antitumour therapeutic approach. However, clinical application of current DC-based cancer vaccines has been limited by their ineffectiveness. Heat shock protein 70 from Mycobacterium tuberculosis (TBhsp70) is known to have a potent adjuvant capability to induce maturation of DCs and thus acts as an alternative ligand to the CD40 ligand (CD40L) on T cells to induce a T-cell response. The aim of this study is to investigate whether the combination of TBhsp70-H22 tumour-peptide complexes and CD40L might improve the antitumour efficacy for development of therapeutic DC-based vaccines against hepatoma. METHODS: The CD40, CD80, CD86 and HLA-DR expression on DCs pulsed with TBhsp70-H22 tumour-peptide complexes and soluble CD40L was studied by flow cytometric analysis, and T-helper type 1 cytokine secretion, such as IL-12p70 secretion, was tested by ELISA. The H22-specific cytotoxic T-lymphocytes (CTLs) were detected by a (51)Cr-release assay, and the in vivo antitumour immunity against hepatoma was measured by utilising H22-tumour-bearing mice after therapeutic administration. RESULTS: Up-regulation of CD40, CD80, CD86 and HLA-DR expression on DCs pulsed with TBhsp70-H22 tumour-peptide complexes and CD40L was found, which stimulated a high level of T-helper type 1 cytokine secretion, such as IL-12p70, and resulted in the induction of H22-specific CTLs. The therapeutic administration of DCs pulsed in vitro with TBhsp70-H22 tumour-peptide complexes and CD40L significantly reduced the progression of H22 tumours in mice compared with DC-Hsp70-H22 peptide complexes or DC-CD40L alone. CONCLUSIONS: Our findings demonstrate that DCs pulsed with Hsp70-H22-peptide complexes and CD40L enhance the antitumour immunity against hepatoma, which provides a novel immunotherapeutic approach against cancer.

[The effects of curcumin derivative on experimental steatohepatitis].

OBJECTIVE: To observe the effects of curcumin derivative on non-alcoholic steatohepatitis (NASH). METHODS: 60 SD male rats were randomly divided into 5 groups. The NASH model was induced by high fat diet combined with carbon tetrachloride. These rats were then treated with curcumin and curcumin derivative, saline treating group as control. The serum biochemical parameters and liver histological examinations were observed. The TNF alpha, NF-kappa B and HMG-CoA reductase mRNA transcriptions of liver tissue were detected with RT-PCR. The protein expressions of TNF alpha and NF-kappa B were detected by western blot. RESULTS: Compared with the saline group, A remarkable reduction was observed in serum ALT (U/L), AST (U/L) and TC (mmol/L) in rats treated with curcumin derivatives [(69.20 +/- 27.58) vs (102.43 +/- 47.29), (158.00 +/- 39.15) vs (229.50 +/- 105.20) and (2.08 +/- 0.30) vs (2.58 +/- 1.02), P < 0.05]. The degrees of fibrosis were significantly alleviated; Compared with curcumin group, liver index and serum ALT, AST of curcumin derivative group were also significantly decreased [(4.88 +/- 0.62) vs (5.16 +/- 0.61); (69.20 +/- 27.58) vs (82.5 +/- 33.23); (158.00 +/- 39.15) vs (211.75 +/- 106.30), P < 0.05]; The liver steatosis and inflammation grade were also significantly improved .The gene transcriptions of TNF alpha, NF-kappa B and HMG-CoA reductase in curcumin derivative group were significantly lower than those in curcumin and saline group (P < 0.05). CONCLUSION: These results indicate that the water-soluble curcumin derivative displays superior bioavailability to the parent curcumin, which can effectively improve the lipid metabolism and delay the progression of hepatic fibrosis in rats with steatohepatitis.

A novel approach for transferring oleic acid capped iron oxide nanoparticles to water phase.

A novel and simple method was described to transfer oleic acid stabilized iron oxide nanoparticles from organic solutions to water. The oxidation of OA by sodium periodate in mixed solvents formed a carboxyl group or vicinal diol to make the hydrophobic groups to hydrophilic groups on the surface of the nanoparticles. The characterization of nanoparticles indicated that the phase transfer based on the oxidation of OA was successful performed without change in the size and shape of the iron oxide nanoparticles. The hydrophilic groups on the iron oxide surface stabilized the nanoparticles in aqueous solution and the oxidized nanoparticles can be applied to bimolecular immobilization.

Cytotoxicity of Fe3O4/Au composite nanoparticles loaded with doxorubicin combined with magnetic field.

GoldMag (Fe3O4/Au) nanoparticles have the advantages of both magnetic response in an external magnetic field and the immobilization of molecules on their surface in a single step. The cytotoxicities of GoldMag nanoparticles and GoldMag nanoparticles loaded with doxorubicin (Dox-GoldMag) combined with an external magnetic field were tested in vitro on HepG2 malignant tumor cells. The results showed that cell viability remained above 92% when using GoldMag nanoparticles at a concentration as high as 2.0 mg/ml, suggesting the biocompatibility of the nanoparticles. The IC50 (0.731 microg/ml) of the Dox-GoldMag group was higher than that (0.522 microg/ml) of the Dox group (P < 0. 05). However, the Dox-GoldMag group combined with a magnetic field had an obviously increased inhibition rate for the HepG2 cell line and the IC50 was lower than that of the Dox group (0.421 microg/ml). These results indicated that GoldMag nanoparticles loaded with doxorubicin combined with a permanent magnetic field are more cytotoxic and could be a potential targeted drug delivery system.

Silica- and polymer-supported platinum(II) polypyridyl complexes: synthesis and application in photosensitized oxidation of alkenes.

Square-planar polypyridine platinum(II) complexes have been introduced into a silica/polymer matrix by covalent ligand modification. The photophysical properties of the supported matrices are well retained as their model complexes, and the quantum yields for singlet oxygen ((1)O(2)) generation are comparable with that of TPP (tetraphenylporphyrin) under similar conditions. A preliminary application in photosensitized oxidation indicates the silica/polymer-supported matrices are promising, which can be reused without loss of reactivity by a simple filtration. Moreover, the polymer-supported matrix exhibits excellent compatibility in various solvents.

Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma.

IL-23 and IL-27 are two novel IL-12 cytokine family members who are quite similar to, but yet clearly distinct from IL-12 in their structures and T-cell stimulatory mechanisms. Here, we demonstrated that either IL-27 or IL-23 has potent antitumor activity in murine models of MM45T.Li hepatocellular carcinoma (HCC). These potent antitumor effects were induced primarily by CD8(+)T cells, secreting IFN-gamma while CD4(+)T cells were also involved as a help of antitumor immunity. However, the antitumor response induced by IL-27 was observed from an early stage of tumor growth whereas that of IL-23 was only evident in the late stage of tumor cell proliferation. IL-23 could induce mice to develop a long-term systemic immunologic memory response against parental MM45T.Li tumors cells, an effect IL-27 was not able to accomplish. CTLs specific for MM45T.Li cells were significantly induced by IL-23, whereas antitumor efficacy mediated by IL-27 and IL-12 involved NK cells, which IL-23 failed to activate. Furthermore, we demonstrated that CD40 expression also plays an important role in the induction of antitumor activities by IL-27, IL-23 or IL-12. Together our data suggest that IL-27 and IL-23 may be two novel and attractive candidate agents to apply to cancer immunotherapy.

A DNA vaccine against chimeric AFP enhanced by HSP70 suppresses growth of hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is produced principally in fetal liver, gastrointestinal tract and the yolk sac which is temporarily present during embryonic development. AFP is overexpressed in the majority of hepatocellular carcinoma (HCC) and thus offers an attractive target for immunotherapy against this neoplasm. Here, we report that anti-HCC effects were achieved in a therapeutic setting with a DNA vaccine encoding mouse AFP and co-expressing heat shock protein 70 (HSP70) gene. We also demonstrated that this vaccine elicited a marked and highly effective AFP specific CTL response against AFP-positive target cells. This vaccine also induced the prolongation of life span in mice bearing the tumor and the eradication of HCC. It is anticipated that vaccine strategies such as this may contribute to the effective future treatment of hepatocellular carcinoma.

[Specific immune responses in Balb/c mice induced by plasmid coexpressing hepatitis B surface antigen and granulocyte-macrophage colony stimulating factor].

OBJECTIVES: To investigate the improvement of specific immune responses induced by plasmid coexpressing hepatitis B surface antigen (HBsAg) and granulocyte-macrophage colony stimulating factor (GM-CSF). METHODS: All Balb/c (H-2d) mice were immunized with pGM-CSF/S, pS/GM-CSF, pS or control plasmids. 4 weeks later, anti-HBs titer and the levels of IL-2, IL-4 and IFN-gamma in the supernatant of splenocytes were detected using enzyme- linked immunosorbent assay (ELISA), and HBsAg-specific cytotoxic T lymphocytes (CTL) activity was measured with a 51Cr release assay, using P815/S transfectants as target cells. RESULTS: The anti-HBs antibody titers in the serum, the levels of IL-2 and IFN-gamma, and the CTL activity in pcDNA3.1-GM-CSF-S immuned mice were higher than those in PcDNA3.1-S immunized mice (F=4.176, P<0.01; F=31.188, P<0.01; F=31.796, P<0.01; F

[Heat shock protein 70-HBsAg complex inducing antigen-specific cytotoxic T lymphocyte immune response].

OBJECTIVE: To explore the possibility of cell-medicated immune response induced with heat shock protein 70 (HSP70)-HBsAg protein complex in vitro. METHODS: HSP70-HBsAg complex was reconstituted in vitro which was injected into mice in order to observe that whether HSP70-HBsAg would stimulate humoral and cellular immune responses. HSP70, HSP70-HBsAg complex and HBsAg were used to activate the dentritic cell (DC) individually, which would initiate homogeneic T lymphocyte to transform to cytotoxic T lymphocyte (CTL). The cytotoxicity of CTL was detected with MTT assay. RESULTS: HSP70-HBsAg complex elicited both humoral and cellular immune responses against HBsAg in mice. Specific CD8+ CTL response was readily induced by HSP70-HBsAg complex and HBsAg, especially the former. CONCLUSIONS: HSP70-HBsAg complex is immunogenic and HSP70 can lead to great efficient CTL response. And HSP70-HBsAg complex may be used as a protein vaccine for immunotherapy for chronic hepatitis B.

[Secretion expression of Mt. heat shock protein 70 in Pichia pastoris and identification of the protein].

To obtain the expression of Mycobacterium tuberculosis heat shock protein 70 in methylotropic yeast. The expression vector pPIC9K-hsp70 was constructed, linearized and introduced into Pichia pastoris GS115 by electroporation. The result protein was secreted into the supernatant induced by 0.5% methanol at 30 degrees C and purified by centrifugation, ultrafiltration and ATP-agarose. The recombinant Hsp70 was identified by SDS-PAGE, Western blot, mice experiment and effect on the immature DC. The SDS-PAGE and Western blot analysis showed that the apparent molecular weight of expressed Hsp70 was about 70 kD and the expressed protein could specifically react with anti-Mt. Hsp70 IgG. And mice immunization indicated the expressed hsp70 had immunogenicity. Hsp70 could induce DC maturation and release Th1 cytokine. The secreted 70 kD protein was about 120 mg/L which accounted for more than 30% of the total supernatant protein and was purified to electrophoretic purity. The Hsp70, which had the biological activity, is successfully secretorily expressed in the Pichia pastoris GS115.