Baoan Chen

A strategy for ZnO nanorod mediated multi-mode cancer treatment

Combinations of cancer therapy modalities are attracting attention to improve the outcome of treatment, since single modality has not always been sufficiently effective. The aim of this study was to investigate a new strategy of combined application of ZnO nanorods with anticancer drug daunorubicin (DNR) in photodynamic therapy (PDT). Using a simple one-step solid state reaction in air at room temperature, we were able to fabricate ZnO nanorods as the drug carrier of DNR in drug delivery system. The combination of ZnO nanorods with DNR induced the remarkable improvement in the anti-tumor activity, which has been demonstrated by the flow cytometry, MTT assay and nuclear DAPI staining. Furthermore, the possible signaling pathway was explored by immunocytochemistry. It was noted that the notable photodynamic activity of the non-cytotoxic ZnO nanorods could considerably increase cancer cell injury mediated by reactive oxygen species (ROS). For instance, in human hepatocarcinoma cells (SMMC-7721 cells), our observations demonstrated that ZnO nanorods could obviously increase the intracellular concentration of DNR and enhance its potential anti-tumor efficiency, indicating that ZnO nanorods could act as an efficient drug delivery carrier importing DNR into target cancer cells. Furthermore, photodynamic ZnO nanorods loaded chemotherapeutic agent could induce distinguished improvement in anti-tumor activity with UV illumination. These findings revealed that such modality combinations represent a promising approach in cancer therapy.

Pharmacokinetic parameters and tissue distribution of magnetic Fe(3)O(4) nanoparticles in mice.

Background This study explored the pharmacokinetic parameters and tissue distribution of magnetic iron oxide nanoparticles (Fe3O4 MNPs) in imprinting control region (ICR) mice. Methods The Fe3O4 MNPs were synthesized by chemical coprecipitation, and their morphology and appearance were observed by transmission electron microscopy. ICR mice were divided into a control group and a Fe3O4 MNP-treated group. Probable target organs in ICR mice were observed, and the pharmacokinetic parameters and biodistribution of Fe3O4 MNPs in tissues were identified using atomic absorption spectrophotometry. Results Fe3O4 MNPs were spherical with a well distributed particle diameter, and were distributed widely in various target organs and tissues including the heart, liver, spleen, lungs, kidneys, brain, stomach, small intestine, and bone marrow. The majority of Fe3O4 MNPs were distributed to the liver and the spleen. Fe3O4 MNP levels in brain tissue were higher in the Fe3O4 MNP-treated group than in the control group, indicating that Fe3O4 MNPs can penetrate the blood–brain barrier. Conclusion These results suggest that the distribution of Fe3O4 MNPs was mostly in the liver and spleen, so the curative effect of these compounds could be more pronounced for liver tumors. Furthermore, Fe3O4 MNPs might be used as drug carriers to overcome physiologic barriers.

MRP2 and GSTP1 polymorphisms and chemotherapy response in advanced non-small cell lung cancer

PurposeThe level of drug metabolism and drug transport is correlated with the sensitivity of cancer cells towards platinum-based chemotherapy. We hypothesize that genetic polymorphisms in metabolising enzymes gene GSTP1 (glutathione S-transferase P1), and MRP2 (multidrug resistance-associated protein 2) (ABCC2), which result in inter-individual differences in metabolism and drug disposition, may predict clinical response to platinum agents in advanced non-small cell lung cancer (NSCLC) patients.MethodsTotally 113 patients with advanced NSCLC were routinely treated with platinum-based chemotherapy, and clinical response was evaluated after four cycles. MRP2 C-24T (−24C>T), MRP2 Val417Ile (1249G>A), MRP2 Ile1324Ile (3972C>T), and GSTP1 Ile105Val (342A>G) genotype were determined by gene-chip method (a 3-D (three dimensions) polyacrylamide gel-based DNA microarray method) using DNA samples isolated from peripheral blood collected before treatment. Pearson Chi-square test and Fisher’s exact test were performed to measure the differences of the chemotherapeutic efficacy among variant genotype. The odds ratios and 95% confidence intervals were computed by logistic regression.ResultsThe C→T change of MRP2 C-24T and the A→G change of GSTP1 Ile105Val polymorphism significantly increased platinum-based chemotherapy response.ConclusionThe polymorphic status of MRP2 C-24T and GSTP1 Ile105Val might be the predictive markers for the treatment response of advanced NSCLC patients. The DNA microarray-based method is accurate, high throughput and inexpensive, suitable for single-nucleotide polymorphism genotyping in a large number of individuals.

The Photodynamic Effect of Different Size ZnO Nanoparticles on Cancer Cell Proliferation In Vitro

Nanomaterials have widely been used in the field of biological and biomedicine, such as tissue imaging, diagnosis and cancer therapy. In this study, we explored the cytotoxicity and photodynamic effect of different-sized ZnO nanoparticles to target cells. Our observations demonstrated that ZnO nanoparticles exerted dose-dependent and time-dependent cytotoxicity for cancer cells like hepatocellular carcinoma SMMC-7721 cells in vitro. Meanwhile, it was observed that UV irradiation could enhance the suppression ability of ZnO nanoparticles on cancer cells proliferation, and these effects were in the size-dependent manner. Furthermore, when ZnO nanoparticles combined with daunorubicin, the related cytotoxicity of anticancer agents on cancer cells was evidently enhanced, suggesting that ZnO nanoparticles could play an important role in drug delivery. This may offer the possibility of the great potential and promising applications of the ZnO nanoparticles in clinical and biomedical areas like photodynamic cancer therapy and others.

Layer-by-layer assembly of graphene, Au and poly(toluidine blue O) films sensor for evaluation of oxidative stress of tumor cells elicited by hydrogen peroxide

High level of oxidative stress is involved in formation of incipient tumor and carcinomatous cells. Here in this contribution we have explored a facile strategy to assess the oxidative stress elicited by hydrogen peroxide (H(2)O(2)) in cells with amperometric current-time technique in vitro. An electrochemical biosensor exhibiting high sensitivity and selectivity to H(2)O(2) is fabricated by integration of graphene with gold nanoparticles and poly(toluidine blue O) films. The efflux of H(2)O(2) from several representative tumor cells and normal cells on exposure to ascorbic acid could be detected by using the graphene-based nanocomposite films. The results indicate that tumor cells release much more H(2)O(2) than do the normal cells. The novel sensor raises the possibility for clinical diagnostic application to evaluate the higher level of intracellular oxidative stress of tumor cells in comparison with normal cells.

Daunorubicin-TiO2 nanocomposites as a "smart" pH-responsive drug delivery system.

Daunorubicin (DNR) has a broad spectrum of anticancer activity, but is limited in clinical application due to its serious side effects. The aim of this study was to explore a novel “smart” pH-responsive drug delivery system (DDS) based on titanium dioxide (TiO2) nanoparticles for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of DNR. DNR was loaded onto TiO2 nanoparticles by forming complexes with transition metal titanium to construct DNR-TiO2 nanocomposites as a DDS. DNR was released from the DDS much more rapidly at pH 5.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. DNR-TiO2 nanocomposites induced remarkable improvement in anticancer activity, as demonstrated by flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and nuclear 4′,6-diamidino- 2-phenylindole staining. Furthermore, the possible signaling pathway was explored by western blot. For instance, in human leukemia K562 cells, it was demonstrated that DNR-TiO2 nanocomposites increase intracellular concentration of DNR and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that DNR-TiO2 nanocomposites could act as an efficient DDS importing DNR into target cancer cells. These findings suggest that “smart” DNR delivery strategy is a promising approach to cancer therapy.

Dasatinib inhibits the proliferation and function of CD4+CD25+ regulatory T cells.

CD4+CD25+ regulatory T cells (Tregs) can influence various immune responses. Little is known about the effects of the Abl/Src kinase inhibitor dasatinib on Tregs which regulate anti‐tumor/leukaemia immune responses. The present study demonstrated that dasatinib inhibited proliferation of Tregs and CD4+CD25− T cells in a dose‐dependent manner, which was associated with the decreased production of corresponding cytokines. Treatment of Tregs with dasatinib inhibited the suppressive capacity of Tregs. The mechanisms of this inhibition included arrest of cells in the G0/G1 phase of cell cycle, down‐regulation of the transcription factor forkhead box P3, glucocorticoid‐induced tumour necrosis factor receptor and the cytotoxic T lymphocyte associated protein 4 as well as inhibition of signaling events through Src and nuclear factor κB. Dasatinib showed an inhibitory effect on the proliferation and function of both Tregs and CD4+CD25− T cells at therapeutically relevant concentrations of the drug. Clinical administration of dasatinib might influence not only the graft‐versus‐leukaemia effect but also the graft‐versus‐host‐disease in patients receiving dasatinib after allogeneic stem cell transplantation and/or donor lymphocytes infusion as the function of both Tregs and effector T cells are hampered in a similar way by dasatinib.

Association between polymorphisms of ERCC1 and XPD and clinical response to platinum-based chemotherapy in advanced non-small cell lung cancer.

Background and Objective:DNA repair capacity is correlated with sensitivity of cancer cells toward platinum-based chemotherapy. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in polymorphisms of DNA repair gene ERCC1 (excision repair cross-complementation group 1) and XPD (ERCC2, excision repair cross-complementation group 2) were associated with the tumor response in advanced non–small-cell lung cancer (NSCLC) patients received platinum-based chemotherapy in Chinese population. Methods:Totally 115 patients with advanced NSCLC were routinely treated with cisplatin- or carboplatin-based chemotherapy, and clinical response was evaluated after 2 cycles. Three dimensions (3-D) polyacrylamide gel-based DNA microarray method was used to evaluate the genotypes of ERCC1 Asn118Asn (354 CT), Gln504Lys (8092 CA) and XPD Lys751Gln (35931 AC). Results:The C→T change of ERCC1 Asn118Asn polymorphism and the C→A change of ERCC1 Gln504Lys polymorphism have statistically significant association with elevated or descendent platinum-based chemotherapy response respectively. Conclusion:The polymorphic status of ERCC1 might be the promising ancillary marker for predicting treatment response of advanced stage NSCLC patients. The DNA microarray-based method is accurate, high-throughput and inexpensive, suitable for SNP genotyping in a large number of individuals.

Multifunctional magnetic Fe3O4 nanoparticles combined with chemotherapy and hyperthermia to overcome multidrug resistance

Background Multidrug resistance in cancer is a major obstacle for clinical therapeutics, and is the reason for 90% of treatment failures. This study investigated the efficiency of novel multifunctional Fe3O4 magnetic nanoparticles (Fe3O4-MNP) combined with chemotherapy and hyperthermia for overcoming multidrug resistance in an in vivo model of leukemia. Methods Nude mice with tumor xenografts were randomly divided into a control group, and the treatment groups were allocated to receive daunorubicin, 5-bromotetrandrine (5-BrTet) and daunorubicin, Fe3O4-MNP, and Fe3O4-MNP coloaded with daunorubicin and 5-bromotetrandrine (Fe3O4-MNP-DNR-5-BrTet), with hyperthermia in an alternating magnetic field. We investigated tumor volume and pathology, as well as P-glycoprotein, Bcl-2, Bax, and caspase-3 protein expression to elucidate the effect of multimodal treatment on overcoming multidrug resistance. Results Fe3O4-MNP played a role in increasing tumor temperature during hyperthermia. Tumors became significantly smaller, and apoptosis of cells was observed in both the Fe3O4-MNP and Fe3O4-MNP-DNR-5-BrTet groups, especially in the Fe3O4-MNP-DNR-5-BrTet group, while tumor volumes in the other groups had increased after treatment for 12 days. Furthermore, Fe3O4-MNP-DNR-5-BrTet with hyperthermia noticeably decreased P-glycoprotein and Bcl-2 expression, and markedly increased Bax and caspase-3 expression. Conclusion Fe3O4-MNP-DNR-5-BrTet with hyperthermia may be a potential approach for reversal of multidrug resistance in the treatment of leukemia.

Biocompatibility of Fe3O4/DNR magnetic nanoparticles in the treatment of hematologic malignancies.

Purpose The objectives of this research were to assess the biocompatibility of self-assembled Fe3O4 magnetic nanoparticles (MNPs) loaded with daunorubicin (DNR), ie, (Fe3O4-MNPs/DNR), and to explore their potential application in the treatment of hematologic malignancies. Methods A hemolysis test was carried out to estimate the hematologic toxicity of Fe3O4- MNPs/DNR and a micronucleus assay was undertaken to identify its genotoxicity. Fe3O4-MNPs/ DNR were injected intraperitoneally into mice to calculate the median lethal dose (LD50). The general condition of the mice was recorded, along with testing for acute toxicity to the liver and kidneys. Results Hemolysis rates were 2.908%, 2.530%, and 2.415% after treatment with different concentrations of Fe3O4-MNPs/DNR. In the micronucleus assay, there was no significant difference in micronucleus formation rate between the experimental Fe3O4-MNPs/DNR groups and negative controls (P > 0.05), but there was a significant difference between the experimental groups and the positive controls (P < 0.05). The LD50 of the Fe3O4-MNPs/DNR was 1009.71 mg/kg and the 95% confidence interval (CI) was 769.11–1262.40 mg/kg, while that of the DNR groups was 8.51 mg/kg (95% CI: 6.48–10.37 mg/kg), suggesting that these nanoparticles have a wide safety margin. Acute toxicity testing showed no significant difference in body weight between the treatment groups at 24, 48, and 72 hours after intraperitoneal injection. The mice were all in good condition, with normal consumption of water and food, and their stools were formed and yellowish-brown. Interestingly, no toxic reactions, including instability of gait, convulsion, paralysis, and respiratory depression, were observed. Furthermore, alanine transaminase, blood urea nitrogen, and creatinine clearance in the experimental Fe3O4-MNPs/ DNR groups were 66.0 ± 28.55 U/L, 9.06 ± 1.05 mmol/L, and 18.03 ± 1.84 μmol/L, respectively, which was not significantly different compared with the control and isodose DNR groups. Conclusion Self-assembled Fe3O4-MNPs/DNR appear to be highly biocompatible and safe nanoparticles, and may be suitable for further application in the treatment of hematologic malignancies.