Zinc nanoparticles coated with doxorubicin-conjugated alginate as a radiation sensitizer in triple-negative breast cancer cells.

The main treatment modalities for breast cancer include surgery, chemotherapy, and radiotherapy, and each treatment will bring different side effects. Design and synthesizing a novel nanostructure for chemo-radiotherapy has been proposed as an effective method in consideration to enhance the drug efficiency as well as improve the effect of radiotherapy. This study aimed to synthesize zinc nanoparticles (ZnNPs) coated with alginate conjugated with Doxorubicin (Dox) drug and investigate its effects along with X-irradiation on MDA-MB-231 triple-negative breast cancer cell line. ZnNPs coated with alginate were synthesized and conjugated to Dox by covalent bonding and characterized using various physicochemical tests. A hemolysis test was used to assess blood biocompatibility. The radiosensitization properties and anti-cancer effects of the synthesized nanostructures were tested by cell uptake, cell viability, apoptosis, cell cycle, and scratch assays with and without radiation exposure. The physicochemical characterization results showed that the synthesis of nanostructures was successfully carried out. The obtained results from the cell uptake assay showed the effective absorption of nanostructures by the cells. The Zn@Alg-Dox NPs significantly reduced cell growth, increased apoptosis, inhibited cell migration, and led to the arrest of different cell cycle phases in both conditions with and without X-ray exposure. Coating ZnNPs with alginate and Doxorubicin conjugation leads to an increase the radiation sensitivity in radiotherapy as well as therapeutic efficiency. Therefore, Zn@Alg-Dox NPs can be used as radiosensitizing nanomedicine for in vivo studies in the future.

Investigating the effectiveness of iron nanoparticles synthesized by green synthesis method in chemoradiotherapy of colon cancer.

Current methods of colon cancer treatment, especially chemotherapy, require new treatment methods due to adverse side effects. One important area of interest in recent years is the use of nanoparticles as drug delivery vehicles since several studies have revealed that they can improve the target specificity of the treatment thus lowering the dosage of the drugs while preserving the effectiveness of the treatment thus reducing the side effects. The use of traditional medicine has also been a favorite topic of interest in recent years in medical research, especially cancer research. In this research work, the green synthesis of Fe nanoparticles was carried out using Mentha spicata extract and the synthesized nanoparticles were identified using FT-IR, XRD, FE-SEM and EDS techniques. Then the effect of Mentha spicata, Fe nanoparticles, and Mentha spicata -loaded Fe nanoparticles on LS174t colon cancer cells, and our result concluded that all three, especially Mentha spicata -loaded Fe nanoparticles, have great cytotoxic effects against LS174t cells, and exposure to radiotherapy just further intensified these results. The in vitro condition revealed alterations in the expression of pro-apoptotic BAX and anti-apoptotic Bcl2, suggesting a pro-apoptotic effect from all three components, particularly the Mentha spicata-loaded Fe nanoparticles. After further clinical trials, these nanoparticles can be used to treat colon cancer.

Synthesis and characterization of actively HER-2 Targeted Fe3O4@Au nanoparticles for molecular radiosensitization of breast cancer.

Introduction: The present study was done to assess the effect of molecularly-targeted core/shell of iron oxide/gold nanoparticles (Fe3O4@AuNPs) on tumor radiosensitization of SKBr-3 breast cancer cells. Methods: Human epidermal growth factor receptor-2 (HER-2)-targeted Fe3O4@AuNPs were synthesized by conjugating trastuzumab (TZ, Herceptin) to PEGylated (PEG)-Fe3O4@AuNPs (41.5 nm). First, the Fe3O4@Au core-shell NPs were decorated with PEG-SH to synthesize PEG-Fe3O4@AuNPs. Then, the TZ was reacted to OPSS-PEG-SVA to conjugate with the PEG-Fe3O4@AuNPs. As a result, structure, size and morphology of the developed NPs were assessed using Fourier-transform infrared (FT-IR) spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM), and ultraviolet-visible spectroscopy. The SKBr-3 cells were treated with different concentrations of TZ, Fe3O4@Au, and TZ-PEG-Fe3O4@AuNPs for irradiation at doses of 2, 4, and 8 Gy (from X-ray energy of 6 and 18 MV). Cytotoxicity was assessed by MTT assay, BrdU assay, and flow cytometry. Results: Results showed that the targeted TZ-PEG-Fe3O4@AuNPs significantly improved cell uptake. The cytotoxic effects of all the studied groups were increased in a higher concentration, radiation dose and energy-dependent manner. A combination of TZ, Fe3O4@Au, and TZ-PEG-Fe3O4@AuNPs with radiation reduced cell viability by 1.35 (P=0.021), 1.95 (P=0.024), and 1.15 (P=0.013) in comparison with 8 Gy dose of 18 MV radiation alone, respectively. These amounts were obtained as 1.27, 1.58, and 1.10 for 8 Gy dose of 6 MV irradiation, respectively. Conclusion: Radiosensitization of breast cancer to mega-voltage radiation therapy with TZ-PEG-Fe3O4@AuNPs was successfully obtained through an optimized therapeutic approach for molecular targeting of HER-2.

IMPACT OF PELVIC AND RAD-BOARD LEAD SHIELDS ON OPERATOR AND PATIENT RADIATION DOSE IN TRANS-RADIAL CORONARY PROCEDURES.

BACKGROUND: Trans-radial approach for cardiac catheterisation procedures has long been associated with high operator and patient radiation dose. The aim of the present study was to determine the effect of pelvic and radial shields on decreasing coronary procedure radiation doses. METHODS: A total of 418 patients randomly underwent diagnostic and therapeutic cardiac procedures with and without the pelvic and rad-board lead shields during the procedures. The operator and patient doses were then determined by means of a personal dosimeter and dose area product (DAP), respectively. RESULTS: The shields decreased the operator radiation dose by 40% in coronary angiography (CA) and by 45% during angioplasty (PCI). These results were achieved at the cost of increased patient radiation dose. CONCLUSION: Pelvic lead shields combined with rad-board shields are highly effective in reducing operator radiation dose in trans-radial approach, but it is only achieved at the cost of increased patient DAP.

Induction of Apoptosis by a Combination of 2-Deoxyglucose and Metformin in Esophageal Squamous Cell Carcinoma by Targeting Cancer Cell Metabolism.

BACKGROUND: Both mitochondrial dysfunction and aerobic glycolysis are signs of growing aggressive cancer. If altered metabolism of cancer cell is intended, using the glycolysis inhibitor (2-deoxyglucose (2DG)) would be a viable therapeutic method. The AMP-activated protein kinase (AMPK), as a metabolic sensor, could be activated with metformin and it can also launch a p53-dependent metabolic checkpoint and might inhibit cancer cell growth. METHODS: After treatment with 5 mM metformin and/or 500 µM 2DG, the TE1, TE8, and TE11 cellular viability and apoptosis were assessed by MTT, TUNEL, and ELISA methods. The changes in p53 and Bcl-2 genes expression levels were examined using real-time PCR method. Data were analyzed by Kruskal-Wallis test using the SPSS 17.0 software. RESULTS: Metformin and 2DG, alone and in combination, induced apoptosis in the cell lines. Real-time PCR revealed that metformin induced apoptosis in TE8 and TE11 cells by activating p53, down-regulating Bcl-2 expression. The induced apoptosis by 2DG raised by metformin and the combination modulated the expression of Bcl-2 protein in all cell lines and it was more effective in TE11 cell line. CONCLUSION: Metformin induced apoptosis in ESCC by down-regulating Bcl-2 expression, and up-regulating p53 and induced apoptosis increased by 2-deoxy-d-glucose. Thus, the combination therapy is an effective therapeutic strategy for esophageal squamous cell carcinoma.

The effect of SiO2/Au core-shell nanoparticles on breast cancer cell's radiotherapy.

INTRODUCTION: Recently it has been shown that radiation dose enhancement could be achievable in radiotherapy using nanoparticles (NPs). In this study, evaluation was made to determine efficiency of gold-silica shell-core NP in megavoltage irradiation of MCF7 breath cancer cells. MATERIALS AND METHODS: Gold-silicon oxide shell-core NPs were obtained by conjugation of gold NP with amine or thiol functionalized silica NPs (AuN@SiO2 and AuS@SiO2). Cellular uptake and cytotoxicity of NPs were examined by fluorescent microscopy and MTT assay, respectively. MCF-7 breast cancer cells were treated with both NPs and irradiation was made with X-ray energies of 6 and 18 MV to the absorbed dose of 2, 4 and 8 Gy using Simense linear accelerator. The efficiency of radiation therapy was then evaluated by MTT and Brdu assay, DAPI staining and cell cycle analysis. RESULTS: TEM images indicated that synthesized NPs had average diameter of 25 nm. Cellular uptake demonstrated that the internalization of AuS@SiO2 and AuN@SiO2 NPs amounted to 18% and 34%, 3 h post treatment, respectively. Nontoxicity of prepared NPs on MCF-7 cells was proved by MTT and Brdu assays as well as DAPI staining and cell cycle studies. The highest enhancement in radiation dose was observed in the cells that irradiated with radiation energy of 18 MV and absorbed of 8 Gy at NPs concentration of 200 ppm. The Brdu findings revealed that the cytotoxicity and apoptosis on MCF-7 cells are dose dependent with a significantly more death in AuN@SiO2 (amine) exposed cells (p < .05). Analysis also revealed interruption in cell cycle by demonstrating lack of cells, in S phase in amine treated cells (AuN@SiO2) at given dose of 8 Gy using 18 MV X-ray in comparison to thiol treated cells. CONCLUSIONS: Based on the results of the study it can be concluded that the gold-silicon oxide shell-core NPs could play an effective role in radiotherapy of MCF-7 breast cancer cells.

Beam projections and radiation exposure in transradial and transfemoral approaches during coronary angiography.

OBJECTIVE: We aimed to compare the operator and patient radiation exposure in standard projections during elective diagnostic coronary angiography procedures via transradial (TRA) versus transfemoral (TFA) approaches. METHODS: In this analytical cross-sectional study, a total of 202 consecutive patients who were candidates for diagnostic coronary angiography were randomized to undergo the procedure via TFA or TRA approaches (101 in each group). Patients with abnormal Allen test and history of coronary artery bypass surgery, valvular heart disease, and unsuccessful coronary angiography were excluded from the study. A single operator performed all of the procedures using a single angiography system. Patient and operator radiation exposure were measured using diamentor and an electronic personal dosimeter, respectively. Each procedure comprised a standardized sequence of projections including four standard views for the left coronary system and two standard views for the right coronary system. RESULTS: Left anterior oblique (LAO) caudal (50°/30°) and right anterior oblique RAO (30°) projections were associated with the highest and lowest patient radiation exposure, respectively. The operator received a significantly higher radiation exposure in the TRA approach for LAO cranial (for both left and right coronary systems) and LAO caudal (for left coronary system) projections during coronary angiography compared with the TFA approach. CONCLUSION: Though a similar amount of patient radiation exposure in each projection was observed among TFA and TRA groups; LAO cranial and LAO caudal projections were associated with a significantly higher operator radiation exposure in the TRA group. These findings need to be considered when choosing the optimal arterial approach for patients scheduled for coronary angiography.

MLN4924 and 2DG combined treatment enhances the efficiency of radiotherapy in breast cancer cells.

PURPOSE: Two-deoxy-D-glucose (2DG) causes cytotoxicity in the cancer cells by disrupting the thiol metabolism, and MLN4924 inactivates the SCF E3 ligase and so causes the accumulation of its substrates which trigger apoptosis and hence might enhance the efficiency of radiotherapy and overcame on the radioresistance of the cancer cells. MATERIALS AND METHODS: SKBR3 and MCF-7 breast cancer cells were treated with 500 µM 2DG and/or MLN4924 (30, 100, 200 and 300 nM), and in combination in the presence and absence of 1, 1.5 and 2 Gy gamma irradiation. The effects of the treatments - 2DG, MLN4924, irradiation alone and combined - on MCF-7 and SKBR3 cell lines were evaluated by MTT assay, TUNEL assay, cell death detection, Q-PCR for caspase-3 and Bcl-2 expression analysis, and finally clonogenic survival assay. RESULTS: The treatments enhanced the further radio cytotoxicity via inducing the apoptosis cell signaling gene, caspase-3. The 2DG and MLN4924 treatments could act as a radiosensitizer, especially on the SKBR3 cells, and further sensitized the cells with a sensitivity enhancement ratio (SER) of 1.41 and 1.27 in SKBR3 and MCF-7 cells, respectively. CONCLUSION: The combined chemo-radiotherapy might improve the breast cancer treatment outcome.

Enhancing radiosensitivity of TE1, TE8, and TE 11 esophageal squamous carcinoma cell lines by Hdm2-siRNA targeted gene therapy in vitro.

INTRODUCTION: Human double minute2 (hdm2) level increases in most human malignancies. Therefore, inhibition of tumor growth and also induction of radiosensitivity may be provided by hdm2 inhibitors. The effects of hdm2-siRNA on hdm2 protein expression, cell apoptosis rate, and radiosensitivity of human esophageal squamous cell carcinoma (ESCC) were studied. METHODS: The hdm2 gene was silenced in TE1, TE8, and TE11 ESCC cell lines using 200nM siRNA by liposomal transfection method followed by irradiation with 0.5, 1, 2, 4, and 6 Gy γ-rays in vitro. The gene expression levels were evaluated by real time PCR and Western Blotting methods. MTT, TUNEL, and also colony forming assays were used to compare the radiosensitivity of the cell lines before and after the treatments. RESULTS: Hdm2-siRNA reduced the hdm2 protein as compared to the vehicle control and scrambled groups, and also increased the radiation-induced apoptosis especially in TE11 cells. The related dose reduction factors (DRFs) for the silenced TE1, TE8, and TE11 cells calculated to be 1.20, 1.30, and 2.75, respectively. CONCLUSION: Increasing radiosensitivity of tumor cells may be provided by silencing the oncogenes.

Radioprotective Effects of Amifostine and Lycopene on Human Peripheral Blood Lymphocytes In Vitro.

BACKGROUND: Radiation protection is a pivotal challenge for radiation workers employed in medical fields, industry, and also space professionals with an increasing role in medical diagnostic and therapeutic applications. Radioprotective effects of amifostine and lycopene and their ability to moderate the level of radiation-induced chromosomal aberrations were investigated using the dicentric chromosome assay. METHODS: Parallel human whole blood samples, pretreated with amifostine (250 µg/mL), lycopene (5 µg/mL), and/or their combinations were irradiated for 30 minutes with 60Co γ rays (1, 2, 3, and 4 Gy) with a dose rate of 98.46 cGy/min at SAD = 100 cm, in vitro and cocultured with control groups. The frequencies of chromosomal aberrations in the lymphocyte of the cells were analyzed. RESULTS: There were no apparent chromosome aberrations in controls and also in the drug-treated groups in the absence of radiation. Radiodrug treatment significantly decreased frequency of the radiation-induced chromosome aberrations compared with radiation alone (P < .05). Amifostine reduced the frequency of radiation-induced dicentrics by 15.8%, 21.9%, 4.5%, and 11.6%, with dose protection factors (DPFs) of 1.2 ± 0.02, 1.3 ± 0.1, 1.05 ± 0.03, and 1.13 ± 0.02. Lycopene reduced the frequency by 17.2%, 3.07%, 1.63%, and 16.6%, with DPFs of 1.21 ± 0.12, 1.03±0.05, 1.02±0.03 and 1.12±0.03. The combination treatment reduced the frequency by 28%, 24.9%, 9%, and 31.2%, with DPFs of 1.38 ± 0.06, 1.33 ± 0.06, 1.09 ± 0.02, and 1.45 ± 0.03 with radiation doses of 1, 2, 3, and 4 Gy, respectively. CONCLUSIONS: It can be suggested that pretreatment with combined amifostine and lycopene may reduce the extent of ionizing radiation damage in cells.

High Efficiency Apoptosis Induction in Breast Cancer Cell Lines by MLN4924/2DG Co-Treatment.

2-deoxy-D-Glucose (2DG) causes cytotoxicity in cancer cells by disrupting thiol metabolism. It is an effective component in therapeutic strategies. It targets the metabolism of cancer cells with glycolysis inhibitory activity. On the other hand, MLN4924, a newly discovered investigational small molecule inhibitor of NAE (NEDD8 activating enzyme), inactivates SCF E3 ligase and causes accumulation of its substrates which triggers apoptosis. Combination of these components might provide a more efficient approach to treatment. In this research, 2DG and MLN4924 were co-applied to breast cancer cells (MCF-7 and SKBR-3) and cytotoxic and apoptotic activity were evaluated the by Micro culture tetrazolium test (MTT), TUNEL and ELISA methods. Caspase3 and Bcl2 genes expression were evaluated by real time Q-PCR methods. The results showed that MLN4924 and MLN4924/2DG dose-dependently suppressed the proliferation of MCF7 and SKBR-3 cells. Cell survival of breast cancer cells exposed to the combination of 2DG/MLN4924 was decreased significantly compared to controls (p<0.05), while 2DG and MLN4924 alone had less pronounced effects on the cells. The obtained results suggest that 2DG/MLN4924 is much more efficient in breast cancer cell lines with enhanced cytotoxicity via inducing a apoptosis cell signaling gene, caspase-3.

Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy.

Doxorubicin (DOX) was introduced as an effective chemotherapeutic for a wide range of cancers but with some severe side effects especially on myocardia. 2-Deoxy-D-glucose (2DG) enhances the damage caused by chemotherapeutics and ionizing radiation (IR) selectively in cancer cells. We have studied the effects of 1µM DOX and 500 µM 2DG on radiation induced cell death, apoptosis and also on the expression levels of p53 and PTEN genes in T47D and SKBR3 breast cancer cells irradiated with 100, 150 and 200 cGy x-rays. DOX and 2DG treatments resulted in altered radiation-induced expression levels of p53 and PTEN genes in T47D as well as SKBR3 cells. In addition, the combination along with IR decreased the viability of both cell lines. The radiobiological parameter (D0) of T47D cells treated with 2DG/DOX and IR was 140 cGy compared to 160 cGy obtained with IR alone. The same parameters for SKBR3 cell lines were calculated as 120 and 140 cGy, respectively. The sensitivity enhancement ratios (SERs) for the combined chemo-radiotherapy on T47D and SKBR3 cell lines were 1.14 and 1.16, respectively. According to the obtained results, the combination treatment may use as an effective targeted treatment of breast cancer either by reducing the single modality treatment side effects.

Patient's Radiation Exposure in Coronary Angiography and Angioplasty: The Impact of Different Projections.

INTRODUCTION: We aimed to determine angiography projections with lower Dose Area Product (DAP) rate by measuring the mean DAP and fluoroscopy times in coronary angiography (CAG) and percutaneous coronary intervention (PCI) and calculating DAP rate in different projections. METHODS: DAP and fluoroscopy times were measured in all employed projections in real-time in 75 patients who underwent CAG or PCI by a single cardiologist in Madani Cardiovascular University Hospital (45 in CAG group and 30 in PCI group). DAP rate was calculated in both groups and in all projections. The projections with highest and lowest DAP rate were determined. RESULTS: Mean DAP was 436.73±315.85 dGy×cm(2) in CAG group and 643.26±359.58 dGy×cm(2) in PCI group. The projection 40° LAO/0° had the highest DAP rate in CAG group (28.98 dGy×cm(2)/ sec) and it was highest in 20° RAO/30° CR in PCI group (29.83 dGy×cm(2)/sec). The latter projection was also the most employed projection in PCI group. CONCLUSION: The amount of radiation dose in this study is in consistent with the previous reports. Specific angiographic projections expose patients to significantly higher radiation and they should be avoided and replaced by less irradiating projections whenever possible.

Influencing Factors on Reproducibility and Stability of MRI NIPAM Polymer Gel Dosimeter.

INTRODUCTION: At present, the polymer gel dosimeter is considered to be the best possible dosimeter for measuring 3-dimesional radiation dose distribution in radiotherapy. These gels are normally toxic; therefore, manufacturing, handling and discarding them require special attention. In order to find less toxic recipe, N-isopropyle acrylamide polymer gel (NIPAM) was introduced. In this study, the reproducibility and stability of NIPAM polymer gel dose response together with some influencing factors related to MR imaging were studied. METHODS: The NIPAM gel was prepared according to a method, described by senden et al in 2006. The gels were irradiated approximately 2 h after manufacturing and MR images of the gel were made 24 h after irradiation. The effects of different batches, post-irradiation time and the MRI room temperature on reproducibility and stability of polymer gel dose response were explored by analyzing the NMR response (R2) of the gel. RESULTS: : In a fixed temperature, the response of the gel was found to be stable 24 h after irradiation. The results showed that the dose response of the NIPAM polymer gel is highly reproducible in the same and different batches of chemical. No inhomogeneity was observed for magnetic fields in the specified position of measurements and 5°C fluctuation was recorded for MRI room temperature. CONCLUSION: Fluctuation in MRI room temperature necessitates that stringent attention to be paid to controlling the gel temperature at the time of imaging. The new formulation of polymer gel ensures stability of the gels' spatial resolution and makes it a suitable dosimeter for distant or remote measurements.

Dosimetric properties of a flattening filter-free 6-MV photon beam: a Monte Carlo study.

PURPOSE: The dosimetric features of an unflattened 6-MV photon beam of an Elekta SL-25 linac was calculated by the Monte Carlo (MC) method. MATERIAL AND METHODS: The head of the Elekta SL-25 linac was simulated using the MCNP4C MC code. The accuracy of the model was evaluated using measured dosimetric features, including depth dose values and dose profiles in a water phantom. The flattening filter was then removed, and beam dosimetric properties were calculated by the MC method and compared with those of the flattened photon beam. RESULTS: Our results showed a significant (twofold) increase in the dose rate for all field sizes. Also, the photon beam spectra for an unflattened beam were softer, which led to a steeper reduction in depth doses. The decrease in the out-of-field dose and increase in the contamination electrons and a buildup region dose were the other consequences of removing the flattening filter. CONCLUSION: Our study revealed that, for recent radiotherapy techniques, the use of multileaf collimators for beam shaping removing the flattening filter could offer some advantages, including an increased dose rate and decreased out-of-field dose.

Monte Carlo dose calculations for a 6-MV photon beam in a thorax phantom.

PURPOSE: In this study we evaluated the accuracy of the Monte Carlo (MC) and effective path length (EPL) methods for dose calculations in the inhomogeneous thorax phantom. MATERIALS AND METHODS: The Philips SL 75/5 linear accelerator head was modeled using the MCNP4C Monte Carlo code. An anatomic inhomogeneous thorax phantom was irradiated with a 6-MV photon beam, and the doses along points of the central axis of the beam were measured by a small ionization chamber. The central axis relative dose was calculated by the MCNP4C code and the EPL method in a conventional treatment planning system. The results of calculations and measurements were compared. RESULTS: For all measured points on the thorax phantom the results of the MC method were in agreement with the actual measurement (local difference was less than 2%). For the EPL method, the amount of error was dependent on the field size and the point location in the phantom. The maximum error was +19.5 and +26.8 for field sizes of 10 x 10 and 5 x 5 cm2 for lateral irradiation. CONCLUSION: Our study showed large, unacceptable errors for EPL calculations in the lung for both field sizes. The accuracy of the MC method was better than the recommended value of 3%. Thus, application of this method is strongly recommended for lung dose calculations, especially for small field sizes.