The future opportunities and remaining challenges in the application of nanoparticle-mediated hyperthermia combined with chemo-radiotherapy in cancer.

A pivotal cause of death in the modern world, cancer is an insidious pathology that should be diagnosed at an early stage for successful treatment. Development of therapeutic interventions with minimal invasiveness and high efficacy that can discriminate between tumor and normal cells is of particular interest to the clinical science, as they can enhance patient survival. Nanoparticles are an invaluable asset that can be adopted for development of such diagnostic and therapeutic modalities, since they come in very small sizes with modifiable surface, are highly safe and stable, and can be synthesized in a controlled fashion. To date, different nanoparticles have been incorporated into numerous modalities such as tumor-targeted therapy, thermal therapy, chemotherapy, and radiotherapy. This review article seeks to deliver a brief account of recent advances in research and application of nanoparticles in hyperthermia-based cancer therapies. The most recent investigations are summarized to highlight the latest advances in the development of combined thermo-chemo-radiotherapy, along with the challenges associated with the application of nanoparticles in cancer therapy. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Nonlinear optical response of cancer cells following conventional and nano-technology based treatment strategies: Results of chemo-, thermo- and radiation therapies.

BACKGROUND: Although traditional treatments are able to increase cancer survival rate, undesirable impact on off-target tissues are considered a limitation of these approaches. Nanotechnology-based treatments have been proposed as a possible option to enhance targeting., Further,current methods for evaluating cellular damage, are time consuming, highly dependent on the operator skills, and expensive. The aim of this study was to evaluate the capability of nonlinear optical response of cells to determine cellular damages during conventional and nano-technology based treatments. METHODS: Three different cancer cell lines, CT26, KB, and MCF-7 were used in this study. The alginate hydrogel co-loaded with cisplatin and Au nanoparticle (ACA) nanocomplex and gold-coated iron oxide nanoparticle (Au@IONP) were considered for chemo- and chemo-photothermal therapies, and thermo-radiation therapy, respectively. The sign and value of nonlinear optical absorption coefficient and imaginary part of the third-order nonlinear susceptibility of cells were computed. MTT assay was utilized as a reference method. RESULTS: The value of nonlinear optical indices increased with increasing cellular damage and cell death. The linear regression analysis indicated high correlation between nonlinear optical indices and MTT results, in all treatments. CONCLUSION: The nonlinear optical indices are robust from confounding factors, namely treatment approach (traditional and nano-technology based), treatment modality (chemotherapy, thermotherapy, photothermal therapy, and radiation therapy), and cell types. Nonlinear optical properties of cells can be used as a rapid estimation method for cell damage, at the nanoscale level.

Cardioprotective Effects of Mebudipine in a Rat Model of Doxorubicin-Induced Heart Failure.

Background: Mebudipine, a dihydropyridine calcium-channel blocker (CCB), shows greater time- and voltage-dependent inhibitory effects than nifedipine. Its significant negative chronotropic effects without having considerable negative inotropic properties may make it a suitable candidate for the pharmacotherapy of heart failure (HF). This study aimed to investigate the possible beneficial action of mebudipine in a rat model of HF. Methods: The present study carried out in the Department of Pharmacology at the Iran University of Medical Sciences during the years of 2009-2011. An experimental model of HF was induced in male Wistar rats using doxorubicin (DOX). The rats were divided into five groups with seven animals in each group: normal control group, DOX-induced HF control groups, and treatment groups. The animals were administered DOX for 15 days. A consistent deterioration occurred after a four-week rest period. The animals were then treated with intraperitoneal mebudipine (0.5 mg/kg) and intraperitoneal amlodipine (0.35 mg/kg), as well as an equal volume of distilled water for 15 days. The plasma levels of big endothelin-1 (BET-1), creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as the clinical status (heart rate and blood pressure), were assessed before and after treatment. Statistical analysis was performed with SPSS software using parametric and nonparametric ANOVA. Results: Mebudipine and amlodipine reversed the increased plasma BET-1 values in the treated animals when compared with the HF control group (0.103 and 0.112 vs 0.231 pg/mL, respectively). The increased plasma levels of AST, ALT, CK-MB, and LDH were also reversed in the HF animals that received mebudipine or amlodipine. Conclusion: The administration of mebudipine to HF animals, akin to amlodipine, palliated the clinical and biochemical signs of the disease in the present study. The abstract was presented in the Iranian Congress of Physiology and Pharmacology as a poster and published in the Scientific Information Database as a supplement (2015; Vol 22).

Multifunctional Theranostic Graphene Oxide Nanoflakes as MR Imaging Agents with Enhanced Photothermal and Radiosensitizing Properties.

The integration of multiple therapeutic and diagnostic functions into a single nanoplatform for image-guided cancer therapy has been an emerging trend in nanomedicine. We show here that multifunctional theranostic nanostructures consisting of superparamagnetic iron oxide (SPIO) and gold nanoparticles (AuNPs) scaffolded within graphene oxide nanoflakes (GO-SPIO-Au NFs) can be used for dual photo/radiotherapy by virtue of the near-infrared (NIR) absorbance of GO for photothermal therapy (PTT) and the Z element radiosensitization of AuNPs for enhanced radiation therapy (RT). At the same time, this nanoplatform can also be detected by magnetic resonance (MR) imaging because of the presence of SPIO NPs. Using a mouse carcinoma model, GO-SPIO-Au NF-mediated combined PTT/RT exhibited a 1.85-fold and 1.44-fold higher therapeutic efficacy compared to either NF-mediated PTT or RT alone, respectively, resulting in a complete eradication of tumors. As a sensitive multifunctional theranostic platform, GO-SPIO-Au NFs appear to be a promising nanomaterial for enhanced cancer imaging and therapy.

Magneto-plasmonic nanoparticle mediated thermo-radiotherapy significantly affects the nonlinear optical properties of treated cancer cells.

In order to determine the level of cell damage in cancerous cells, current cytogenetic tests have limitations such as time consumption and high cost. The aim of this study was to demonstrate the ability of nonlinear refractive (NLR) index as a predictor of breast cell damage caused by magneto-plasmonic nanoparticle based thermo-radiotherapy treatments. MCF-7 breast cancer cells were subjected individually to the treatment of radiation, radio-frequency (RF) hyperthermia, and radiation + RF hyperthermia. These treatments were repeated in the presence of magneto-plasmonic nanoparticle (Au@IONP). The MTT and nonlinear optical assays were used to evaluate the damage induced by different treatment modalities. The results of MTT were correlated with Z-scan, as the magnitude of nonlinear refraction increased with higher intensity of induced cell damages. In this regard, the lowest cell viability (38 %,) and highest magnitude of NLR index (+28.12) were obtained from combination of radiation (at 4 Gy dose) and hyperthermia treatment in the presence of nanoparticles. The proposed optical index (NLR) indicated high capability and can be used as an auxiliary tool to monitor induced cell damage during different treatment strategies. This technique is fast, noninvasive, does not impose cost, and finally does not waste materials.

Insights into Nano-Photo-Thermal Therapy of Cancer: The Kinetics of Cell Death and Effect on Cell Cycle.

BACKGROUND: Despite considerable advances in nano-photo-thermal therapy (NPTT), there have been a few studies reporting in-depth kinetics of cell death triggered by such a new modality of cancer treatment. OBJECTIVE: In this study, we aimed to (1) investigate the cell death pathways regulating the apoptotic responses to NPTT; and (2) ascertain the effect of NPTT on cell cycle progression. METHODS: Folate conjugated gold nanoparticle (F-AuNP) was firstly synthesized, characterized and then assessed to determine its potentials in targeted NPTT. The experiments were conducted on KB nasopharyngeal cancer cells overexpressing folate receptors (FRs), as the model, and L929 normal fibroblast cells with a low level of FRs, as the control. Cytotoxicity was evaluated by MTT assay and the cell death mode (i.e., necrosis or apoptosis) was determined through AnnexinV/FITC-propidium iodide staining. Next, the gene expression profiles of some key apoptotic factors involved in the mitochondrial signaling pathway were investigated using RT-qPCR. Finally, cell cycle phase distribution was investigated at different time points post NPTT using flow cytometric analysis. RESULTS: The obtained results showed that KB cell death following targeted NPTT was greater than that observed for L929 cells. The majority of KB cell death following NPTT was related to apoptosis. RT-qPCR analysis indicated that the elevated expression of Bax along with the depressed expression of Bcl-xL, Survivin and XIAP may involve in the regulation of apoptosis in response to NPTT. Flow cytometric analysis manifested that 16-24 hours after NPTT, the major proportion of KB cells was in the most radiosensitive phases of the cell cycle (G2/M). CONCLUSION: This study extended the understanding of the signaling pathway involved in the apoptotic response to NPTT. Moreover, the potential effect of NPTT on sensitizing cancer cells to subsequent radiation therapy was highlighted.

Gold nanoparticles promote a multimodal synergistic cancer therapy strategy by co-delivery of thermo-chemo-radio therapy.

Multimodal cancer therapy has become a new trend in clinical oncology due to potential generation of synergistic therapeutic effects. Herein, we propose a multifunctional nanoplatform comprising alginate hydrogel co-loaded with cisplatin and gold nanoparticles (abbreviated as ACA) for triple combination of photothermal therapy, chemotherapy and radiotherapy (thermo-chemo-radio therapy). The therapeutic potential of ACA was assessed in combination with 532 nm laser and 6 MV X-ray against KB human mouth epidermal carcinoma cells. The results demonstrated that tri-modal thermo-chemo-radio therapy using ACA induced a superior anticancer efficacy than mono- or bi-modality treatments. The intracellular reactive oxygen species (ROS) level in KB cells treated with tri-modal therapy was increased by 4.4-fold compared to untreated cells. The gene expression analysis demonstrated the up-regulation of Bax pro-apoptotic factor (by 4.5-fold) and the down-regulation of Bcl-2 anti-apoptotic factor (by 0.3-fold). The massive cell injury and the appearance of morphological characteristics of apoptosis were also evident in the micrograph of KB cells caused by thermo-chemo-radio therapy. Therefore, ACA nanocomplex can be offered as a promising platform to combine photothermal therapy, chemotherapy and radiotherapy, thereby affording an opportunity for combating chemo- and radio-resistant tumors.

MRI-based numerical modeling strategy for simulation and treatment planning of nanoparticle-assisted photothermal therapy.

Nanoparticle-assisted photothermal therapy (NPTT) has recently emerged as a promising alternative to traditional thermal therapy methods. Computational modeling for simulation and treatment planning of NPTT seems to be essential for clinical translation of this modality. Non-invasive identification of nanoparticle distribution within the tissue is a key perquisite for accurate prediction of NPTT in real conditions. In the present study, we have developed a magnetic resonance imaging (MRI)-based numerical modeling strategy for simulation and treatment planning of NPTT. To this end, we have utilized the core-shell γ-Fe2O3@Au nanoparticle comprising a gold layer with plasmonic properties and a magnetic core that enables to track the location of this structure via MRI. The map of nanoparticle distribution in the tumor derived from T2-weighted MR image was imported into a finite element simulation software, and Pennes bioheat equation and Arrhenius damage model were applied to simulate the temperature and damage distributions, respectively. The validation of the model developed herein was assessed by monitoring the superficial and the central temperature variations of the tumor in experiment. Both the numerical modeling and experimental study proved that a localized heating and then a focused damage could be achieved due to nanoparticle inclusion. There is quite satisfactory agreement between the numerical and experimental results. The model developed in this study has a good capability to be used as a promising planning method for NPTT of cancer.

Combined thermo-chemotherapy of cancer using 1 MHz ultrasound waves and a cisplatin-loaded sonosensitizing nanoplatform: an in vivo study.

PURPOSE: The aim of the present study was to develop a new strategy for combined thermo-chemotherapy of cancer. For this purpose, we used ultrasound waves [1 MHz; 1 W/cm2; 10 min] in combination with a sonosensitizing nanoplatform, named ACA, made of alginate co-loaded with cisplatin and gold nanoparticles (AuNPs). METHODS: Various combinatorial treatment regimens consisting of ultrasound, AuNPs, cisplatin, and ACA nanoplatform were studied in vivo. The CT26 colon adenocarcinoma cell line was used for tumor induction in BALB/c mice. During the ultrasound exposure, we monitored the temperature variations in each treatment group using infrared thermal imaging. Furthermore, tumor metabolism was assessed by [18F]FDG (2-deoxy-2-[18F]fluoro-D-glucose)-positron emission tomography (PET) imaging. RESULTS: The combination of ultrasound with nanoplatform showed an improved therapeutic efficacy than free cisplatin or ultrasound alone. It was revealed that the examined thermo-chemotherapy protocol has the potential to intensively decrease the metabolic activity of CT26 tumors. CONCLUSIONS: The data obtained in this study confirmed a potent anti-tumor efficacy caused by the ACA nanoplatform and ultrasound combination. It may provide a beneficial cancer therapy strategy in which the thermal and mechanical effects of ultrasound can intensify the therapeutic ratio of conventional chemotherapy methods.

Simulation-guided photothermal therapy using MRI-traceable iron oxide-gold nanoparticle.

Despite the immense benefits of nanoparticle-assisted photothermal therapy (NPTT) in cancer treatment, the limited method and device for detecting temperature during heat operation significantly hinder its overall progress. Development of a pre-treatment planning tool for prediction of temperature distribution would greatly improve the accuracy and safety of heat delivery during NPTT. Reliable simulation of NPTT highly relies on accurate geometrical model description of tumor and determining the spatial location of nanoparticles within the tissue. The aim of this study is to develop a computational modeling method for simulation of NPTT by exploiting the theranostic potential of iron oxide­gold hybrid nanoparticles (IO@Au) that enable NPTT under magnetic resonance imaging (MRI) guidance. To this end, CT26 colon tumor-bearing mice were injected with IO@Au nanohybrid and underwent MR imaging. The geometrical model description of tumor and nanoparticle distribution map were obtained from MR image of the tumor and involved in finite element simulation of heat transfer process. The experimental measurement of tumor temperature confirmed the validity of the model to predict temperature distribution. The constructed model can help to predict temperature distribution during NPTT and then allows to optimize the heating protocol by adjusting the treatment parameters prior to the actual treatment operation.

Iron oxide-gold core-shell nano-theranostic for magnetically targeted photothermal therapy under magnetic resonance imaging guidance.

Recent efforts in the area of photothermal therapy (PTT) follow two important aims: (i) selective targeting of plasmonic nanoparticles to the tumor and (ii) real-time guidance of PTT operation through employing multimodal imaging modalities. In the present study, we utilized a multifunctional theranostic nanoplatform constructed from iron (III) oxide-gold (Fe2O3@Au) core-shell nanoparticles to fulfill these aims. The Au shell exhibits surface plasmon resonance, a property that is exploited to realize PTT. The magnetic core enables Fe2O3@Au to be employed as a magnetic resonance imaging (MRI) contrast agent. Furthermore, the magnetic core has the potential to establish a magnetic drug targeting strategy through which Fe2O3@Au can be directed to the tumor site by means of magnetic field. To test these potentials, Balb/c mice bearing CT26 colorectal tumor model were intravenously injected with Fe2O3@Au. Immediately after injection, a magnet was placed on the tumor site for 3 h to concentrate nanoparticles, followed by the near infrared (NIR) laser irradiation. MRI study confirmed the accumulation of nanoparticles within the tumor due to T2 enhancement capability of Fe2O3@Au. The in vivo thermometry results demonstrated that the tumors in magnetic targeting group had a significantly higher temperature elevation rate upon NIR irradiation than non-targeted group (~ 12 °C vs. 8.5 °C). The in vivo antitumor assessment revealed that systemic injection of Fe2O3@Au in combination with magnetic targeting and NIR irradiation resulted in complete remission of tumor growth. Therefore, Fe2O3@Au can establish a targeted PTT strategy for efficient eradication of tumor cells under the guidance of MRI.

A thermo-responsive alginate nanogel platform co-loaded with gold nanoparticles and cisplatin for combined cancer chemo-photothermal therapy.

The current interest in cancer research is being shifted from individual therapy to combinatorial therapy. In this contribution, a novel multifunctional nanoplatform comprising alginate nanogel co-loaded with cisplatin and gold nanoparticles (AuNPs) has been firstly developed to combine photothermal therapy and chemotherapy. The antitumor efficacy of the as-prepared nanocomplex was tested against CT26 colorectal tumor model. The nanocomplex showed an improved chemotherapy efficacy than free cisplatin and caused a significantly higher tumor inhibition rate. The in vivo thermometry results indicated that the tumors treated with the nanocomplex had faster temperature rise rate under 532 nm laser irradiation and received dramatically higher thermal doses due to optical absorption properties of AuNPs. The combined action of chemo-photothermal therapy using the nanocomplex dramatically suppressed tumor growth up to 95% of control and markedly prolonged the animal survival rate. Moreover, tumor metabolism was quantified by [18F]FDG (2-deoxy-2-[18F]fluoro-D-glucose)-positron emission tomography (PET) imaging and revealed that the combination of the nanocomplex and laser irradiation have the potential to eradicate microscopic residual tumor to prevent cancer relapse. Therefore, the nanocomplex can afford a potent anticancer efficacy whereby heat and drug can be effectively deliver to the tumor, and at the same time the high dose-associated side effects due to the separate application of chemotherapy and thermal therapy could be potentially reduced.

Ultrastructural and optical characteristics of cancer cells treated by a nanotechnology based chemo-photothermal therapy method.

The current chemotherapy method demonstrates the need for improvement in terms of efficacy and safety. Given the beneficiary effect of heat in combination with chemotherapy, the purpose of this study is to develop a multifunctional nanoplatform by co-incorporating gold nanoparticles (AuNPs) as photothermal agent and cisplatin as anticancer drug into alginate hydrogel (named as ACA) to enable concurrent thermo-chemotherapy. The in vitro cytotoxicity experiment showed that the as-developed nanocomplex was able to induce greater cytotoxicity in KB human nasopharyngeal cancer cells compared to free cisplatin at the same concentration. Moreover, the interaction of ACA and laser irradiation acted synergistically and resulted in higher cell death rate compared to separate application of photothermal therapy and chemotherapy. The micrograph of KB cells also revealed that ACA was able to selectively accumulate into the mitochondria, so that laser irradiation of KB cells pre-treated with ACA resulted in intensive morphological damages such as plasma membrane disruption, chromatin condensation, autophagic vacuoles formation and organelle degeneration. Moreover, the sign and magnitude of optical nonlinear refractive index measured by Z-scan technique was shown to be significantly altered in cells exposed to ACA with and without laser irradiation. Consequently, the nanocomplex developed herein could be a promising platform to combine photothermal therapy and chemotherapy effectively, thereby achieving synergistic therapeutic outcome.

Reducing urinary oxalate by simultaneous using Sankol herbal drop with oxalate-degrading bacteria.

BACKGROUND AND OBJECTIVES: Oxalate degrading bacteria and herbal extracts are new strategy for reducing hyperoxaluria. In Iranian traditional medicine, Sankol oral drop is widely used as an antispasmodic drug to reduce stones from urinary tract. This study aimed to evaluate the synergistic effect of oxalate-degrading bacteria and Sankol oral drop in reducing urinary oxalate in rat model. MATERIALS AND METHODS: Several bacterial strains, including Lactobacillus (4), Bifidobacterium (2) and L. paracasei (2) (very strong in degrading oxalate in vitro) were used in this study. Male Wistar rats were divided into 6 groups (n = 6). The rats of Group I received normal diet and drinking water + 60% ethanol (positive group). Groups II (negative group), III, IV, V, and VI rats received diet containing ethylene glycol (3%) for 30 days. Groups III rats received Sankol with minimum concentration (7.5 ml/kg/b.w), Group IV rats received Sankol with maximum concentration (9 ml/kg/b.w), Group V rats received Sankol with minimum concentration + probiotic, and Group VI rats received Sankol with maximum concentration + probiotic for 30 days. RESULTS: Treatment with Sankol (maximum concentration) and oxalate-degrading probiotic bacteria significantly reduced urinary oxalate (P = .0001). At the end of treatment period, rats in groups II (negative control) showed a high score of CaOx crystal, while rats in VI groups did not show any CaOx crystal. CONCLUSION: This is the first study on the simultaneous use of Sankol herbal drop and oxalate-degrading probiotic bacteria that showed a significant reduction in urinary oxalate.

Gold-coated iron oxide nanoparticles trigger apoptosis in the process of thermo-radiotherapy of U87-MG human glioma cells.

Recently, gold-coated iron oxide nanoparticles (Au@IONPs) have received a great deal of attention in cancer therapy. In this in vitro study we aimed to investigate the anti-cancer effects of Au@IONPs core-shell nanoparticles when applied in thermo-radiotherapy. Moreover, we investigated the level of apoptosis induced in U87-MG human glioma cells after receiving a combinatorial treatment regimen (Au@IONPs + hyperthermia + radiotherapy). Firstly, the Au@IONPs nanocomplex was prepared and characterized. Cytotoxicity of the nanoparticles (various concentrations; 4 h incubation time) was investigated on U87-MG cells and finally the concentrations of 10 and 15 µg/mL were selected for further studies. After incubation of the cells with nanoparticles, they received hyperthermia (43 °C; 1 h) and then were immediately exposed to 6 MV X-ray (2 and 4 Gy). Following the treatments, MTT assay was used to analyze cell viability and flow cytometry was used to determine the level of apoptosis in each treatment group. The results revealed that nanoparticles have no significant cytotoxicity at concentrations lower than 10 µg/mL. Also, we observed that nanoparticles are able to enhance the cytotoxic effect of hyperthermia and radiation. The major mode of cell death was apoptosis when nanoparticles, hyperthermia and radiation were concomitantly applied to cancer cells. In conclusion, Au@IONP nanoparticle can be considered as a good thermo-radio-sensitizer which triggers significant levels of apoptosis in cancer therapy. In this in vitro study, we report the anti-cancer effects of gold-coated iron oxide nanoparticles (Au@IONPs) when applied in thermo-radiotherapy.

Selective apoptosis induction in cancer cells using folate-conjugated gold nanoparticles and controlling the laser irradiation conditions.

In this study, we explained in detail a targeted nano-photo-thermal therapy (NPTT) method to induce selective apoptosis in cancer cells. Folate-conjugated gold nanoparticles (F-AuNPs) were synthesized by tailoring the surface of AuNPs with folic acid to enhance the specificity of NPTT. KB cancer cells, as a folate receptor over-expressing cell line, and L929 normal cells with low level of folate receptors were incubated with the synthesized F-AuNPs and then irradiated with various laser intensities and exposure durations. Following various regimes of NPTT, we assessed the level of cell viability and the ratio of apoptosis/necrosis. No significant cytotoxicity was observed for both cell lines at concentrations up to 40 µM of F-AuNPs. Moreover, no significant cell lethality occurred for various laser irradiation conditions. The viability of KB and L929 cells incubated with F-AuNPs (40 µM; 6 h) and then irradiated by laser (1 W/cm2; 2 min) was 57 and 83%, respectively. It was also demonstrated that the majority of cancer cell death is related to apoptosis (41% apoptosis of 43% overall cell death). In this process of F-AuNPs based NPTT, it may be concluded that the main factor determining whether a cell dies due to apoptosis or necrosis depends on laser irradiation conditions. In this study, we explained in detail a targeted nano-photo-thermal therapy (NPTT) method to induce selective apoptosis in cancer cells.

Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats.

Hepatotoxicity is one of the major side effects of methotrexate (MTX), which restricts the clinical use of this drug. Berberine (BBR) is a natural compound with multiple pharmacological activities such as antioxidant, antiapoptotic and anti-inflammatory effects. In this study, the effect of BBR on MTX-induced hepatotoxicity was studied. A total number of 28 male Wistar rats were randomly divided into four experimental groups. Rats were pretreated with BBR orally with dose of 100mg/kg for 10 consecutive days and MTX (20mg/kg, intraperitoneally) was administrated on the 9th day. Then on day 11, blood samples were collected to determine serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The extracted livers were used for histological examination, biochemical assays and real time PCR studies. Malondialdehyde (MDA), glutathione (GSH), protein carbonyl (PC), nitric oxide (NO) levels, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed in hepatic tissue. In addition, the expression of SOD and PGx was measured using real-time PCR method in hepatic tissue. Results showed that MTX administration significantly increases AST, ALT and ALP levels (all p<0.001). It also, increases MDA, PC, NO levels and MPO activity (p<0.001, p<0.01, p<0.05 and p<0.01 respectively). Moreover, MTX decreases hepatic GSH level, SOD, GPx and CAT activities (all p<0.001). Pre-treatment with BBR for 10days prevented some of these changes. Serum levels of AST and ALT decreased (all p<0.001). Hepatic MDA level decreased (p<0.001) and GSH level as well as GPx activity increased (p<0.05 and p<0.01 respectively). Our results indicated that BBR might be useful for prevention of the hepatotoxicity induced by MTX via ameliorative effects on biochemical and oxidative stress indices.

Folic acid conjugated PEG coated gold-iron oxide core-shell nanocomplex as a potential agent for targeted photothermal therapy of cancer.

This study reports the synthesis and characterization of poly(ethylene glycol) coated gold@iron oxide core-shell nanoparticles conjugated with folic acid (FA-PEG-Au@IONP). Also, targeted therapeutic properties of such a nanocomplex were studied on human nasopharyngeal carcinoma cell line KB and human breast adenocarcinoma cell line MCF-7 in vitro. The synthesized nanocomplex was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), UV-Vis spectroscopy, vibrating sample magnetometry (VSM), and Fourier transform infrared (FTIR) spectroscopy. The photothermal effects of nanocomplex on both KB and MCF-7 cell lines were studied. Cell death and apoptosis were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry using an annexin V-fluorescein isothiocyanate/propidiumiodide apoptosis detection kit. It was found that nanocomplex is spherical in shape and its size is approximately 60 nm. UV-vis spectrum showed that nanocomplex has appropriate absorption near infrared region. FTIR spectra obtained from nanocomplex before and after conjugation with FA confirmed the formation of folate conjugated nanocomplex. Significant cell lethality was observed for KB (∼62%) and MCF-7 (∼33%) cells following photothermal therapy. Also, it was found that majority of the cell deaths were related to apoptosis process. It can be concluded that, the synthesized nanocomplex is an effective and promising multifunctional nanoplatform for targeted photothermal therapy of cancer.

Gold-coated magnetic nanoparticle as a nanotheranostic agent for magnetic resonance imaging and photothermal therapy of cancer.

Because of their great scientific and technological potentials, iron oxide nanoparticles (IONPs) have been the focus of extensive investigations in biomedicine over the past decade. Additionally, the surface plasmon resonance effect of gold nanoparticles (AuNPs) makes them a good candidate for photothermal therapy applications. The unique properties of both IONPs (magnetic) and AuNPs (surface plasmon resonance) may lead to the development of a multi-modal nanoplatform to be used as a magnetic resonance imaging (MRI) contrast agent and as a nanoheater for photothermal therapy. Herein, core-shell gold-coated IONPs (Au@IONPs) were synthesized and investigated as an MRI contrast agent and as a light-responsive agent for cancer photothermal therapy.The synthesized Au@IONPs were characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta potential analysis. The transverse relaxivity (r 2) of the Au@IONPs was measured using a 3-T clinical MRI scanner. Through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the cytotoxicity of the Au@IONs was examined on a KB cell line, derived from the epidermal carcinoma of a human mouth. Moreover, the photothermal effects of Au@IONPs in the presence of a laser beam (λ = 808 nm; 6.3 W/cm2; 5 min) were studied.The results show that the Au@IONPs are spherical with a hydrodynamic size of 33 nm. A transverse relaxivity of 95 mM-1 S-1 was measured for the synthesized Au@IONPs. It is evident from the MTT results that no significant cytotoxicity in KB cells occurs with Au@IONPs. Additionally, no significant cell damage induced by the laser is observed. Following the photothermal treatment using Au@IONPs, approximately 70% cell death is achieved. It is found that cell lethality depended strongly on incubation period and the Au@IONP concentration.The data highlight the potential of Au@IONPs as a dual-function MRI contrast agent and photosensitizer for cancer photothermal therapy.

Folate-conjugated gold nanoparticle as a new nanoplatform for targeted cancer therapy.

Conventional cancer treatment methods suffer from many limitations such as non-specificity and low efficacy in discrimination between healthy and cancer cells. Recent developments in nanotechnology have introduced novel and smart therapeutic nanomaterials that basically take advantage of various targeting approaches. Targeted nanomaterials selectively bind to the cancer cells and affect them with minor effects on healthy cells. Folic acid (folate) is an essential molecule in DNA synthesis pathway which is highly needed for cancer cell duplication. Some certain cancer cells overexpress folate receptors higher than normal cells, and this fact is the basis of folate targeting strategy. There are many publications reporting various folate conjugated nanomaterials among which folate-conjugated gold nanoparticles hold great promises in targeted cancer therapy. Gold nanoparticles have been identified as promising candidates for new cancer therapy modalities because of biocompatibility, easy synthesis and functionalization, chemo-physical stability, and optical tunable characteristics. In the last decade, there has been a significant explosion in gold nanoparticles research, with a rapid increase in publications related to the area of biomedicine. Although there are many reports published on "gold nanoparticles" and "folate targeting," there are a few reports on "folate-conjugated gold nanoparticles" in biomedical literature. This paper intends to review and illustrate the recent advances in biomedicine which have been designed on the basis of folate-conjugated gold nanoparticles.