A 2D nanotheranostic platform based on graphene oxide and phase-change materials for bimodal CT/MR imaging, NIR-activated drug release, and synergistic thermo-chemotherapy.

Recent years have seen considerable progress in the development of nanomedicine by the advent of 2D nanomaterials serving as ideal platforms to integrate multiple theranostic functions. We synthesized multifunctional stimuli-responsive 2D-based smart nanocomposites (NCs), comprising gold nanoparticles (AuNPs) and superparamagnetic iron oxides (SPIOs) scaffolded within graphene oxide (GO) nanosheets, coated with doxorubicin (DOX)-loaded 1-tetradecanol (TD), and further modified with an alginate (Alg) polymer. TD is a phase-change material (PCM) that confines DOX molecules to the GO surface and melts when the temperature exceeds its melting point (Tm=39 °C), causing the PCM to release its drug payload. By virtue of their strong near-infrared (NIR) light absorption and high photothermal conversion efficiency, GO nanosheets may enable photothermal therapy (PTT) and activate a phase change to trigger DOX release. Upon NIR irradiation of NCs, a synergistic thermo-chemotherapeutic effect can be obtained by GO-mediated PTT, resulting an accelerated and controllable drug release through the PCM mechanism. The biodistribution of these NCs could also be imaged with computed tomography (CT) and magnetic resonance (MR) imaging in vitro and in vivo. Hence, this multifunctional nanotheranostic platform based on 2D nanomaterials appears a promising candidate for multimodal image-guided cancer therapy.

Fe3O4@Au core-shell hybrid nanocomposite for MRI-guided magnetic targeted photo-chemotherapy.

The combination of multiple therapeutic and diagnostic functions is fast becoming a key feature in the area of clinical oncology. The advent of nanotechnology promises multifunctional nanoplatforms with the potential to deliver multiple therapeutics while providing diagnostic information simultaneously. In this study, novel iron oxide-gold core-shell hybrid nanocomposites (Fe3O4@Au HNCs) coated with alginate hydrogel carrying doxorubicin (DOX) were constructed for targeted photo-chemotherapy and magnetic resonance imaging (MRI). The magnetic core enables the HNCs to be detected through MRI and targeted towards the tumor using an external magnetic field, a method known as magnetic drug targeting (MDT). The Au shell could respond to light in the near-infrared (NIR) region, generating a localized heating for photothermal therapy (PTT) of the tumor. The cytotoxicity assay showed that the treatment of CT26 colon cancer cells with the DOX-loaded HNCs followed by laser irradiation induced a significantly higher cell death as opposed to PTT and chemotherapy alone. The in vivo MRI study proved MDT to be an effective strategy for targeting the HNCs to the tumor, thereby enhancing their intratumoral concentration. The antitumor study revealed that the HNCs can successfully combine chemotherapy and PTT, resulting in superior therapeutic outcome. Moreover, the use of MDT following the injection of HNCs caused a more extensive tumor shrinkage as compared to non-targeted group. Therefore, the as-prepared HNCs could be a promising nanoplatform for image-guided targeted combination therapy of cancer.

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.

Optimal scheduling of the nanoparticle-mediated cancer photo-thermo-radiotherapy.

Maximal synergistic effect between photothermal therapy and radiotherapy (RT) may be achieved when the interval between these two modalities is optimal. In this study, we tried to determine the optimal schedule of the combined regime of RT and nano-photothermal therapy (NPTT), based on the cell cycle distribution and kinetics of cell death. To this end, alginate-coated iron oxide-gold core-shell nanoparticles (Fe3O4@Au/Alg NPs) were synthesized, characterized, and their photo-radio sensitization potency was evaluated on human nasopharyngeal cancer KB cells. Our results demonstrated that synthesized NPs have a good potential in radiotherapy and near-infrared (NIR) photothermal therapy. However, results from flow cytometry analysis indicated that a major portion of KB cells were accumulated in the most radiosensitive phases of cell cycle (G2/M) 24 h after NPTT. Moreover, the maximal synergistic anticancer efficacy (12.3% cell viability) was observed when RT was applied 24 h following the administration of NPTT (NPs [30 µg/mL, 4 h incubation time] + Laser [808 nm, 1 W/cm2, 5 min] + RT [6 Gy]). It is noteworthy that apoptosis was the dominant cell death pathway in the group of cells treated by combination of NPTT and RT. This highly synergistic anticancer efficacy provides a mechanistic basis for Fe3O4@Au/Alg NPs-mediated photothermal therapy combined with RT. Knowing such a basis is helpful to promote novel nanotechnology cancer treatment strategies.

Recent advances in ultrasound-triggered drug delivery through lipid-based nanomaterials.

The high prescribed dose of anticancer drugs and their resulting adverse effects on healthy tissue are significant drawbacks to conventional chemotherapy (CTP). Ideally, drugs should have the lowest possible degree of interaction with healthy cells, which would diminish any adverse effects. Therefore, an ideal scenario to bring about improvements in CTP is the use of technological strategies to ensure the efficient, specific, and selective transport and/or release of drugs to the target site. One practical and feasible solution to promote the efficiency of conventional CTP is the use of ultrasound (US). In this review, we highlight the potential role of US in combination with lipid-based carriers to achieve a targeted CTP strategy in engineered smart drug delivery systems.

Triple combination of heat, drug and radiation using alginate hydrogel co-loaded with gold nanoparticles and cisplatin for locally synergistic cancer therapy.

Although multimodal cancer therapy has shown superior antitumor efficacy in comparison to individual therapy due to the potential generation of synergistic interactions among the treatments, its clinical usage is highly hampered by systemic dose-limiting toxicities. Herein, we developed a multi-responsive nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and gold nanoparticles (AuNPs) (abbreviated as ACA) to combine chemotherapy, radiotherapy (RT) and photothermal therapy. The nanocomplex markedly improved the efficiency of drug delivery where ACA resulted in noticeably higher tumor growth inhibition than free cisplatin. The tumor treated with ACA showed an increased heating rate upon 532 nm laser irradiation, indicating the photothermal conversion ability of the nanocomplex. While RT alone resulted in slight tumor growth inhibition, thermo-chemo therapy, chemoradiation therapy and thermo-radio therapy using ACA dramatically slowed down the rate of tumor growth. Upon 532 nm laser and 6 MV X-ray, the nanocomplex could enable a trimodal thermo-chemo-radio therapy that yielded complete tumor regression with no evidence of relapse during the 90-days follow up period. The results of this study demonstrated that the incorporation of AuNPs and cisplatin into alginate hydrogel network can effectively combine chemotherapy, RT and photothermal therapy to achieve a locally synergistic cancer therapy.

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.

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.

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.

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.

Enhancement of chemoradiation by co-incorporation of gold nanoparticles and cisplatin into alginate hydrogel.

Nonspecificity and high toxicity limit the treatment efficacy and safety of chemoradiation therapy. Effective tumor targeting of anticancer drugs and radiosensitizing agents is highly desirable to amplify the efficacy of this standard cancer therapy approach. To achieve this goal, we exploited the synergy of cisplatin and gold nanoparticles (AuNPs) co-loaded into alginate hydrogel network, forming so-called ACA nanocomplex, and X-ray radiation. Cisplatin is a commonly used anticancer agent, and at the same time, along with AuNPs could function as radiosensitizers to enhance the radiation-induced damages through various pathways. The ACA nanocomplex improved the therapeutic efficiency of standard chemotherapy and yielded 79% growth inhibition in CT26 colon adenocarcinoma tumor after 28 days, which was significantly higher than that of 9% for free cisplatin administration. Moreover, the combination of ACA nanocomplex with 6 MV X-ray dramatically suppressed tumor growth up to 95%, showing 51% enhancement in antitumor activity compared to standard chemoradiation. The nanocomplex developed herein holds the promise to promote the efficiency of standard chemoradiation while maintaining the patient's safety through reducing the clinically administered doses of anticancer drug and X-ray. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2658-2663, 2019.

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.

Folate-modified and curcumin-loaded dendritic magnetite nanocarriers for the targeted thermo-chemotherapy of cancer cells.

A novel multifunctional nanoplatform constructed from methoxy-PEGylated poly(amidoamine) (PAMAM) generation 3 dendrimers with superparamagnetic iron oxide nanoparticles (SPIONs) entrapped in their core, containing curcumin as the payload drug and folic acid (folate) as the targeting ligand (abbreviated as FA-mPEG-PAMAM G3-CUR@SPIONs), is presented in this study. SPIONs entrapped in the core of the nanocomplex may act as a hyperthermia agent and generate localized heat upon excitation with an alternating magnetic field (AMF), thus enabling a thermo-chemotherapy strategy for cancer treatment. Accordingly, the cytotoxic effect and the mode of cell death triggered by the nanocomplex in combination with AMF were evaluated on two different cancer cell lines with various folate receptor (FR) expression levels, including KB nasopharyngeal cancer cells overexpressing FRs as the model and MCF-7 breast cancer cells with low level of FRs as the blank sample. The obtained results showed that KB cell death was greater than the cell death observed in MCF-7 cells. Moreover, a majority of cell death in both cell lines were related to apoptosis when the folate-modified nanocomplex was used instated of the non-folate-modified nanocomplex. Therefore, functionalizing the nanocomplex with folate modulated the response to thermo-chemotherapy by shifting the cell death pathways toward apoptosis.

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.

Gold nanoparticle-induced sonosensitization enhances the antitumor activity of ultrasound in colon tumor-bearing mice.

PURPOSE: As a noninvasive and nonionizing radiation, ultrasound can be focused remotely, transferring acoustic energy deep in the body, thereby addressing the penetration depth barrier of the light-based therapies. In cancer therapy, the effectiveness of ultrasound can be enhanced by utilizing nanomaterials that exhibit sonosensitizing properties called as nanosonosensitizers. The gold nanoparticle (AuNP) has been recently presented as a potent nanosonosensitizer with the potential to simultaneously enhance both the thermal and mechanical interactions of ultrasound with the tissue of the human body. Accordingly, this paper attempts to evaluate the in vivo antitumor efficiency of ultrasound in combination with AuNP. METHODS: BALB/c mice-bearing CT26 colorectal tumor model was intraperitoneally injected with AuNPs and then subjected to ultrasound irradiation (1 MHz; 2 W/cm2 ; 10 min) for three sessions. Furthermore, [18 F]FDG (2-deoxy-2-[18 F]fluoro-d-glucose) positron-emission tomography (PET) imaging was performed and the radiomic features from different feature categorizes were extracted to quantify the tumors' phenotype. RESULTS: The tumors were dramatically shrunk and the mice appeared healthy over 21 days of study span without the evidence of relapse. The animals treated with AuNP + ultrasound exhibited an obvious decline in tumor metabolic parameters such as standard uptake value (SUV), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) compared to other treatment groups. CONCLUSION: These findings support the use of AuNP as a potent sonosensitizing agent with the potential to use the thermal and mechanical effects of ultrasound so as to cause damage to the focused tumor site, resulting in an improved antitumor efficacy.

Alginate hydrogel co-loaded with cisplatin and gold nanoparticles for computed tomography image-guided chemotherapy.

The biomedical applications of gold nanoparticles (AuNPs) have experienced rapid growth in recent years, due to their expected benefits in medical imaging and therapy. In this work, we report the development of a theranostic nanocomplex constructed from alginate hydrogel co-loaded with cisplatin and AuNPs (abbreviated as ACA) for simultaneous drug delivery and computed tomography imaging. CT26 cells derived from mouse colon adenocarcinoma were exposed to various concentrations of ACA nanocomplex (for 24 h) and the cytotoxicity was measured using MTT assay. Moreover, the cells treated with ACA nanocomplex were imaged in a computed tomography scanner and the contrast enhancement due to the presence of nanocomplex was assessed. The cytotoxicity results showed that ACA nanocomplex had a more potent chemotherapy efficacy than free cisplatin, so that ACA nanocomplex at the concentration of 5 µg/ml (per cisplatin) and 20 µg/ml of free cisplatin resulted in the same cytotoxicity (survival rate: 66%). The computed tomography imaging study revealed that ACA nanocomplex increased the brightness of computed tomography images, the computed tomography number value, and contrast-to-noise ratio (CNR). ACA nanocomplex can be presented as a computed tomography-traceable nanocarrier that allows to monitor the delivery of therapeutics by assessing their localized accumulation and in vivo biodistribution.

Selective heat generation in cancer cells using a combination of 808 nm laser irradiation and the folate-conjugated Fe2O3@Au nanocomplex.

Photothermal therapy (PTT) is a nanotechnology-assisted cancer hyperthermia approach in which the interaction between laser light and plasmonic nanoparticles (NPs) generates localized heating. The exploitation of plasmonic NPs in association with active targeting moieties causes the preferential accumulation of NPs inside cancer cells, thereby providing targeted PTT. Herein, we evaluate the effect of folic acid (FA) as an active targeting agent in enhancing the photothermal efficiency of multifunctional Iron (III) Oxide (Fe2O3)@Au core- shell NPs. Fe2O3@Au NPs were synthesized, modified with FA and then characterized. Human nasopharyngeal (KB) cancer cells were treated with different concentrations of Fe2O3@Au, with and without FA modification and the temperature rise profiles of the cells were measured upon administration of the near-infrared (NIR) laser (808 nm, 6 W/cm2, 10 min). The recorded temperature profiles of the cells were used for thermal dose calculation. Finally, the level of induced apoptosis was determined by flow cytometry using an annexin V-fluorescein isothiocyanate/propidium iodide apoptosis detection kit. The characterization data showed that the Fe2O3@Au NPs are spherical, with a hydrodynamic size of 33 nm. The data corroborated the successful conjugation of the NPs with FA. The thermometry results indicated the superior temperature elevation rate of the cells in the presence of the NPs upon NIR irradiation. Meanwhile, the higher heating rate and the higher thermal dose were obtained for the cells exposed to FA-targeted Fe2O3@Au rather than the non-targeted nanocomplex. Flow cytometry studies revealed that FA-targeted Fe2O3@Au induced higher level of apoptosis than non-targeted Fe2O3@Au NPs. In conclusion, our findings suggest that the synthesized FA-targeted Fe2O3@Au NP has high potentials to be considered as an efficient thermosensitizer in the process of targeted cancer hyperthermia.

The benefits of folic acid-modified gold nanoparticles in CT-based molecular imaging: radiation dose reduction and image contrast enhancement.

X-ray computed tomography (CT) requires an optimal compromise between image quality and patient dose. While high image quality is an important requirement in CT, the radiation dose must be kept minimal to protect the patients from ionizing radiation-associated risks. The use of probes based on gold nanoparticles (AuNPs) along with active targeting ligands for specific recognition of cancer cells may be one of the balanced solutions. Herein, we report the effect of folic acid (FA)-modified AuNP as a targeted nanoprobe on the contrast enhancement of CT images as well as its potential for patient dose reduction. For this purpose, nasopharyngeal KB cancer cells overexpressing FA receptors were incubated with AuNPs with and without FA modification and imaged in a CT scanner with the following X-ray tube parameters: peak tube voltage of 130 KVp, and tube current-time products of 60, 90, 120, 160 and 250 mAs. Moreover, in order to estimate the radiation dose to which the patient was exposed during a head CT protocol, the CT dose index (CTDI) value was measured by an X-ray electrometer by changing the tube current-time product. Raising the tube current-time product from 60 to 250 mAs significantly increased the absorbed dose from 18 mGy to 75 mGy. This increase was not associated with a significant enhancement of the image quality of the KB cells. However, an obvious increase in image brightness and CT signal intensity (quantified by Hounsfield units [HU]) were observed in cells exposed to nanoparticles without any increase in the mAs product or radiation dose. Under the same Au concentration, KB cells exposed to FA-modified AuNPs had significantly higher HU and brighter CT images than those of the cells exposed to AuNPs without FA modification. In conclusion, FA-modified AuNP can be considered as a targeted CT nanoprobe with the potential for dose reduction by keeping the required mAs product as low as possible while enhancing image contrast.

The Measurement and Mathematical Analysis of 5-Fu Release from Magnetic Polymeric Nanocapsules, following the Application of Ultrasound.

OBJECTIVE: To study the effects of ultrasound irradiation on the release profile of 5-fluorouracil (5-Fu) loaded magnetic poly lactic co-glycolic acid (PLGA) nanocapsules. Also, the controlled drug-release behaviour of the nanocapsules was mathematically investigated. METHODS: The nanocapsules were synthesized, dispersed in phosphate buffered saline (PBS), transferred to a dialysis bag, and finally, irradiated by various ultrasound parameters (1 or 3MHz; 0.3-1W/cm2; 5-10 minutes). The release profile of the irradiated nanocapsules was recorded for 14 days. To find the in vitro drug release mechanism in the absence and presence of various intensities of ultrasound, the obtained data were fitted in various kinetic models for drug release. RESULTS: The results demonstrated that the ultrasound speeded up the rate of drug release from the nanocapsules. The mathematical analysis illustrated that when the ultrasound intensity is increased, the probability of controlled release behaviour of the nanocapsules is raised. We found that drug release from the irradiated nanocapsules follows an erosion-controlled mechanism with the decrease in the velocity of diffusion. CONCLUSION: In conclusion, to attain a controlled drug-delivery strategy in the area of cancer therapy, the drug release profile of the nano-carriers may be well-controlled by ultrasound.