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.

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.

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.

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.

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.

Multimodal cancer cell therapy using Au@Fe2O3 core-shell nanoparticles in combination with photo-thermo-radiotherapy.

In this study, gold coated iron oxide nanoparticle (Au@Fe2O3 NP) was synthesized in a core-shell structure. Photothermal and radiosensitization effects of Au@Fe2O3 NPs were investigated on KB human mouth epidermal carcinoma cell line. Cell death and apoptosis were measured to study the effects of nanoparticles in combination with both radiotherapy (RT) and photothermal therapy (PTT). The KB cells were treated with Au@Fe2O3 NPs (20 µg/ml; 4 h) and then received different treatment regimens of PTT and/or RT using laser (808 nm, 6 W/cm2, 10 min) and/or 6 MV X-ray (single dose of 2 Gy). Following the various treatments, MTT assay was performed to evaluate the cell survival rate. Also, the mode of cell death was determined by flow cytometry using an annexinV-fluorescein isothiocyanate/propidium iodide apoptosis detection kit. No significant cell death was observed due to laser irradiation. The viability of the cells firstly incubated with NPs and then exposed to the laser was significantly decreased. Additionally, our results demonstrated that Au@Fe2O3 NP is a good radiosensitizer at megavoltage energies of X-ray. When nanoparticles loaded KB cells were received both laser and X-ray, the cell viability substantially decreased. Following such a combinatorial treatment, flow cytometry determined that the majority of cell death relates to apoptosis. In conclusion, Au@Fe2O3 NP has a great potential to be applied as a photo-thermo-radiotherapy sensitizer for treatment of head and neck tumors.

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.