3D modeling of in vivo MRI-guided nano-photothermal therapy mediated by magneto-plasmonic nanohybrids.

BACKGROUND: Nano-photothermal therapy (NPTT) has gained wide attention in cancer treatment due to its high efficiency and selective treatment strategy. The biggest challenges in the clinical application are the lack of (i) a reliable platform for mapping the thermal dose and (ii) efficient photothermal agents (PTAs). This study developed a 3D treatment planning for NPTT to reduce the uncertainty of treatment procedures, based on our synthesized nanohybrid. METHODS: This study aimed to develop a three-dimensional finite element method (FEM) model for in vivo NPTT in mice using magneto-plasmonic nanohybrids, which are complex assemblies of superparamagnetic iron oxide nanoparticles and gold nanorods. The model was based on Pennes' bio-heat equation and utilized a geometrically correct mice whole-body. CT26 colon tumor-bearing BALB/c mice were injected with nanohybrids and imaged using MRI (3 Tesla) before and after injection. MR images were segmented, and STereoLithography (STL) files of mice bodies and nanohybrid distribution in the tumor were established to create a realistic geometry for the model. The accuracy of the temperature predictions was validated by using an infrared (IR) camera. RESULTS: The photothermal conversion efficiency of the nanohybrids was experimentally determined to be approximately 30%. The intratumoral (IT) injection group showed the highest temperature increase, with a maximum of 17 °C observed at the hottest point on the surface of the tumor-bearing mice for 300 s of laser exposure at a power density of 1.4 W/cm2. Furthermore, the highest level of tissue damage, with a maximum value of Ω = 0.4, was observed in the IT injection group, as determined through a simulation study. CONCLUSIONS: Our synthesized nanohybrid shows potential as an effective agent for MRI-guided NPTT. The developed model accurately predicted temperature distributions and tissue damage in the tumor. However, the current temperature validation method, which relies on limited 2D measurements, may be too lenient. Further refinement is necessary to improve validation. Nevertheless, the presented FEM model holds great promise for clinical NPTT treatment planning.

Physico-chemical and MR relaxometry study of bovine serum albumin-coated magneto-plasmonic nanoparticles designed for potential use in cancer nanotheranostics.

PURPOSE: In recent years, the use of nanoparticles has been developed to improve MRI contrast. To improve the contrast agents in image-guided therapy by Multifunctional nanoparticles, in this study, we synthesized a theranostic magneto-plasmonic nanocomplex based on magnetic iron oxide nanoparticles and bovine serum albumin-modified gold nanorod (Au@BSA-Fe3O4@CMD). The purpose of synthesizing these nanoparticles was to use them as MRI contrast agent and photothermal agents in in vitro and in vivo experiments. MATERIALS AND METHODS: Initially, the properties of the synthesized nanoparticles were investigated by methods such as DLS, TEM, FTIR. MTT assay was used to evaluate the toxicity of nanoparticles. Finally, to evaluate the contrast ability of nanoparticles, MRI images were taken in in vitro and in vivo conditions and then the images were analyzed. RESULTS: MTT test results on CT26 cell line showed no significant cytotoxicity for Au@BSA-Fe3O4@CMD nanoparticles at concentrations up to 20 ppm. The in vitro results demonstrated that the Au@BSA-Fe3O4@CMD nanocomplex has high T2 relaxation rate and great relaxivities (r2 = 140.14 mM-1 s-1, r1 = 2.066 mM-1 s-1, r2/r1 = 67.83). For in vivo conditions, a decrease in T2 signal of 9.64 and 11.01, respectively, was observed for intratumoral and intraperitoneal injection of nanoparticles. CONCLUSION: These in vitro and in vivo studies show that Au @ BSA-Fe3O4@CMD nanoparticles can significantly reduce the signal intensity of T2-weight MRI images, and therefore can offer significant potential as a theranostic platform for effective tumor MR imaging.

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.

Study of the Parameters Affecting the Loading of Fluorescein on Coated Gold Nanoparticles: Promising Nanostructure for Cancer Diagnosis.

BACKGROUND: Recent advances in nanotechnology have led to the use of nanomaterials in the diagnosis of cancer by imaging techniques. OBJECTIVE: This study aimed to synthesize fluorescein-conjugated gold nanoparticles and study the parameters affecting the loading of fluorescein on synthesized coated gold nanoparticles with the ability to be used in medical diagnostic methods. METHODS: The synthesized gold nanoparticles were functionalized with polyethylene glycol. Then, these particles were conjugated with fluorescein under different conditions. To investigate the optical and structural features as well as the factors affecting the loading, the nanoparticles were evaluated by ultraviolet-visible, fluorescence and FT-IR spectrophotometer, fluorescence spectrophotometer, transmission electron microscopy, dynamic light scattering, and zeta potential measuring device. Also, the use of these particles in cancer diagnosis on the skin melanoma cell (B16F10) was examined using a fluorescence microscope. RESULTS: PEG-coated spherical gold nanoparticles were synthesized as a carrier for the fluorescein dye detector. The coating agent concentration, incubation time, temperature, and pH of the medium affected the loading efficiency of fluorescein on the nanoparticles. Also, optimal conditions for use in the diagnostic applications were investigated. Ten micromolar of the sample were selected for cell imaging studies. The fluorescence signal of B16F10 cells containing nanoparticles was relatively strong, indicating the amount of nanoparticles uptaken by the cells. CONCLUSION: The results showed that by designing fluorescent gold nanoparticles with fluorescein as fluorescent detectors and considering their diagnostic importance, an efficient way to diagnose incurable diseases can be found.

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.

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.

Investigating the mechanisms behind extensive death in human cancer cells following nanoparticle assisted photo-thermo-radiotherapy.

We have recently reported the synthesis and characterization of gold-coated iron oxide nanoparticle and demonstrated such a nanoparticle (Au@Fe2O3 NP) was able to significantly enhance the lethal effects of photo-thermo-radiotherapy. The purpose of this study was to determine the mechanisms behind such an enhancement by investigating the changes induced in cancer cell viability, proliferation, and morphology as well as monitoring the alteration of some genes which play important role in the process of cell death. Using MTT assay and transmission electron microscopy (TEM), the KB cells viability and morphology were assessed after treating with various combinations of NPs, photothermal therapy (PTT), and radiotherapy (RT). Clonogenic assay was used to assess the proliferation ability of treated KB cells. Nanoparticle internalization into the cells was investigated by TEM and inductively coupled plasma (ICP). During the treatment procedures, temperature changes were monitored using an IR-camera. Furthermore, the changes occurred in Bax, BCL2 and HSP70 genes expression level were measured using real-time PCR. The results showed that combination of NP, PTT, and RT caused more cell death compared to PTT or RT alone. Following such a combination therapy, massive cell injury was detected. We also observed an extensive increase in Bax/Bcl2 ratio and HSP70 expression for the KB cells treated by combination therapy procedure. Our results showed that massive cell injury and apoptosis induction are the main reasons of extensive cell death observed in cancer cells when a nanoparticle assisted photo-thermo-radiotherapy procedure is applied.

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.