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.

Optimization of cobalt ferrite magnetic nanoparticle as a theranostic agent: MRI and hyperthermia.

OBJECTIVE: Magnetic nanoparticles (MNPs) are considered a theranostic agent in MR imaging, playing an effective role in inducing magnetic hyperthermia. Since, high-performance magnetic theranostic agents are characterized by superparamagnetic behavior and high anisotropy, in this study, cobalt ferrite MNPs were optimized and investigated as a theranostic agent. METHODS: CoFe2O4@Au@dextran particles were synthesized and characterized by DLS, HRTEM, SEM, XRD, FTIR, and VSM methods. After cytotoxicity evaluation, MR imaging parameters (r1, r2 and r2 / r1) were calculated for these nanostructures. Afterward, magnetic hyperthermia at the frequency of 425 kHz was applied to calculate specific loss power (SLP). RESULTS: Formation of CoFe2O4@Au@dextran was confirmed by UV-Visible spectrophotometry. On the basis of the relaxometric and hyperthermia induction findings of nanostructures in all stages of synthesis, the CoFe2O4@Au@dextran could produce the highest parameters of r2 and r2/r1 and SLP with values ​​of 389.7, 51.2 mM-1 s-1, and 2449 W/g, respectively. CONCLUSION: The formation of multi-core MNPs by dextran coating is expected to improve the magnetic properties of the nanostructure, leading to optimization of theranostic parameters, so that CoFe2O4@Au@dextran NPs can create contrast-enhanced images more than three times the clinical use and require less contrast agent, reducing side effects. Accordingly, CoFe2O4@Au@dextran can be introduced as a suitable theranostic nanostructure with optimal efficiency.

Triptorelin Peptide Conjugated Alginate Coated Gold Nanoparticles as A New Contrast Media for Targeted Computed Tomography Imaging of Cancer Cells.

OBJECTIVE: Increasing research has been focused on the development of various nanocomplexes as targeted contrast media in diagnostic modalities, mainly in computed tomography (CT) scan imaging. Herein, we report a new method that uses Triptorelin [a luteinizing hormone-releasing hormone (LHRH) agonist]-targeted gold nanoparticles (AuNPs) via alginate for early detection of cancer by molecular CT imaging. MATERIALS AND METHODS: In the experimental study, the formed multifunctional AuNPs coated with alginate conjugated with Triptorelin peptide (Triptorelin-Alginate-AuNPs) were synthesized and characterized via different techniques, including transmission electron microscopy (TEM), dynamic light scattering (DLS), and fourier transform infrared (FTIR) spectroscopy. The MTT assay was applied to calculate the toxicity of the NPs. RESULTS: The results indicated that the formed Triptorelin-Alginate-AuNPs with an Au core size of ~18 nm are noncytotoxic at 127-, 254-, 381- and 508-mM concentrations and revealed significant improvement in the attenuation of X-rays intensity and contrast to noise ratio (CNR), compared with non-targeted cells at the highest energies (90, 120, 140 kVp). At 90 kVp, compared to non-targeted cells, targeted cells (Triptorelin-Alginate-AuNPs) enable 1.58, 1.69, 3.7 and 3.43 times greater contrast at a concentration of 127 mM, 254 mM, 381 mM, and 508 mM, respectively. CONCLUSION: These results suggest that the developed Triptorelin-Alginate-AuNPs may be considered an effective contrast agent for molecular CT imaging of gonadotropin-releasing hormone (GnRH) receptor-expressing cancer cells.

Modified Bismuth Nanoparticles: A New Targeted Nanoprobe for Computed Tomography Imaging of Cancer.

OBJECTIVE: Recently, development of multifunctional contrast agent for effective targeted molecular computed tomography (CT) imaging of cancer cells stays a major problem. In this study, we explain the ability of Triptorelin peptide-targeted multifunctional bismuth nanoparticles (Bi2S3@ BSA-Triptorelin NPs) for molecular CT imaging. MATERIALS AND METHODS: In this experimental study, the formed nanocomplex of Bi2S3@ BSA-Triptorelin NPs was characterized using different methods. The MTT cytotoxicity test was performed to determine the appropriate concentration of nanoparticles in the MCF-7 cells. The X-ray attenuation intensity and Contrast to Noise Ratio (CNR) of targeted and non-targeted nanoparticles were measured at the concentrations of 25, 50, and 75 µg/ml and X-ray tube voltages of 90, 120 and 140 kVp. RESULTS: We showed that the formed Bi2S3@ BSA-Triptorelin NPs with a Bi core size of approximately ~8.6 nm are nontoxic in a given concentration (0-200 µg/ml). At 90, 120, and 140 tube potentials (kVp), the X-ray attenuation of targeted cells were 1.35, 1.36, and 1.33-times, respectively, more than non-targeted MCF-7cells at the concentration of 75 µg/ml. The CNR values at 90, 120, and 140 kVp tube potentials were 171.5, 153.8 and 146.3 c/Ï­, respectively. CONCLUSION: These findings propose that the diagnostic nanocomplex of Bi2S3@ BSA-Triptorelin NPs can be applied as a good contrast medium for molecular CT techniques.

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.

Magnetic Resonance Imaging of Tumor-Infiltrating Lymphocytes by Anti-CD3-Conjugated Iron Oxide Nanoparticles.

Immune checkpoint blockade, considered a revolutionary approach in cancer treatment, is only effective in patients with high tumor-infiltrating lymphocytes (TILs). This work aimed to investigate the feasibility of targeted contrast agent (CA) based on dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs-DEX) for TILs detection by magnetic resonance imaging (MRI) studies. To do so, we synthesized an MRI CA by conjugating SPIONs-DEX to an anti-CD3 monoclonal antibody via cyanogen bromide as a cross-linker. In vitro assessments demonstrated the higher labeling efficiency of the developed CA to CD3+ lymphocytes compared to SPIONs-DEX. In vivo MRI of a xenograft model of CD3+ lymphocytes revealed the significant signal loss after the intravenous injection of the bioconjugate by ∼34 % and 21 % in T2 *-weighted and T2 -weighted images, respectively. The histopathological evaluation of xenograft tumors confirmed the labeling of lymphocytes by the targeted CA. This approach could open up a new horizon in the non-invasive assessment of TILs to identify patients eligible for immunotherapy.

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.

Investigation of Specific Targeting of Triptorelin-Conjugated Dextran-Coated Magnetite Nanoparticles as a Targeted Probe in GnRH+ Cancer Cells in MRI.

In recent years, the conjugation of superparamagnetic iron oxide nanoparticles (SPIONs), as tumor-imaging probes for magnetic resonance imaging (MRI), with tumor targeting peptides possesses promising advantages for specific delivery of MRI agents. The objective of the current study was to design a targeted contrast agent for MRI based on Fe3O4 nanoparticles conjugated triptorelin (SPION@triptorelin), which has a great affinity to the GnRH receptors. The SPIONs-coated carboxymethyl dextran (SPION@CMD) conjugated triptorelin (SPION@CMD@triptorelin) were synthesized using coprecipitation method and characterized by DLS, TEM, XRD, FTIR, Zeta, and VSM techniques. The relaxivities of synthetized formulations were then calculated using a 1.5 Tesla clinical magnetic field. MRI, quantitative cellular uptake, and cytotoxicity level of them were estimated. The characterization results confirmed that the formation of SPION@CMD@triptorelin has been conjugated with a suitable size. Our results demonstrated the lack of cellular cytotoxicity of SPION@CMD@triptorelin, and it could increase the cellular uptake of SPIONs to MDA-MB-231 cancer cells 6.50-fold greater than to SPION@CMD at the concentration of 75 µM. The relaxivity calculations for SPION@CMD@triptorelin showed a suitable r 2 and r 2/r 1 with values of 31.75 mM-1·s-1 and 10.26, respectively. Our findings confirm that triptorelin-targeted SPIONs could provide a T 2-weighted probe contrast agent that has the great potential for the diagnosis of GnRH-positive cancer in MRI.

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.

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.

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.

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.

An electrochemical immunosensor for detection of a breast cancer biomarker based on antiHER2-iron oxide nanoparticle bioconjugates.

A label free immunosensor was designed for ultra-detection of human epidermal growth factor receptor 2 (HER2) in real samples using a differential pulse voltammetry (DPV) method. In a separate process, antiHER2 antibodies were attached to iron oxide nanoparticles (Fe3O4 NPs) to form stable bioconjugates which were later laid over the gold electrode surface. In this way, by the advantage of their long terminals, the bioconjugates provided the most possible space for the immuno-reaction between biomolecules. Under optimal conditions, the immunosensor was responsive to HER2 concentrations over the ranges of 0.01-10 ng mL(-1) and 10-100 ng mL(-1) linearly and benefited from a satisfactory detection limit as low as 0.995 pg mL(-1) and a favorable sensitivity as sharp as 5.921 µA mL ng(-1). The reliability of the method in clinical analysis was proved by successful quantization of HER2 levels in serum samples obtained from patients. Furthermore, the precision and the stability of the method were evaluated and verified to be acceptable in immunoassay studies.