دکترعلی شاکری زاده پنجمین جلسه ژورنال کلاب Graphene oxide-BaGdF5 nanocomposites for multi-modal imaging and photothermal therapy ارائه دهنده: دکترعلی شاکری زاده

Introduction As we all know, chemotherapy, radiotherapy and surgery are important therapeutic approaches for malignant tumors. All cause strong side effects!!! Photothermal therapy (PTT), as a novel method for cancer treatment. Precise energy delivery to target tissue. To date, a variety of nanomaterials, such as: gold nanostructures, palladium nanosheets, metal sulfide nanoparticles, tungsten oxide nanowires, carbon nanomaterials (carbon nanotubes and nano-graphenes), and various organic NPs have been demonstrated to have potential PTT applications.

Introduction Graphene oxide, a well known two-dimensional (2D) carbon material with excellent electronic, optical, thermal, and mechanical properties, has been extensively studied in the past decade. Potential applications of graphene in biomedical fields: nanocarriers for drug and gene delivery biosensing platforms molecular imaging agents photothermal agents for tumor therapy Considering their large surface area, graphene oxide (GO) nanosheets can be integrated with various types of NPs to form multifunctional nanomaterials for different application purposes: Therapy Imaging

Introduction Nowadays, magnetic resonance (MR) and X-ray computed tomography (CT) imaging modalities are widely used for various experimental and clinical applications. MR imaging is a noninvasive and nonionizing imaging method that can offer high sensitivity and good discrimination for soft tissues. Gadolinium (Gd3+) metal ion based complexes (e.g. Gd-DTPA) are currently being used clinically as T1 relaxation agents due to their unique high spin paramagnetism. However, MR imaging is not suitable for imaging in patients who possess magnetic hardware, and it also shows no signal for high density calcification.

Introduction In comparison, CT affords better spatial resolution than other imaging modalities, and it could give high-resolution 3D anatomic structure information of tissues. The clinically used iodine-based small molecular CT contrast agents are subject to severe limitations including short imaging time and renal toxicity. New nanoparticulate CT contrast agents with high Z metal elements Nevertheless, even if highly efficient CT agents were employed, the low sensitivity and poor resolution for soft tissue still limit the clinical application of CT technology.

Dual mode MR/CT imaging Introduction Dual mode MR/CT imaging To satisfy the high requirements of efficiency and accuracy for the clinical diagnosis, combination of multimodal data is often required. It is believed that the combination of MR imaging with CT modality could achieve more useful information of soft tissues or tumors with much enhanced accuracy.

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Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology

Methods & Results

Methods & Results EDS spectrum of nanocomposite UV-vis-NIR absorption of: GO (100 µg/mL) GO/BaGdF5/PEG (100 µg/mL) BaGdF5/PEG (500 µg/mL)

Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology

MR imaging of GO/BaGdF5/PEG in solution Methods & Results Magnetic sensitivity of GO/BaGdF5/PEG solutions was investigated on a 0.5 T MR scanner. T1-weighted MR images were acquired with a conventional spin-echo sequence The longitudinal relaxivity (r1) was measured to be 4.8 /mM x s which is higher than that of Gd-DTPA (3.5 /mM x s).

MR imaging in vitro Methods & Results Hela cells incubated with different concentrations of nanocomposite was investigated on a 3.0 T system. Incubation time: 4 h ICP analysis for Gd3+

MR imaging in vivo Methods & Results MR imaging in vivo was investigated with HeLa tumor-bearing nude mice. Injection: (20 mg/kg body weight; i.v.) Time-dependent brightening in the tumor The signal intensity in tumor site increases remarkably by 3.7 times after injection for 24 h. EPR effect

CT imaging of GO/BaGdF5/PEG in solution Methods & Results HU/mM

CT imaging in vivo Methods & Results CT imaging in HeLa tumor-bearing mice using a small animal micro-CT system. Images were taken 0.5 h after injection

Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology

In vitro cytotoxicity of GO/BaGdF5/PEG in Hela cells (MTT assay) Methods & Results

In vitro cytotoxicity of GO/BaGdF5/PEG in L929 cells (MTT assay) Methods & Results

Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology

Photothermal properties in solution Methods & Results Different concentrations were exposed to an 808-nm laser at a power density of 0.4 W/cm2 for 10 min. time- and concentration-dependent temperature increase upon irradiation. 33 °C No temperature variation for BaGdF5/PEG concentration even at 3 mg/mL.

Photothermal properties in solution Methods & Results The temperature of the solutions was monitored using an infrared thermal imaging system. Infrared thermal images before and after 10 min of laser irradiation for GO/BaGdF5/PEG with the concentration of 200 mg/mL.

In vivo cancer PTT Methods & Results Infrared thermal images of HeLa tumor-bearing mice with (a1) or without (a2) injection of GO/BaGdF5/PEG exposed to 808-nm laser irradiation (0.5 W/cm2) for 10 min (24 h post-injection)

In vivo cancer PTT Methods & Results

Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology

PTT of cancer cells in vitro (MTT assay) Methods & Results (200 µg/mL) 0.4 W/cm2

PTT of cancer cells in vitro (Flow cytometry) Methods & Results

In vivo cancer PTT Methods & Results

In vivo cancer PTT Methods & Results PTT did not bring significant side effects

H&E-stained histology images of tumor In vivo cancer PTT Methods & Results H&E-stained histology images of tumor (a) PBS only, (b) laser irradiation only, (c) GO/BaGdF5/PEG only, (d) both GO/BaGdF5/PEG and laser irradiation.

Conclusion Experiments at a glance NPs Characteristics FTIR, UV-Visible, EDS,… Diagnostics studies MRI In Solution In Vitro In Vivo CT Scan Therapeutic Studies Cytotoxicity Healthy Cells Cancer Cells PPT Studies MTT Flow cytometry Tumor Size Body Weight Pathology Conclusion

Conclusion GO/BaGdF5/PEG shows: good stability low cytotoxicity even at high concentrations Promising properties to be used as T1-weighted MR and X-ray CT duel-mode contrast agent excellent photothermal behavior for in vivo photothermal cancer treatment This nanocomposite may be further conjugated with different targeting ligands to construct multifunctional systems for targeted theranosis of cancers.