Magneto-Acoustic Theranostic Approach: Integration of Magnetomotive Ultrasound Shear Wave Elastography and Magnetic Hyperthermia.

OBJECTIVES: Although magnetically induced hyperthermia has shown great efficiency in the treatment of solid tumors, it is still a challenge to avoid incomplete ablation or overtreatment. In this study, we applied magnetomotive ultrasound shear wave elastography (MMUS-SWE) as a tool for real-time image guidance and feedback in the magnetic hyperthermia (MH) process. We called this new method as magneto-acoustic theranostic approach (MATA). METHODS: In MATA, a ferromagnetic particle (fMP) was simultaneously used as a thermoseed for MH and a shear wave source for MMUS-SWE. The fMP was excited by a high-frequency magnetic field to induce the heating effect for MH. Meanwhile, the fMP was stimulated by a pulsed magnetic field to generate shear wave propagation for MMUS-SWE. Thus, the changes in elastic modulus surrounding fMP can be used to estimate the therapy effect of MH. RESULTS: The phantom and in vitro experiments were conducted to verify the feasibility of MATA, which has good performance in magnetothermal conversion and treatment efficacy feedback. The shear wave speed of the isolated pork liver changed significantly after the MH process, which varied from about 1.36 to 4.85 m/s. CONCLUSIONS: Preliminary results proved that changes in elastic modulus could be useful to estimate the therapy effect of MH. We expect that MATA, which is the integration of MMUS-SWE and MH, will be a novel theranostic method for clinical translation.

Magnetomotive Ultrasound Shear Wave Elastography (MMUS-SWE): A Validation Study From Simulations to Experiments.

Ultrasound elastography is a functional imaging method that enables the measurement of soft tissue elasticity, which is associated with the pathological process of many diseases. However, the measurement area of the conventional elastography method is subjectively selected. Inspired by the targeted imaging technology, we propose a method of magnetomotive ultrasound shear wave elastography (MMUS-SWE). This method utilizes the magnetic force between the magnetic nanoparticles (MNPs) and the external magnetic field to generate shear waves. Then, it can detect the distribution of MNPs and the elasticity of the tissue around the MNPs. As MNPs have been widely used for targeted labeling, the strategy to induce local vibration by MNPs will be more specific than that of the conventional SWE. In this study, the theoretical feasibility was verified by the finite element simulation model. Then, an experimental system was built, and the experimental feasibility of the method was demonstrated through phantom experiments, in vitro tissue experiments, and in vivo experiments. The results show that the distribution of the MNPs and the elastic information of tissues surrounding the MNPs can be detected simultaneously. This technology is expected to realize targeted elasticity measurement based on the MNPs and has potential applications for disease diagnosis.

Viscoelasticity measured by shear wave elastography in a rat model of nonalcoholic fatty liver disease: comparison with dynamic mechanical analysis.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming one of the most common liver diseases. Ultrasound elastography has been used for the diagnosis of NAFLD. However, clinical research on steatosis by elastography technology has mainly focused on steatosis with fibrosis or non-alcoholic steatohepatitis (NASH), while steatosis without fibrosis has been poorly studied. Moreover, the relationship between liver viscoelasticity and steatosis grade is not clear. In this study, we evaluated the degree of liver steatosis in a simple steatosis rat model using shear wave elastography (SWE). RESULTS: The viscoelasticity values of 69 rats with hepatic steatosis were measured quantitatively by SWE in vivo and validated by a dynamic mechanical analysis (DMA) test. Pathological sections were used to determine the steatosis grade for each rat. The results showed that the elasticity values µ obtained by the two methods followed the same trend, and µ is significantly correlated with liver steatosis. The Pearson's correlation coefficients indicate that [Formula: see text] obtained by SWE is positively linear correlated with DMA (r = 0.628, p = 7.85 × 10-9). However, the viscosity values [Formula: see text] obtained by SWE were relatively independent of those obtained by DMA with a correlation coefficient of - 0.01. The combined Voigt elasticity measurements have high validity in the prediction of steatosis (S0 vs. S1-S4), with an AUROC of 0.755 (95% CI 0.6175-0.8925, p < 0.01) and the optimal cutoff value was 2.08 kPa with a sensitivity of 78% and specificity of 63%. CONCLUSION: SWE might have the feasibility to be introduced as an auxiliary technique for NAFLD patients in clinical settings. However, the viscosity results measured by SWE and DMA are significantly different, because the two methods work in different frequency bands.

An in vitro study on sonodynamic treatment of human colon cancer cells using sinoporphyrin sodium as sonosensitizer.

BACKGROUND: Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Sonodynamic therapy (SDT) is an emerging cancer therapy, and in contrast to photodynamic therapy, could non-invasively reach deep-seated tissues and locally activates a sonosensitizer preferentially accumulated in the tumor area to produce cytotoxicity effects. In comparison with traditional treatments, SDT may serve as an alternative strategy for human colon cancer treatment. Here, we investigated the sonodynamic effect using sinoporphyrin sodium (DVDMS) as a novel sonosensitizer on human colon cancer cells in vitro. RESULTS: The absorption spectra of DVDMS revealed maximum absorption at 363 nm wavelength and emission peak at 635 nm. Confocal microscopy images revealed the DVDMS was primarily localized in the cytoplasm, while no evident signal was detected within the nuclei. Flow cytometry analysis showed rapid intracellular uptake of DVDMS by two types of human colon cancer cells (HCT116 and RKO). Cell viability of HCT116 was tolerant with the concentration of DVDMS up to 20 µg/mL, while the case of RKO was 5 µg/mL. In comparison with the control group, the SDT-treated groups of these two types of human colon cancer cells showed significant increase in cellular apoptosis and necrosis ratio. Increased intracellular reactive oxygen species (ROS) production was detected, indicating the involvement of ROS in mediating SDT effects. CONCLUSION: DVDMS results an effective sonosensitizer for the ultrasound-mediated cancer cell killing, and its anticancer effect seems to rely on its ability to produce ROS under ultrasound exposure.

Sonodynamic Therapy on Intracranial Glioblastoma Xenografts Using Sinoporphyrin Sodium Delivered by Ultrasound with Microbubbles.

Sonodynamic therapy (SDT) is a promising noninvasive method for cancer treatment. The anti-tumor effect of sinoporphyrin sodium (DVDMS)-mediated SDT on nude mice bearing intracranial U87 MG-Red-FLuc human glioblastoma was investigated. Focused ultrasound (FUS) with microbubbles (MBs) was utilized to open the blood-brain barrier for enhancing the delivery of the sonosensitizer DVDMS to the brain tumor first, and then the SDT treatment was performed. The in vitro study showed obvious cytotoxicity of DVDMS-mediated SDT (center frequency: 0.996 MHz, acoustic power: 1.7 W, pulse repletion frequency: 1 Hz, duty cycle: 30%, duration: 1 min) on U87 MG-Red-FLuc cells. The results indicated that more DVDMS accumulation in the tumor sites was induced by FUS with MBs by 3.43 folds of unsonicated ones. Longitudinal bioluminescence imaging illustrated that the intracranial glioblastoma progression in nude mice treated with SDT was retarded compared to the untreated group. The median survival time was prolonged to 30.25 days after SDT treatment by 27.37%. The anti-proliferation effect and cell apoptosis induction was further confirmed by immunohistochemical examinations. These results of the study suggested that SDT using the sonosensitizer DVDMS delivered by FUS with MBs may provide a new promising therapeutic strategy against glioblastoma.

Enhanced delivery of paclitaxel liposomes using focused ultrasound with microbubbles for treating nude mice bearing intracranial glioblastoma xenografts.

Paclitaxel liposomes (PTX-LIPO) are a clinically promising antineoplastic drug formulation for the treatment of various extracranial cancers, excluding glioblastoma. A main reason for this is the presence of the blood-brain barrier (BBB) or blood-tumor barrier (BTB), preventing liposomal drugs from crossing at a therapeutically meaningful level. Focused ultrasound (FUS) in conjunction with microbubbles (MBs) has been suggested in many studies to be an effective approach to increase the BBB or BTB permeability. In this study, we investigated the feasibility of enhancing the delivery of PTX-LIPO in intracranial glioblastoma-bearing nude mice using pulsed low-intensity FUS exposure in the presence of MBs. Our results showed that the delivery efficiency of PTX-LIPO could be effectively improved in terms of the penetration of both the BBB in vitro and BTB in vivo by pulsed FUS sonication with a 10 ms pulse length and 1 Hz pulse repetition frequency at 0.64 MPa peak-rarefactional pressure in the presence of MBs. Quantitative analysis showed that a 2-fold higher drug concentration had accumulated in the glioblastoma 3 h after FUS treatment, with 7.20±1.18 µg PTX per g glioma tissue. Longitudinal magnetic resonance imaging analysis illustrated that the intracranial glioblastoma progression in nude mice treated with PTX-LIPO delivered via FUS with MBs was suppressed consistently for 4 weeks compared to the untreated group. The medium survival time of these tumor-bearing nude mice was significantly prolonged by 20.8%, compared to the untreated nude mice. Immunohistochemical analysis further confirmed the antiproliferation effect and cell apoptosis induction. Our study demonstrated that noninvasive low-intensity FUS with MBs can be used as an effective approach to deliver PTX-LIPO in order to improve their chemotherapy efficacy toward glioblastoma.