Katsutoshi Sugimoto

Systemic delivery of miR-126 by miRNA-loaded Bubble liposomes for the treatment of hindlimb ischemia

Currently, micro RNA (miRNA) is considered an attractive target for therapeutic intervention. A significant obstacle to the miRNA-based treatments is the efficient delivery of miRNA to the target tissue. We have developed polyethylene glycol-modified liposomes (Bubble liposomes (BLs)) that entrap ultrasound (US) contrast gas and can serve as both plasmid DNA (pDNA) or small interfering RNA (siRNA) carriers and US contrast agents. In this study, we investigated the usability of miRNA-loaded BLs (mi-BLs) using a hindlimb ischemia model and miR-126. It has been reported that miR-126 promotes angiogenesis via the inhibition of negative regulators of VEGF signaling. We demonstrated that mi-BLs could be detected using diagnostic US and that mi-BLs with therapeutic US could deliver miR-126 to an ischemic hindlimb, leading to the induction of angiogenic factors and the improvement of blood flow. These results suggest that combining mi-BLs with US may be useful for US imaging and miRNA delivery.

Analysis of morphological vascular changes of hepatocellular carcinoma by microflow imaging using contrast-enhanced sonography.

Aim:  To determine whether the findings of microflow imaging (MFI), composed of a flash replenishment and a maximum intensity holding sequence, using contrast‐enhanced sonography, correlate with the degree of histological differentiation of hepatocellular carcinoma (HCC).

Assessment of arterial hypervascularity of hepatocellular carcinoma: comparison of contrast-enhanced US and gadoxetate disodium-enhanced MR imaging

AbstractObjectiveTo compare contrast-enhanced (CE) ultrasound with gadoxetate disodium-enhanced magnetic resonance (MR) imaging in the assessment of arterial hypervascularity of hepatocellular carcinoma (HCC) and dysplastic nodule (DN), with CT during hepatic arteriography (CTHA) as the reference standard.MethodsThis study included 54 consecutively diagnosed patients, with 57 histologically confirmed HCCs and 3 DNs (high-grade). All patients underwent CE ultrasound, gadoxetate disodium-enhanced MR imaging and CTHA. Two trained diagnostic radiologists interpreted the CTHA images and rated the degree of intratumoral arterial vascularity by consensus using a five-point confidence scale as the reference standard. In the observer study, the degrees of vascularity on CE ultrasound and gadoxetate disodium-enhanced MR images were qualitatively analysed by four independent readers using a five-point confidence scale. Diagnostic accuracy was analysed by receiver-operating characteristic (ROC) analysis.ResultsThe diagnostic accuracies of the average area under the ROC curve (AUC) were significantly greater with CE ultrasound (average AUC: 0.94; 95% confidence interval [CI]: 0.88–1.00) than with gadoxetate disodium-enhanced MR imaging (average AUC 0.84, 95% CI 0.74–0.93, P = 0.0014).ConclusionContrast-enhanced ultrasound yields a significantly higher AUC value than gadoxetate disodium-enhanced MR imaging in the assessment of arterial hypervascularity of HCC and DN. Key Points • Arterial hypervascularity is an important feature determining treatment options in hepatocellular carcinoma. • It can be assessed by contrast-enhanced (CE) ultrasound or magnetic resonance (MR) imaging. • CE ultrasound was more accurate than Gd-EOB-DTPA MRI in assessing intratumoral vascularity. • Hypovascular hepatic nodules should be further investigated using CE ultrasound.

pDNA-loaded Bubble liposomes as potential ultrasound imaging and gene delivery agents

We have developed polyethyleneglycol (PEG)-modified liposomes (Bubble liposomes; BLs) that entrap ultrasound (US) contrast gas, and we have reported that the combination of BLs and US exposure was an effective tool for delivering pDNA and siRNA in vitro and in vivo. In this study, we prepared pDNA-loaded BLs using three types of cationic lipids to enhance the US imaging effect and the transfection efficiency via systemic injection. We investigated the US imaging abilities of these BLs, their protective effects on pDNA from serum component, and their transfection effects in vitro and in vivo. As a result, we demonstrated that the US imaging ability and transfection effect varied with lipid component and that p-BLs containing DSDAP could be the most stable and effective tool the among three types of p-BLs. Indeed, in ischemic muscle, p-BLs containing DSDAP could be detected using diagnostic US and could deliver bFGF-expressing pDNA using therapeutic US, leading to the induction of angiogenic factors and the improvement of blood flow. These results suggest that combining p-BLs with US exposure may be useful for stable US imaging and efficient gene delivery and may lead to the establishment of a theranostic approach, which is a combination of disease diagnosis and therapy.

Hepatocellular carcinoma treated with sorafenib: early detection of treatment response and major adverse events by contrast-enhanced US

Early prediction of tumour response and major adverse events (AEs), especially liver failure, in patients with hepatocellular carcinoma (HCC) is essential for maximizing the clinical benefits of sorafenib. To evaluate the usefulness of dynamic contrast‐enhanced ultrasound (DCE‐US) for the early prediction of tumour response and major AEs in HCC patients.

Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading.

To determine the relative wash‐out of hepatocellular carcinomas and dysplastic nodules using Kupffer‐phase sonography with Sonazoid (Daiichi‐Sankyo, Tokyo, Japan) enhancement and hepatobiliary‐phase gadoxetic acid‐enhanced magnetic resonance imaging (MRI) in the evaluation of the histopathologic grades of individual nodules.

Parametric imaging of contrast ultrasound for the evaluation of neovascularization in liver tumors.

Aim:  To assess the efficacy of parametric imaging for the diagnosis of neovascularization in liver tumors.

Histological grade of differentiation of hepatocellular carcinoma: comparison of the efficacy of diffusion-weighted MRI with T2-weighted imaging and angiography-assisted CT.

Introduction: The purpose of this study is to determine the usefulness of diffusion‐weighted imaging (DWI) for evaluating the histological grade of differentiation of hepatocellular carcinoma (HCC) compared with T2‐weighted imaging (T2WI) and tumour haemodynamics.

Quantification in molecular ultrasound imaging: a comparative study in mice between healthy liver and a human hepatocellular carcinoma xenograft.

The purpose of this study was to quantitatively assess the contrast kinetics of vascular endothelial growth factor receptor 2 (VEGFR2)‐targeted microbubbles (BR55; Bracco Suisse, Geneva, Switzerland) compared to clinically used microbubbles (SonoVue; Bracco SpA, Milan, Italy) in both normal liver and human hepatocellular carcinoma xenograft tumors in mice.

Correlation between parametric imaging using contrast ultrasound and the histological differentiation of hepatocellular carcinoma

Aim:  To determine whether parametric imaging correlates with the degree of histological differentiation of hepatocellular carcinoma (HCC).