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The liver contrast effects of Sonazoid in two ultrasonographic imaging modes, gray-scale conventional and harmonic, were examined as a time-related study in normal rabbits, and evaluated quantitatively and visually with tumor-model rabbits to estimate the diagnostic potential. Peak enhancement of vessels and parenchyma was observed 1 min after injection in both modes, although signal enhancement in the parenchyma lasted for 120 min compared with rapid decay (5-10 min) in vessels. When Sonazoid was intravenously injected into metastatic carcinoma-model (VX-2) rabbits, all hepatic tumors showed ring enhancement in the early phase followed by clear contrast defects in the delayed phase, because signal enhancement remained only in normal parenchyma. Visual analysis scores for the diagnosis of tumors were improved by Sonazoid injection, and the videodensitometric differences between tumor and normal tissues were significantly greater after injection. Although the harmonic mode tended to show better contrast effects, the conventional mode provided significant contrast enhancement in this hepatic tumor-model. Sonazoid might be useful for the detection of undifferentiated tumors in the liver by making it possible to visualize neovascularity in the early phase and clear contrast defects in the delayed phase, not only in the harmonic but also in the conventional mode.

Purpose: HER3 is a compelling target for cancer treatment; however, no HER3-targeted therapy is currently clinically available. Here, we produced U3-1402, an anti-HER3 antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DXd), and systematically investigated its targeted drug delivery potential and antitumor activity in preclinical models.Experimental Design: In vitro pharmacologic activities and the mechanisms of action of U3-1402 were assessed in several human cancer cell lines. Antitumor activity of U3-1402 was evaluated in xenograft mouse models, including patientderived xenograft (PDX) models. Safety assessments were also conducted in rats and monkeys.Results: U3-1402 showed HER3-specific binding followed by highly efficient cancer cell internalization. Subsequently, U3-1402 was translocated to the lysosome and released its payload DXd. While U3-1402 was able to inhibit HER3activated signaling similar to its naked antibody patritumab, the cytotoxic activity of U3-1402 in HER3-expressing cells was predominantly mediated by released DXd through DNA damage and apoptosis induction. In xenograft mouse models, U3-1402 exhibited dose-dependent and HER3-dependent antitumor activity. Furthermore, U3-1402 exerted potent antitumor activity against PDX tumors with HER3 expression. Acceptable toxicity was noted in both rats and monkeys.Conclusions: U3-1402 demonstrated promising antitumor activity against HER3-expressing tumors with tolerable safety profiles. The activity of U3-1402 was driven by HER3mediated payload delivery via high internalization into tumor cells.

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Ultrasonography (US) is useful for diagnosis of hepatic focal lesions, which is based on their distinctive echogenicities; the gray-scale morphologic features. To improve diagnostic ability of detection and characterization of tumors, contrast imaging has been used in diagnostic imaging, e.g. X-ray computed tomography (CT) or magnetic resonance imaging (MRI), but has not yet been popular in US since contrast agents for US are not at clinical satisfaction level. Intravenous US contrast agents available for clinical use or the agents under development are basically microbubbles whose size is comparable to or less than red blood cells. First-generation agent consisted of air-microbubbles, Levovist (SH U 508A; Schering, Berlin, Germany), is commercially available in many countries, 1-6) but short imaging duration and weak contrast effect due to instability of the microbubbles could provide only limited diagnostic information.1,2) In order to improve the contrast effects, second-generation agents that use less soluble gases for microbubbles are being developed and now clinically available in limited western countries.1,6-9) Viewpoint from US imaging machine, to detect microbubbles more sensitively, harmonic imaging technology has been developed to visualize the harmonic echo from the microbubbles: backscatter signal (echo) from the microbubbles contains more harmonic component than that from tissues. 1)One of the second-generation agents, Sonazoid (previously NC100100, Amersham Health, Oslo, Norway) 7,10) has been reported to enhance perfusion of the myocardium and other organs. 7,[11][12][13][14] In the previous study, 15) we have characterized contrast enhancement of Sonazoid on the liver of metastatic carcinoma-model (VX-2) in rabbits, 16,17) and demonstrated promising contrast effect on the detection and delineation of liver tumors. This is due to uniqueness of Sonazoid whose microbubbles are likely to be taken up by Kupffer cells (liver macrophages) in the healthy liver and enhances contrast of the liver parenchyma during the delayed phase, which usually occurs within 10 min after the injection. In contrast, tumor that lacks Kupffer cells was not enhanced resulting in clear negative contrast of the tumor.In the previous study, comparison of the tumor contrast with histopathology of the tumors could not be examined in detail, since resolution of US images that had been acquired using the harmonic imaging technique was not enough to compare with microscopic images. To improve resolution and signal-to-noise ratio of this harmonic technique, phase inversion imaging (PII) technique was then developed and now become available in the commercial US machine. 6,18,19) PII can detect harmonic echoes from the microbubble contrast agent with greater sensitivity and without the loss of spatial resolution often seen in the harmonic imaging.Localization of the microbubbles in the liver Kupffer cells has been demonstrated in rat by using transmission electron microscopy (TEM). 20) However, the liver contrast effect in rats, such...

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Summary To design hybrid tumour necrosis factor-a (TNF-a) applicable to systemic anti-tumour therapeutic use, we assessed the relationships among the molecular size of hybrid TNF-a, in vitro bioactivity and in vivo anti-tumour potency. Natural human TNF-a was covalently modified with polyethylene glycol (PEG) of various number-average molecular weights (Mn = 2000, 5000, 12 000). The in vitro bioactivity of PEGmodified TNF-as decreased with an increase in the degree of PEG modification, irrespective of the molecular weight of PEG. This decrease in the specific bioactivity markedly increased with an increase in the molecular weight of the attached PEG. The in vivo anti-tumour effects of the hybrid TNF-cxs with a molecular size from 100 to 110 kDa, which had more than 50% of specific bioactivity of native TNF-a, were significantly superior to other PEG-TNF-as. These hybrid TNF-as showed over ten times greater anti-tumour effects than native TNF-a. Thus, the molecular size, which was determined by the degree of PEG modification and PEG molecular weight, influences the specific activity and anti-tumour effects of hybrid TNF-a.