Nami Sugita

Nanoparticles with Multiple Perfluorocarbons for Controllable Ultrasonically Induced Phase Shifting

In studying the feasibility of developing tissue-targeted contrast media that can be administered as liquids and vaporized by an external stimulus such as ultrasound, we have investigated the properties of emulsions of nanometer-size particles containing perfluoropentane and 2H,3H-perfluoropentane. We found that the ultrasound intensity required to induce echographically significant vaporization can be controlled by changing the ratio of 2H,3H-perfluoropentane to perfluoropentane and that the intensity threshold increases as this ratio increases. Significant azeotropic phenomena were not observed when the perfluorocarbon mixtures were heated, which indicates that mechanisms other than azotropy are involved in the threshold change. The vaporization of 2H,3H-perfluoropentane may have been due not only to ultrasound energy but also to the energy deposited by ultrasonically induced bubbles of perfluoropentane. Our results might lead to a phase-shift contrast agent with controllable ultrasound energy for phase shifting.

Fabrication of High-Resolution and High-Aspect-Ratio Patterns on a Stepped Substrate by Using Scanning Probe Lithography with a Multilayer-Resist System

The high-resolution and high-aspect-ratio resist-patterning method using a trilayer-resist system with atomic force microscopy (AFM) lithography is described. This system consists of a high-resolution negative-type resist as a top layer, p-Si as an intermediate layer, and an organic resist as a bottom layer. Since the bottom layer planarizes the surface, the patterns can be fabricated on a stepped surface. Using this method, we successfully fabricate 50-nm-wide and 340-nm-thick line-and-space resist patterns on a 200-nm-stepped substrate.

Fabrication of High-Resolution and High-Aspect-Ratio Pattering on a Stepped Substrate by Scanning Probe Lithography Using a Multilayer-Resist System

l.Introduction Nanofabrication techniques are indispensable for fabricating promising devices. Scanning probe lithography (SPL), which is based on scanning tunneling rnicroscopy (STM) or atomic force rnicroscopy (AFM), is an effective method of fabricating nanoscale structures[1]. In a previous paper, we reported some of the advantages of AFM-based lithography using a constant-current-controlled exposure system, they include high resolution, low variation in the linewidth of the pattern and a negligible proximity effect[2]. Scanning probe lithography has the following disadvantages, however; l. A thin-resist film is required to fabricate small patterns since the resolution depends on the thickness of the resist. 2. Topography or existing steps on the surface cause deviation from the designed pattern . 3. Resist patterns cannot be formed on insulating surfaces. Multilayer-resist systems [3], which have been used in optical lithography and electron-beam lithography to avoid the standing-wave and proximity effect, are an effective solution to these problems. K. Kragler et al. fabricated 100nm-wide resist patterns, 300 nm thick by STM lithography using a bilayer-resist system consisting of silicon-containing positive resist and amorphous hydrogenated carbon[4]. In this report, we describe how we used a trilayer-resist system to fabricate high-aspect-ratio and high-resolution resist patterns on a stepped substrate using currentconffolled AFM lithography.

Synthesis and structural study of a novel nonlinear optical material: the tolane derivative ethyl 2-(4-benzyloxyphenylethynyl)-5-nitrobenzene-1-carbamate

We have synthesized the tolane derivative ethyl 2-(4-benzyloxyphenylethynyl)-5-nitrobenzene-1-carbamate1, a promising material for nonlinear optics. Compound 1 has several crystal forms and we have characterized their structural properties by X-ray diffraction. One of the three forms, which is crystallized from a strong polar solvent, has a non-centrosymmetric structure and is ca. ten times as strong a second-harmonics generator as meta-nitroaniline. A hydrogen bond is found to perform an important role in forming the non-centrosymmetric geometry, which is necessary for a nonlinear optical crystal.

Sonodynamically-induced cytotoxicity by rose bengal derivative and microbubbles in isolated sarcoma 180 cells

It is known that the combination of ultrasound and sonodynamic sensitizer (SDS) is effective in noninvasive tumor treatment, referred to as sonodynamic therapy (SDT). Microbubbles have been used in ultrasound therapy as well. The purpose of this paper is to clarify the effect of microbubbles on SDT. Sarcoma 180 cells were suspended in air-saturated phosphate-buffered saline and exposed to ultrasound with the SDS rose bengal derivative (RBD) in standing wave mode in the presence and absence of microbubbles [sonazoid (SZ)]. The ultrasonically induced cytotoxicity with RBD and SZ was about 20 times higher than without either, and about 80% of the SZ microbubbles were destructed by ultrasonic exposure in as short as five seconds. Since microbubbles induce significant cytotoxicity even with short duration, low intensity ultrasound, the application of microbubbles in SDT shows promise in anti-tumor treatment.

Phase-shift nanoparticle system for ultrasonic imaging and therapy

In studying the feasibility of developing tissue-targeted contrast media that can be administered as liquids and vaporized by an external stimulus such as ultrasound, we have investigated the properties of emulsions of nanometer-size particles containing perfluoro- pentane (n-PFP) and 2H,3H-perfluo-ropentane (H2-PFP). We found that the ultrasound intensity required to induce echographically significant vaporization can be controlled by changing the ratio of H2-PFP to PFP and that the intensity threshold increases as this ratio increases. We further determined if our nano-particles could change their phase in colon 26 mouse tumor tissues in vivo. Ultrasound exposure under the same conditions as the above in vitro experiments was found to induce a phase shift in the particles in tumor tissues. It was also found that focused ultrasound at an acoustic intensity of 20 W/cm 2 contiguously exposed after the phase shift is established in the tumor tissues induce therapeutic effects at the focus. Our results indicated the potential usefulness of the nano-particle system as a versatile agent for ultrasonic diagnosis and therapy.

Reduction of cavitation threshold by second‐harmonic superimposition and its potential application to sonodynamic therapy

Acoustic cavitation is known to induce bioeffects under certain conditions. Cavitation threshold, the acoustic strength needed to induce such cavitation, in various biological systems was intensively studied by Dr. Dunn’s group. Their results have significantly contributed to the safety concerns of diagnostic and therapeutic uses of ultrasound. Acoustic cavitation is also known to be the primary cause of sonochemical reactions. Chemical compounds such as hematoporphyrin were found to be activated by acoustic cavitation and induce in vitro and in vivo antitumor effects thereby. In order to make use of this effect in therapeutic practice, cavitation must be generated reproducibly without depending on standing waves at acoustic power inducing no significant heating. It was also found that the cavitation threshold can be significantly reduced by superimposing the second harmonic onto the fundamental in insonation. The threshold was reduced by more than an order of magnitude, especially in the presence of a certain compound such as Rose Bengal (RB). An amphiphilic derivatives of RB, selectively accumulating in tumor tissues, was synthesized and used in combination with focused ultrasound with second‐harmonic superimposition to treat experimental murine tumors, resulting in significant reduction of their sizes. A hypothesis on the mechanism behind this will also be discussed.

Construction of artificial monolayer assemblies on Si(111) surface using silicon monofluoride as a chemisorption site

Abstract Adsorption of molecules from a solution onto a fluorine-terminated Si(111) surface has been examined using X-ray photoelectron spectroscopy. The decrease in the F1s peak intensity assigned to the surface Si–F bond is accompanied by a quantitative increase in the core electron peaks ascribed to the molecule, while some Si–F remain intact. The adsorption of molecules with larger dimensions results in a decrease in the proportion of surface fluorine that is replaced. These results show that the substitution reaction proceeds until the steric hindrance of adsorbed molecules limits further adsorption. Fourier transform infrared attenuated total reflection reveals the molecule to be covalently bonded to the silicon surface giving monomolecular coverage. Dicarboxylic acids are shown to adsorb through only one of the two carboxyl groups, the other end being exposed at the monolayer–air or monolayer–liquid interface. Free carboxyl groups on the adlayer, after being converted to chloroformyl groups by chlorination reagents, act as chemisorption sites for other molecules.

Advanced Cavitation Induction for Improved Reproducibility and In Situ Monitoring of Sonodynamic Cancer Treatment

We developed a method for in situ monitoring of sonodynamic cancer treatment. When we used a protocol composed of ultrasound exposure at an acoustic intensity of several hundreds of W/cm2 for a few seconds prior to exposure at an intensity of several tens of W/cm2 for 60 s, the generation of bubbles that caused cavitation were observed as brightness changes in ultrasound images. These brightness changes could be observed not only in in vitro experiments using a 10% Ethanol solution but also in in vivo experiments using tumor‐bearing mice. The results suggest that as the brightness changes persisted for longer periods, the treatment had a severer effect.

Effect of periodic shifting of relative phase in second-harmonic superimposition on inducing cavitation in vitro and in vivo

We reported that ultrasound exposure with second-harmonic superimposition (SHS) efficiently induced cavitational effects both in vitro and in vivo. This time we investigated the effect of periodical shifting of the relative phase on the cavitation induction by using SHS. In an aqueous solution, subharmonic emission intensity, a measure of cavitation intensity, obtained by using SH phase shifting with a shift pitch not larger than 1/2 /spl pi/ and a shift interval time not shorter than 30 ms was as much as that obtained with the optimum fixed SH phase. When exposed to tumor tissues subcutaneously implanted in mice, SH phase shifting with a shifting period larger than 10 ms was effective to suppress tumor growth, which roughly agree with in vitro results. This result may be important for the application of SHS to in vivo treatment in which it is difficult to maintain the relative phase in a target tissue constant because of movements and biophysical changes.