VEGFR2-targeted ultrasound contrast agents such as BR55 will likely prove useful in human for the early detection of tumors as well as for the assessment of response to specific treatments.

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Subharmonic scattering of phospholipid-shell microbubbles excited at relatively low acoustic pressure amplitudes (<30 kPa) has been associated with echo responses from compression-only bubbles having initial surface tension values close to zero. In this work, the relation between subharmonics and compression-only behavior of phospholipid-shell microbubbles was investigated, experimentally and by simulation, as a function of the initial surface tension by applying ambient overpressures of 0 and 180 mmHg. The microbubbles were excited using a 64-cycle transmit burst with a center frequency of 4 MHz and peak-negative pressure amplitudes ranging from 20 of 150 kPa. In these conditions, an increase in subharmonic response of 28.9 dB (P < 0.05) was measured at 50 kPa after applying an overpressure of 180 mmHg. Simulations using the Marmottant model, taking into account the effect of ambient overpressure on bubble size and initial surface tension, confirmed the relation between subharmonics observed in the pressure-time curves and compression-only behavior observed in the radius-time curves. The trend of an increase in subharmonic response as a function of ambient overpressure, i.e., as a function of the initial surface tension, was predicted by the model. Subharmonics present in the echo responses of phospholipid-shell microbubbles excited at low acoustic pressure amplitudes are indeed related to the echo responses from compression-only bubbles. The increase in subharmonics as a function of ambient overpressure may be exploited for improving methods for noninvasive pressure measurement in heart cavities or big vessels in the human body.

In this work, the use of a new carrier agent for intravascular laser-polarized 3 He imaging is reported. Lipid-based helium microbubbles were investigated. Their average diameter of 3 m, which is smaller than that of the capillaries, makes it possible to conduct in vivo studies. The NMR relaxation parameters T 1 , T 2 , and T* 2 of a microbubble suspension were measured as 90 s, 300 ms, and 4.5 ms, respectively, and in vivo images of encapsulated 3 He with signal-to-noise ratios (SNRs) larger than 30 were acquired. Dynamic cardiac images and vascular images of encapsulated 3 He were obtained in rats using intravenous injections of microbubble suspensions. Excellent preservation of Several optical pumping techniques (1-3) have been developed for polarization of the nuclear magnetic moments of two noble gas isotopes, 3 He and 129 Xe. These techniques offer NMR signal enhancements of five orders of magnitude compared to thermally polarized nuclei at room temperature.One important biomedical application of these hyperpolarized (HP) gases is the visualization by MRI of cavities such as the lungs (4 -7). Another potential application is their use as intravascular contrast agents. Initial in vivo NMR studies of blood-dissolved HP gas have already been performed on animals using polarized 129 Xe. The polarized nuclei can be delivered to blood and tissues directly from inhaled gas (7-11) or can be alternatively dissolved (12,13) in an appropriate emulsion (typically a lipid-enriched solution) and injected in a venous or arterial vessel.3 He possesses a larger nuclear magnetic moment value than 129 Xe and, at present, higher levels of polarization can be achieved with 3 He. Hence, for an equivalent number of nuclear spins, a typical gain of 10 in NMR signal amplitude can be achieved using 3 He instead of 129 Xe. Furthermore, due to the threefold-larger magnetic moment of helium, there is less demand on gradient magnetic field strength in 3 He MRI. Finally, xenon is well known for its lipophilic and anesthetic properties that may limit the amount of dissolved xenon acceptable in the blood.However, compared to xenon, helium is characterized by a much lower solubility (ϳ0.01 ml of dissolved gas per ml of fluid in blood and water (14) vs. ϳ0.1 for xenon). This precludes an efficient delivery of helium to the intravascular system from inhaled polarized helium. Similarly, major difficulties are encountered in the preparation of an injectable solution of dissolved helium. The first in vivo intravascular helium images were obtained (15) using helium microbubble suspensions. However, the large mean bubble diameter of these suspensions reported by the authors (on the order of 30 m) represented a major limitation for the safe in vivo use of these solutions.Fortunately, the problem of low dissolution coefficient can be overcome using an appropriate carrier agent. Recently, in vivo vascular images have been reported using encapsulated 3 He in microspheres of 5.3 m diameter (16) formed from human serum albumin.In this work, we propose...

In this work, the use of hyperpolarized (HP) 3He for in vivo intravascular imaging on animal is reported. To overcome the problem of the low solubility of helium in blood, we propose an approach based on helium encapsulation in lipid-based carrier agents. The mean diameter of the 3He microbubbles, measured equal to 3.0+/-0.2 microm, makes it possible to conduct in vivo studies. In vitro spectroscopy yielded a longitudinal relaxation time T(1) equal to 90 s and an apparent transverse relaxation time T(2)(*) of 4.5 ms. Angiographic imaging (venous and cardiac cavity visualization), as well as lung perfusion imaging, were demonstrated in rats using intravenous injections of microbubble suspensions. Suitable signal and spatial resolution were achieved. The potential of this technique for lung perfusion assessment was assessed using an experimental animal embolism model. Lung perfusion defects and recovery towards a normal perfusion state were visualized. This study was completed with the demonstration of a new ventilation-perfusion lung exploration method based entirely on HP 3He.