Ultrasound-Modulated Fluorescent Contrast Agent for Optical Detection of Cancer Lesions in Deep Tissue

Optical imaging in a highly scattering medium is effective only at very shallow depths which limits its use as a diagnostic tool in biomedical imaging, particularly for tumor detection. By combining optical and acoustic modalities, high-contrast, tumor state-relevant optical information at higher spatial resolutions can be achieved. Hybrid imaging modalities such as acousto-optic and photoacoustic imaging improve resolution over conventional optical imaging [1], but tissue scattering results in poor signal-to-background ratios especially in deeper tissues. To overcome these challenges, we have developed a novel microbubble (MB) contrast agent surface-loaded with a selfquenching fluorophore (Fig. 1a). In response to ultrasound, the MB expands and contracts, generating changes in the fluorophore surface density. The changes in physical separation between fluorophores modulate the quenching efficiency and produce a fluorescence intensity modulation (“blinking”). To our knowledge, this is the first experimental demonstration of ultrasound modulation of fluorescence intensity using a self-quenching MB scheme. The modulation is spatially localized to the ultrasound focal zone where the pressure is the greatest and the largest MB oscillations are induced. The modulated signal can be extracted from a large constant light background, increasing detection sensitivity. This technique can enable sensitive optical imaging with ultrasound-scale submillimeter spatial resolution, overcoming significant challenges of optical imaging in deep tissue.