Dynamic solid-state ultrasound contrast agent for monitoring pH fluctuations .

The key challenge for biosensing is to design biomarker-responsive contrast agents that can be readily detected and monitored by broadly available biomedical imaging modalities. While a range of biosensors have been designed for optical, photoacoustic and magnetic resonance imaging (MRI) modalities, technical challenges have hindered the development of ultrasound biosensors, even though ultrasound is widely available, portable, safe, and capable of both surface and deep tissue imaging. Typically, contrast enhanced ultrasound imaging is generated by gas-filled microbubbles, however they suffer from short imaging times due to diffusion of gas into the surrounding media. We present an alternate approach to generate solid nanosensors that reveal pH-specific changes in ultrasound contrast in biological environments. Silica cores were coated with pH-responsive poly(methacrylic acid) (PMA) in a layer-by-layer (LbL) approach, and subsequently covered in a porous organosilica shell. Transmission electron microcopy (TEM) and confocal laser scanning micros-copy (CLSM) were employed to monitor the successful fabrication of the multilayered particles and to demonstrate pH dependent shrinkage/swelling of the PMA layer. Reduction in pH below healthy physiological levels was then shown to result in significant and reversible increases in ultrasound contrast both in gel phantoms, mouse cadaver tissue, and in live mice. The future of such materials could be developed into a platform of biomarker-responsive ultrasound contrast agents for clinical applications.