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

The key challenge for in vivo 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 because of diffusion of the gas into the surrounding media. This alternate approach to generate nanosensors that reveal pH- specific changes in ultrasound contrast in biological environments. Silica cores were coated with pH-responsive poly(methacrylic acid) (PMASH) in a layer-by-layer (LbL) approach, and subsequently covered in a porous organosilica shell. Transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) was employed to monitor the successful fabrication of the multilayered particles and prove the pH- dependent shrinkage/swelling of the PMASH layer. Demonstrating that reduction in pH below healthy physiological levels resulted in significant 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. KEYWORDS: ultrasound, nanosensor, biosensor, pH, mouse, layer-by-layer, silica, organosilica In