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 the diffusion of the gas into the surrounding media. This demands an 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) (PMA_SH) 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) were employed to monitor the successful fabrication of multilayered particles and prove the pH-dependent shrinkage/swelling of the PMA_SH layer. This demonstrates that reduction in pH below healthy physiological levels resulted in significant increases in ultrasound contrast, in gel phantoms, mouse cadaver tissue, and live mice. The future of such materials could be developed into a platform of biomarker-responsive ultrasound contrast agents for clinical applications.