Echogenic nanoparticles for ultrasound technologies: Evolution from diagnostic imaging modality to multimodal theranostic agent

Ultrasound technology in combination with echogenic particles is currently having a considerable effect on the modern medical field, not only as a conventional diagnostic modality but also as a methodology that administers therapeutics to various lesions. The diagnostic and therapeutic effects of ultrasound technologies on diseased sites are governed by several primary factors such as the ultrasound technique itself and the physicochemical properties of echogenic particles. Therefore, rational design and a good combination of echogenic particles with the ultrasound technique are the most decisive factors in achieving optimal diagnostic and therapeutic goals. In this respect, great research advances in design and engineering of echogenic particles to meet these diagnostic and therapeutic demands have consistently been made. Since echogenic particles exhibit quite different behaviors in response to ultrasound, the most important issue in achieving maximal therapeutic efficacy must be the establishment of technical rationales that depend on these particles' biomedical uses, from the selection of shell materials and gas types to the manufacturing techniques used to make particles of the proper diameter. Several attempts have been made to develop highly effective theranostic echogenic particles that have the proper particle size and yet can sustain intense echo signals for long enough to circulate repeatedly through the body, a primary requirement for targeting and accumulating at a diseased site. However, a very important challenge has been the technical barrier between the most favorable in vivo nano-size for desirable biodistribution and the obtaining of a strong echo intensity. In this review paper, the present status and the critical issues for developing theranostic echogenic particles as an ultrasound contrast agent and drug delivery vehicle will be described. Firstly, conventional micro-sized echogenic particles are comprehensively introduced with their research history, diagnostic applications and intrinsic limitations. Then recent progress in developing more advanced echogenic particles for diagnostic and therapeutic purposes will be described. Most importantly, in this review paper, the design criteria for developing promising theranostic echogenic particles to satisfy recent research and clinicians' demands will be given, with special emphasis on overcoming the conflicting and insuperable size issue of echogenic particles.