Reduction of cavitation threshold by second-harmonic superimposition and its potential application to sonodynamic therapy

Abstract

Acoustic cavitation is known to induce bioeffects under certain conditions. Cavitation threshold, the acoustic strength needed to induce such cavitation, in various biological systems was intensively studied by Dr. Dunn’s group. Their results have significantly contributed to the safety concerns of diagnostic and therapeutic uses of ultrasound. Acoustic cavitation is also known to be the primary cause of sonochemical reactions. Chemical compounds such as hematoporphyrin were found to be activated by acoustic cavitation and induce in vitro and in vivo antitumor effects thereby. In order to make use of this effect in therapeutic practice, cavitation must be generated reproducibly without depending on standing waves at acoustic power inducing no significant heating. It was also found that the cavitation threshold can be significantly reduced by superimposing the second harmonic onto the fundamental in insonation. The threshold was reduced by more than an order of magnitude, especially in the presence of a certain compound such as Rose Bengal (RB). An amphiphilic derivatives of RB, selectively accumulating in tumor tissues, was synthesized and used in combination with focused ultrasound with second-harmonic superimposition to treat experimental murine tumors, resulting in significant reduction of their sizes. A hypothesis on the mechanism behind this will also be discussed.