Gas-stabilizing solid cavitation nuclei for systemic or transdermal ultrasound-enhanced drug and vaccine delivery and immunomodulation

Originally developed for diagnostic purposes and already approved for clinical use, lipid and protein-shelled microbubbles were a natural choice as initial nucleation agents for cavitation-based therapies entering the clinic. However, several emerging therapeutic ultrasound applications require nuclei that: (i) are significantly smaller in size, in order to overcome a particular biological barrier such as the leaky vasculature of tumours or the stratum corneum; (ii) offer greatly increased cavitation persistence, both during a single extended ultrasound pulse and in terms of extended circulation following intravenous administration; (iii) have better resilience to sudden ambient pressure changes in order to enable direct injection without nuclei destruction into tissue targets via a needle and syringe; and (iv) are made of materials or have an increased payload or surface area that can interact beneficially with the relevant tissue target during or following cavitation. Gas-stabilizing solid particles will be reviewed in this context, providing an overview of their known characteristics in terms of size distribution, associated acoustic emissions, cavitation thresholds, cavitation persistence and circulation. The relationship between this acoustic characterization and associated bioeffects including drug and vaccine delivery, and immunomodulation will subsequently be explored.