Effect of polymeric microbubbles properties on their performance as acoustic cavitation enhancers for therapeutic applications

Microbubbles (MBs), gas bubbles encapsulated inside a stabilizing solid shell, have been investigated extensively in the field of therapeutic ultrasound (US). Exposing MBs to US can cause them to oscillate or collapse. When these physical phenomena (called acoustic cavitation) occur near biological tissues, it may lead to various therapeutic effects such as opening of biological barriers. Hard-shell (polymeric) MBs exhibit greater stability in aqueous medium than soft-shell (lipids) MBs. This improved stability is important since gas release should occur only after exposing the MBs to US in the tissue of interest. Among the polymers used for the formation of hard-shell MBs, poly(lactic-co-glycolic acid) (PLGA) is of great interest due to its biocompatibility, biodegradability, and ability to tune its mechanical properties and degradation kinetics. However, very little is known regarding how the PLGA MBs synthesis parameters affect their acoustic cavitation activity, and our ability to tune this activity. Here, we manipulated the MBs internal structure, gas core, size distribution, and shell thickness by modifying MBs synthesis parameters. Single-core MBs were formed by replacing the deionized water of the inner phase with polyvinyl alcohol aqueous solution. We showed that single-core MBs filled with C₃F₈ gas exhibit high stability and can produce cavitation effects for extended periods under continuous circulation compared to air-filled and SF₆-filled MBs. We demonstrated that different acoustic cavitation activities are obtained for MBs with different characteristics, and thus the cavitation behavior of MBs and their characteristics can be tailored to meet specific medical needs. Preliminary safety study done in vivo on a pig demonstrated that intravenously injected MBs were safe and did not cause adverse effects. Moreover, these MBs produced cavitation activity that increased the permeability of a pig’s blood-brain barrier, suggesting that our PLGA MBs have a potential for future therapeutic applications while having a better control over their activity and their performance as acoustic cavitation enhancers.