posted on 2020-03-09, 19:34authored byCarlos J. Brambila, Jacques Lux, Robert F. Mattrey, Dustin Boyd, Mark A. Borden, Caroline de Gracia Lux
Phase-change perfluorocarbon
microdroplets were introduced
over 2 decades ago to occlude downstream vessels in vivo. Interest
in perfluorocarbon nanodroplets has recently increased to enable extravascular
targeting, to rescue the weak ultrasound signal of perfluorocarbon
droplets by converting them to microbubbles and to improve ultrasound-based
therapy. Despite great scientific interest and advances, applications
of phase-change perfluorocarbon agents have not reached clinical testing
because of efficacy and safety concerns, some of which remain unexplained.
Here, we report that the coexistence of perfluorocarbon droplets and
microbubbles in blood, which is inevitable when droplets spontaneously
or intentionally vaporize to form microbubbles, is a major contributor
to the observed side effects. We develop the theory to explain why
the coexistence of droplets and microbubbles results in microbubble
inflation induced by perfluorocarbon transfer from droplets to adjacent
microbubbles. We also present the experimental data showing up to
6 orders of magnitude microbubble volume expansion, which occludes
a 200 μm tubing in the presence of perfluorocarbon nanodroplets.
More importantly, we demonstrate that the rate of microbubble inflation
and ultimate size can be controlled by manipulating formulation parameters
to tailor the agent’s design for the potential theranostic
application while minimizing the risk to benefit ratio.