Sonoporation using nanoparticle-loaded microbubbles increases cellular uptake of nanoparticles compared to co-incubation of nanoparticles and microbubbles

Therapeutic agents can benefit from encapsulation in nanoparticles, due to improved
pharmacokinetics and biodistribution, protection from degradation, increased cellular uptake and
sustained release. Microbubbles in combination with ultrasound have been shown to improve the
delivery of nanoparticles and drugs to tumors and across the blood-brain barrier. Here, we evaluate
two different microbubbles for enhancing the delivery of polymeric nanoparticles to cells in vitro:
a commercially available lipid microbubble (Sonazoid) and a microbubble with a shell composed
of protein and nanoparticles. Various ultrasound parameters are applied and confocal microscopy
is employed to image cellular uptake. Ultrasound enhanced cellular uptake depending on the
pressure and duty cycle. The responsible mechanisms are probably sonoporation and sonoprinting,
followed by uptake, and to a smaller degree enhanced endocytosis. The use of commercial Sonazoid
microbubbles leads to significantly lower uptake than when using nanoparticle-loaded microbubbles,
suggesting that proximity between cells, nanoparticles and microbubbles is important, and that
mainly nanoparticles in the shell are taken up, rather than free nanoparticles in solution.