The partitioning of nanoparticles to endothelium or interstitium during ultrasound-microbubble-targeted delivery depends on peak-negative pressure

Patients diagnosed with advanced peripheral arterial disease often face poor prognoses and have limited treatment options. For some patient populations, the therapeutic growth of collateral arteries (i.e. arteriogenesis) that bypass regions affected by vascular disease may become a viable treatment option. Our group and others are developing therapeutic approaches centered on the ability of ultrasound-activated microbubbles to permeabilize skeletal muscle capillaries and facilitate the targeted delivery of pro-arteriogenic growth factor-bearing nanoparticles. The development of such approaches would benefit significantly from a better understanding of how nanoparticle diameter and ultrasound peak-negative pressure affect both total nanoparticle delivery and the partitioning of nanoparticles to endothelial or interstitial compartments. Toward this goal, using Balb/C mice that had undergone unilateral femoral artery ligation, we intra-arterially co-injected nanoparticles (50 and 100 nm) with microbubbles, applied 1 MHz ultrasound to the gracilis adductor muscle at peak-negative pressures of 0.7, 0.55, 0.4, and 0.2 MPa, and analyzed nanoparticle delivery and distribution. As expected, total nanoparticle (50 and 100 nm) delivery increased with increasing peak-negative pressure, with 50 nm nanoparticles exhibiting greater tissue coverage than 100 nm nanoparticles. Of particular interest, increasing peak-negative pressure resulted in increased delivery to the interstitium for both nanoparticle sizes, but had little influence on nanoparticle delivery to the endothelium. Thus, we conclude that alterations to peak-negative pressure may be used to adjust the fraction of nanoparticles delivered to the interstitial compartment. This information will be useful when designing ultrasound protocols for delivering pro-arteriogenic nanoparticles to skeletal muscle.