Delivery of Colloidal Particles and Red Blood Cells to Tissue Through Microvessel Ruptures Created by Targeted Microbubble Destruction With Ultrasound

TLDR

Ultrasound‑activated microbubbles can rupture microvessel walls (<7 µm) in vivo. The study tests whether microbubble‑induced ruptures can deliver drug‑bearing vehicles across the endothelium. Using an exteriorized rat spinotrapezius muscle, fluorescent red blood cells and 205‑/503‑nm polymer microspheres were injected intravascularly and delivered to muscle interstitium via microbubble‑induced ruptures. Red blood cells dispersed over ~14.5 × 10³ µm² per rupture, whereas 205‑ and 503‑nm microspheres dispersed over ~27.2 × 10³ µm² and 24.2 × 10³ µm², significantly larger than cells (P < 0.05).

Abstract

Background —We have previously shown that the application of ultrasound to thin-shelled microbubbles flowing through small microvessels (&lt;7 μm in diameter) produces vessel wall ruptures in vivo. Because many intravascular drug- and gene-delivery vehicles are limited by the endothelial barrier, we hypothesized that this phenomenon could be used to deliver drug-bearing vehicles to tissue. Methods and Results —An exteriorized rat spinotrapezius muscle preparation was used. Intravascular fluorescent red blood cells and polymer microspheres (PM) (205 and 503 nm in diameter) were delivered to the interstitium of rat skeletal muscle through microvessel ruptures created by insonifying microbubbles in vivo. On intravital microscopy, mean dispersion areas per rupture for red blood cells, 503-nm PM, and 205-nm PM were 14.5×10 3 μm 2 , 24.2×10 3 μm 2 , and 27.2×10 3 μm 2 , respectively. PM dispersion areas were significantly larger than the mean dispersion area for red blood cells ( P &lt;0.05). Conclusions —Microvessel ruptures caused by insonification of microbubbles in vivo may provide a minimally invasive means for delivering colloidal particles and engineered red blood cells across the endothelial lining of a targeted tissue region.