Ultrasound and Microbubble-Induced Nanoparticle Delivery and Inflammatory Response in Ischemic Mouse Skeletal Muscle

Peripheral arterial occlusive disease is a major health problem worldwide. Patients diagnosed with more advanced stages of the disease face very poor prognosis and have limited treatment options. To this end, therapeutic vascular remodeling approaches facilitated by ultrasound and microbubble-mediated therapeutics studied have been developed with encouraging outcomes and demonstrated possibilities of being translated into more targeted and non-invasive therapies. This research sought to explore and examine the therapeutic agent delivery potential and bioeffects of the ultrasound-microbubble treatment modality in a peripheral arterial occlusive disease mouse model to serve as reference for future therapeutic vascular remodeling studies. In particular, this project aimed to determine how ultrasound peak negative pressures of 0.7 MPa, 0.55 MPa, 0.4 MPa and 0.2 MPa affect the distribution of nanoparticles delivered and the inflammatory response generated by ultrasound-microbubble interactions in ischemic mouse skeletal muscle. For studying nanoparticle delivery, 50 nm and 100 nm particles were introduced into mice either through femoral artery cannulations or jugular vein cannulations. For the femoral artery route, increased PNP resulted in increased delivery mostly to the interstitium for both nanoparticle sizes, whereas for the jugular vein route there was increased 50 nm nanoparticle delivery mostly to the endothelium as pressure increased up to 0.55 MPa. It was concluded that in coordination with microbubble concentration and size distribution, adjusting the peak negative pressure applied could be a feasible approach for improving the targeting specificity of NP delivery into the tissue. For studying inflammatory response, CD45+ cells were quantified in ultrasound-microbubble-treated muscle cross sections. The results implied no significant differences across the ultrasound peak negative pressures applied.