Bursting Microbubbles with Ultrasound: A Platform Technology for Targeted Nanoparticle Delivery, Therapeutic Revascularization, and Tumor Ablation
(ERB203, 44 Cummington St.)
The research in our laboratory is focused on developing new therapeutic modalities based on the destruction of ~2-4 mm diameter intravascular contrast agent microbubbles with low frequency and/or high power targeted ultrasound. One major project in the lab is aimed at developing a minimally invasive approach for restoring blood flow to skeletal muscle that has become ischemic in response to peripheral arterial disease. Under certain conditions, ultrasonic microbubble destruction creates pores in capillary walls that subsequently trigger the growth of new capillaries and arterioles in skeletal muscle, leading to enhanced flow capacity. To determine the mechanism of this response, we have used knockout mouse models to show that the creation of these pores induces the recruitment of circulating bone marrow-derived cells, which then serve as paracrine vascular growth factor sources. Some of our earliest work in this area demonstrated that the pores created by ultrasonic microbubble destruction can facilitate the delivery of intravascular drug-bearing polymer nanoparticles to ultrasound-targeted tissue. We have now used this targeted delivery approach to deposit 100 nm diameter fibroblast growth factor-2 bearing polymer nanoparticles in ischemic skeletal muscle and amplify the baseline blood vessel growth responses. A second major project in the lab is aimed at developing an ultrasound-activated composite delivery agent wherein polymer nanoparticles are bound to microbubble shells. Here, our goal is to use ultrasound to enhance the deposition of chemotherapeutic nanoparticles in ultrasound-targeted brain tumors. Using a skeletal muscle model, we have shown that this composite agent is capable of more efficient nanoparticle delivery than the intravenous co-injection of nanoparticles and microbubbles. Ongoing studies now involve injecting this composite agent into the bloodstream of mice with implanted glioma tumors and determining the ability of targeted ultrasound to both mechanically ablate tumor microvessels and enhance nanoparticle transport to tumor tissue.