Nanobubble Ultrasound Contrast Agents for Cancer Detection and Targeted Drug Delivery

A. Exner
Case Western Reserve University,
United States

Keywords: cancer detection, drug delivery, nanomaterials


Interest in ultrasound contrast agents (or microbubbles), has grown rapidly during the past two decades in applications ranging from echocardiography to cancer detection and therapy. Microbubbles typically consist of a gas stabilized by a lipid, polymer or protein shell and range in diameter from 1-10 ┬Ám. Their large size confines them to the vasculature and permits superb detection at very low (nearing picomolar) concentrations, while their shell structure permits robust functionalization with various targeting entities. Furthermore, microbubbles are susceptible to on-demand disruption with higher power ultrasound, which makes them ideal for drug delivery applications, especially in cancer management. Despite their fantastic attributes, a significant challenge in ultrasound contrast agent formulation is development of particles which are highly echogenic yet sufficiently small in size to enable detection of targets residing beyond the vasculature. Contrast agents that could offer the benefits of microbubbles but with a much smaller nanoparticle-like footprint would revolutionize the field. To meet this challenge, our group has formulated a series of nanoparticle-based ultrasound contrast agents, which we call nanobubbles, which appear to be comparable in ultrasound signal to clinically-available microbubbles, but which are also much more stable, offer additional cargo space for drug loading and enable simple functionalization all with a size of ~100 nm. The nanobubbles are a perfluoropropane (C3F8) gas core stabilized with lipids and the surfactant, Pluronic. Additional stabilization with N,N diethylacrylamide provides a scaffold for drug loading. The nanobubbles, functionalized with a superbly selective, high affinity ligand or antibody, are able to penetrate into the tumor from the vasculature, making them ideal for molecular imaging applications. The strategy can also be expanded beyond tumor detection and into image-guided therapeutics. Ultrasound contrast agents have been used for delivery of anticancer agents by a number of groups to target agents to tumor vasculature. With properly targeted nanobubbles, this strategy can be more effective since the bubbles will be in closer proximity to the tumor cells. Together nanobubble-mediated detection and therapy of cancer has the potential to become an exciting alternative direction in management of this disease