Delivery of Encapsulated Doxorubicin by Ultrasound-Mediated Size Reduction of Drug-Loaded Polymer Contrast Agents

Low delivery efficiency combined with systemic toxicity of traditional chemotherapy provides a need for improved chemotherapeutic delivery. Within our laboratory, we have developed polymer ultrasound contrast agents (1.2–1.8 $\mu$m in diameter) containing doxorubicin (Dox) within the shell (100–150 nm). In vivo this platform is expected to circulate through the vasculature until activated at the tumor site with external focused ultrasound (US). In vitro, the agent is responsive to US and when insonated at peak positive pressure amplitudes of 0.69 MPa and above, shows dramatic size reduction, eventually reaching a mean particle size of 350 nm, presumably due to fragmentation of, or gas release from the agent. The resulting Dox-polymer particles retain the drug and are small enough to pass through the leaky pores (350–400 nm) within the tumor vasculature, providing a sustained intratumoral release of chemotherapeutic as the polymer degrades. In vivo studies using a VX2 liver tumor model have shown that the combination of the agent and US results in nearly 50% less drug delivered to the nontargeted, healthy liver ( $p$ $=$ 0.009) and a 110% increase ($p$ $=$ 0.004) in Dox delivery to the viable peripheral tissue of the tumor, relative to the uninsonated controls. This study shows how US-mediated destruction of drug-loaded polymer contrast agent can be used to deliver encapsulated drug for potential sustained release. Penetration mechanisms of these resulting particles and their ability to provide a sustained release from the tumor interstia will be explored in the future.