A Hand-Held Magnetic Acoustic Device With Integrated Real-Time Monitoring for Targeted Drug Delivery

摘要

Advances in magnetic materials have enabled the development of new therapeutic agents that can be localized by external magnetic fields. These agents offer a potential means of improving treatment targeting and reducing the toxicity-related side effects associated with systemic delivery. Achieving sufficiently high magnetic fields at clinically relevant depths in vivo, however, remains a challenge. Similarly, there is a need for techniques for real-time monitoring that do not rely on magnetic resonance imaging (MRI). Here, we present a hand-held device to meet these requirements, combining an array of permanent magnets and a thin 64-element capacitive micromachined ultrasonic transducer (CMUT) interfaced to a real-time imaging system. Drug carrier localization was assessed by measuring the terminal velocity of magnetic microbubbles in a column of fluid above the magnetic array. It was found that the magnetic pull force was sufficient to overcome buoyancy at equivalent tissue depths of at least 35 mm and that the median terminal velocity ranged from 0.7 to 20 $mu text{m}$ /s over the distances measured. A Monte Carlo study was performed to estimate capture effectiveness in tumor microvessels over a range of different tissue depths and flow rates. Finally, B-mode and contrast-enhanced ultrasound (CEUS) imaging were demonstrated using a gel flow phantom containing a 1.6-mm diameter vessel. Real-time monitoring provided visual confirmation of retention of magnetic microbubbles along the vessel wall at a flow rate of 0.5 mL/min. These results indicate that the system can successfully retain and image magnetic microbubbles at tissue depths and flow rates relevant for clinical applications such as molecular ultrasound imaging of atherosclerosis, sonodynamic and antimetabolite cancer therapy, and clot dissolution via sonothrombolysis.