High-sensitivity distribution mapping of iron, zinc and copper during spio-microbubbles facilitated focused ultrasound induced blood-brain barrier opening via laser ablation/inductively coupled plasma mass spectrometry

Focused ultrasound (FUS) with microbubbles (MBs) has been approved to achieve local blood-brain barrier disruption (BBBD), increasing the delivery of therapeutic agents into brain. Previous reports have demonstrated the use of medical imaging system (ultrasound, CT, MRI, SPECT, or PET) to observe the redistribution of the delivered substance. However, the redistribution of elements such as zinc or copper has not yet been discovered, nor their effects and roles to CNS after FUS sonications. Laser ablation/inductively coupled plasma mass spectrometry (LA-ICP-MS) is a sensitive analytical technique and is capable of quantitatively providing solid inorganic matrices distribution in tissues. In this study, LA-ICPMS was used to explore the feasibility of detecting the delivered iron (i.e. SPIO-conjugated MBs, SPIO-MBs) and its redistribution after magnetic targeting (MT), as well as the elements redistribution. The 1-MHz FUS (acoustic energy = 0.4-1.0 MPa, duty cycle = 10%, sonication time = 1 min) was exposed to left brain of rats following SPIO-MBs injection to induce BBBD (SPIO payload was 200 ± 19.6 μg by ICP-AES). A 0.5 T permanent magnet was attached to the rat's scalp for performing MT. The spatial elemental maps were performed with the LA-ICP-MS system excited by 213 nm Nd-YAG laser (energy = 1.6 mJ, frequency = 10 Hz, scanning speed = 90 μm/s). The distribution and concentration of elements including iron, copper, and zinc were analyzed. Results showed that LA-ICPMS performed high sensitivity in the detection of the elements distribution in the brain. The iron mapping revealed that SPIOs were highly concentrated at FUS exposed and MT performed sites. No obvious zinc and copper deposition within sonication regions were found after FUS sonication. This study confirmed the potential of LA-ICP-MS for providing highly-sensitive detection method for solid inorganic matrices in brain tissues, and tracing the redistribution of elements. Moreover, concurrent use of SPIO-MBs with MT further enhanced the SPIO delivery into the BBBD area. Future work includes using SPIO-MBs as a surrogate tracer to estimate drug delivery efficiency during BBBD.