Abstract
For local drug delivery of cerebral-disease treatment, focused ultrasound (FUS) has been proven to be able to disrupt blood brain barrier (BBB) locally and reversibly. In this study, we report on the first demonstration of gold nanorods (AuNRs) as a multi-modal - ultrasound (US) and photoacoustic (PA) - contrast agent for imaging FUS-induced BBB opening in vivo. Due to their nano-scale size, AuNRs tend to extravasate and accumulate at BBB opening foci. AuNRs used here are with the mean size of 40 nm by 10 nm. Under this aspect ratio, AuNRs own peak near-infrared optical absorption at ~800 nm, turning out to be a good PA contrast agent. It has been reported that US contrast enhancement by smaller than 1000-nm solid nanoparticles is not significant. Nonetheless, via transmission electron microscopy, we found that after extravasating from cerebral vessels at FUS-applied regions, AuNRs tend to aggregate, forming micrometer-sized clusters which may serve as strong US scatterers and offer US contrast enhancement. In our in vivo experiments, localized BBB disruption at the rat’s left brain parenchyma was achieved by delivering 1.5 MHz FUS energy in the presence of microbubbles. PEGylated AuNRs were then intravenously administered. 25-MHz ultrasound and photoacoustic imaging results (n = 8) showed that PA and US contrast at BBB disruption area in left brains could be enhanced by accumulated AuNRs while there were no changes observed in the right brains. In addition, in photoacoustic images, we observed higher local concentration of AuNRs at BBB opening foci than that in blood, which as well as the formation of AuNR clusters is inferred as the cause of US contrast enhancement. This discovered US contrast mechanism suggests that metallic nanoparticles smaller than 5 nm, which permits rapid and efficient renal clearance from the body, may potentially be used as a US contrast agent in such a study. In summary, from our results, AuNRs show the promise as a novel multi-modal - US and PA - contrast agent for identifying the location and variation of FUS based BBB opening and local drug delivery.