Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates

Abstract

Purpose Focused Ultrasound (FUS) in conjunction with systemically administered microbubbles has been shown to open the Blood-Brain Barrier (BBB) locally, non-invasively and reversibly in rodents and non-human primates (NHP), suggesting the immense potential of this technique. The objective of this study entailed the investigation of the physiologic changes in the brain following the FUS-induced BBB opening and their relationship with the underlying anatomy. Materials and Methods Pharmacokinetic analysis was implemented in NHP’s that received FUS at various acoustic pressures. Relaxivity mapping enabled the robust quantitative detection of the BBB opening as well as gray and white matter segmentation. Drug delivery efficiency was measured for pre-clinical validation of the technique. Results Based on our results, the opening volume and the amount of the gadolinium delivered were found mostly contained in the grey matter, while FUS-induced permeability and drug concentration varied depending upon the underlying brain inhomogeneity, and increased with the acoustic pressure. Conclusions Overall, apart from the in vivo protocols for BBB analysis developed here, this study also suggests the important role that FUS can have in efficient drug delivery via localized and transient BBB opening.

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…Despite highly positive evidence from preclinical studies, clinical trials of PD testing the delivery of different neurotrophic factors have been largely ineffective for several reasons, including dosage, poor distribution in the brain, poor retrograde transport, and late time points of delivery . FUS can partially address some of these issues primarily by improving the distribution of the deliverable molecule in the targeted location (Fig. ) and thus adjusting the dosage to balance sufficient deposition and saturation, rendering trophic factors a possible alternative for PD treatment …”

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

“…For example, there has not been clear guidance about how far bloodstream‐borne molecules will be able to travel into the interstitial milieu of the brain once having passed through the permeabilized BBB. Investigation of this question has used gadolinium‐enhanced MRI in the nonhuman primate brain; in these studies, penetration was limited to just a few millimeters . Dealing with relatively large brain structures as therapeutic targets in PD (like the putamen) is in need of further methodological experience about the best ways for harnessing FUS to achieve wide tissue distribution.…”

“…Investigation of this question has used gadolinium-enhanced MRI in the nonhuman primate brain; in these studies, penetration was limited to just a few millimeters. 30 Dealing with relatively large brain structures as therapeutic targets in PD (like the putamen) is in need of further methodological experience about the best ways for harnessing FUS to achieve wide tissue distribution. The variable density of capillary vascularity in different brain regions might pose a problem for determining ideal sonication parameters.…”

Focused ultrasound blood brain barrier opening mediated delivery of MRI-visible albumin nanoclusters to the rat brain for localized drug delivery with temporal control

“…We investigated the use of FUS for non-invasive neuromodulation by combining 279 FUS-induced BBBO and nanocluster drug delivery. The method presented takes 280 advantage of the BBB by using FUS BBBO to localize delivery of glutamate for 281 spatially specific neuromodulation [5,15,[33][34][35]. Our most important finding is that 282 ultrasound-triggered glutamate release from nanoclusters in vivo can increase neural 283 activity, as measured with increased cFOS staining.…”

“…(BBB) opening and albumin-based drug carriers that are MRI-visible to achieve 23 targeted drug delivery to the brain. FUS has gained attention as a tool for focal BBB 24 opening (BBBO) [4][5][6][7][8][9][10], and can penetrate the skull to safely open the BBB at specific 25 locations [5,[11][12][13][14][15][16]. It is an ideal tool for focal drug delivery due to its current use in 26 humans [17,18] and its non-invasive nature [19,20].…”