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Review
. 2015 Dec 10:219:61-75.
doi: 10.1016/j.jconrel.2015.08.059. Epub 2015 Sep 8.

Drug and gene delivery across the blood-brain barrier with focused ultrasound

Kelsie F Timbie  1 , Brian P Mead  1 , Richard J Price  2
Affiliations
Review

Drug and gene delivery across the blood-brain barrier with focused ultrasound

Kelsie F Timbie et al. J Control Release. .

Abstract

The blood-brain barrier (BBB) remains one of the most significant limitations to treatments of central nervous system (CNS) disorders including brain tumors, neurodegenerative diseases and psychiatric disorders. It is now well-established that focused ultrasound (FUS) in conjunction with contrast agent microbubbles may be used to non-invasively and temporarily disrupt the BBB, allowing localized delivery of systemically administered therapeutic agents as large as 100nm in size to the CNS. Importantly, recent technological advances now permit FUS application through the intact human skull, obviating the need for invasive and risky surgical procedures. When used in combination with magnetic resonance imaging, FUS may be applied precisely to pre-selected CNS targets. Indeed, FUS devices capable of sub-millimeter precision are currently in several clinical trials. FUS mediated BBB disruption has the potential to fundamentally change how CNS diseases are treated, unlocking potential for combinatorial treatments with nanotechnology, markedly increasing the efficacy of existing therapeutics that otherwise do not cross the BBB effectively, and permitting safe repeated treatments. This article comprehensively reviews recent studies on the targeted delivery of therapeutics into the CNS with FUS and offers perspectives on the future of this technology.

Keywords: Blood–brain barrier; CNS drug delivery; Focused ultrasound; Nanoparticles.

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Figures

Figure 1
Figure 1
Blood-Brain Barrier Biology. The blood-brain barrier presents a major obstacle to therapeutic delivery in the central nervous system. It is comprised of unusually abundant and structurally unique tight junctions between the vascular endothelial cells and a thick basement membrane. Regulation via astrocytes and pericytes maintain this barrier, preventing the passage of the vast majority of therapeutics.
Figure 2
Figure 2
Transcranial FUS with microbubbles is the only modality capable of achieving non-invasive, safe, repeated and targeted BBB disruption, leading to improved drug or gene delivery to the brain. Pre-clinical FUS studies in animals including mice and rats permit use of a single-element FUS transducer, due to favorable skull geometry. FUS can be guided with MR imaging and is capable of sub-millimeter resolution allowing precise targeting of structures in the CNS with minimal off-target effects.
Figure 3
Figure 3
Mechanism of focused ultrasound mediated blood-brain barrier disruption. Circulating microbubbles oscillate in the ultrasonic field, producing forces that act on the vessel wall to generate three bioeffects that permit transport across the blood-brain barrier: disruption of tight juctions, sonoporation of the vascular endothelial cells and upregulation of transcytosis.
Figure 4
Figure 4
Transcranial FUS leads to temporary and localized BBBD with no long term damage. A. Representative transverse contrast enhanced T1 MRI (top) and permeability maps (bottom) obtained at four time points after FUS-mediated BBBD. Arrows indicate the two FUS-treated regions. Ktrans values indicated by the color bar. B. Mean Ktrans values over time in FUS treated regions. Control indicates contralateral hemisphere at same anatomical location. Reprinted from Journal of Controlled Release, 162, J. Park, Y. Zhang, N. Vykhodtseva, F. a Jolesz, N.J. McDannold, The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound, 134–42, (2012) with permission from Elsevier.
Figure 5
Figure 5
FUS mediated delivery of anti-AB antibody reduces plaque load in the TgCRND8 mouse model of Alzheimer’s disease. A) Treatment with FUS increases delivery of anti-AB antibody BAM-10 in the targeted region (right) compared to the non-sonicated control (left). White boxes indicate area selected for inset. Scale bar 1mm, inset 100 µm. B) BAM-10 delivered with FUS (right column) colocalizes with plaque within 4 hrs post delivery and remains up to 4 days. Unsonicated control regions (left column) show no BAM-10 delivery. Scale bars 50 µm. C) FUS-MB enhanced delivery of BAM-10 reduces plaque load 4 days post treatment. Scale bar 1mm. Reprinted from PLoS One, 5(5), Jordão JF, Ayala-Grosso CA, Markham K, Huang Y, Chopra R, McLaurin J, Hynynen K, Aubert I, Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease, e10549, (2010) with permission.
Figure 6
Figure 6
Three weekly FUS BBBD treatments (weeks 1–3) mediated delivery of liposomal doxorubicin and prolonged survival in a rat glioma model. A) T2 weighted images of control, FUS-only and DOX-only groups showing rapid tumor growth during weeks 1–3. T2 weighted images of a long-term survivor in the FUS+DOX group shows rapid tumor growth in weeks 1–4 followed by tumor resolution. Hyperintensity at week 20 is due to an enlarged ventricle. Black box indicates treatment period. B) Tumor growth as measured by MRI for each experimental group. Note that no control animals (untreated tumors) survived past week 3. Black box indicates treatment period. Reprinted from J Control Release, 169, Aryal M, Vykhodtseva N, Zhang YZ, Park J, McDannold N, Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor and blood-brain barriers improve outcomes in a rat glioma model, 103–11, (2015) with permission from
Figure 7
Figure 7
FUS mediated delivery of scAAV9 leads to a dose-dependent transgene expression in mouse brain. Mice were treated with MRI guided FUS in the right striatum (a) or hippocampus (b–e) immediately prior to intravenous injection of scAAV9 bearing a gene for GFP under the ubiquitously active chicken β-actin promoter at doses of 5×108 (a,c,e left), 2.5×109 (b,e middle) or 1.25×1010 (d,e right) vg/g. Twelve days after treatment, GFP expression was assessed in coronal brain sections with immunohistrochemistry (a–d) or fluorescence microscopy (e). GFP expression was higher on the FUS-treated region (a,c,d,e, right) than the corresponding anatomical location on the contralateral hemisphere (a,c,d,e, left) at the two higher doses, but not the lowest dose. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.
Figure 8
Figure 8
FUS delivers large 60-nm brain-penetrating nanoparticles across the BBB. At one hour post sonication, low pressure sonication primarily delivers nanoparticles to the endothelium (A) while higher pressure delivers particles to the interstitium (B). After 24 hours, brain-penetrating particles have diffused away from the vessel, significantly increasing nanoparticle coverage in the interstitial space compared to both low and high pressure 1 hr timepoints (C, G). Control regions show no nanoparticle delivery (D). 60 nm brain-penetrating nanoparticles (BPN) diffuse in ex vivo brain tissue after injection, while uncoated particles (NP) are immobilized (E). 100 nm BPNs also exhibit diffusive behavior in brain tissue, as demonstrated by traces taken by particle tracking software, while 200 nm BPNs and both 100 and 200 nm uncoated NPs are immobilized (F). * indicates p<0.05. A,B,D,G,E reprinted from J Control Release, 189, Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, Shih TY, Swaminathan G, Tamargo RJ, Woodworth GF, Hanes J, Price RJ, Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused, 123–32, (2014) with permission from Elsevier. F reprinted from ACS Nano, 8(10), Nance E, Zhang C, Shih TY, Xu Q, Schuster BS, Hanes J, Brain-penetrating nanoparticles improve paclitaxel efficacy in malignant glioma following local administration, 10655–64, (2013) with permission from AAAS.
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