Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound

Poon, Charissa; McMahon, Dallan; Hynynen, Kullervo

doi:10.1016/j.neuropharm.2016.02.014

Cited by 120 publications

(100 citation statements)

References 170 publications

(237 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, the large neutral amino acid CMT transporter delivers L-3,4-dihydroxyphenylalanine (L-DOPA) to the brain in PD 240 , and the transferrin RMT can deliver therapeutic antibodies to the brain in various neurological conditions 4,241–243 . Other approaches, such as using nanoparticles 244 and/or opening the BBB by focused ultrasound 245,246 to improve the delivery of therapeutic agents to CNS, have been attempted.…”

Section: How Bbb Breakdown Affects Drug Deliverymentioning

confidence: 99%

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

2018

View full text Add to dashboard Cite

The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts, and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation, and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells, and microbial pathogens, and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain, post-mortem tissue and biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery, and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting BBB are presented.

show abstract

Section: How Bbb Breakdown Affects Drug Deliverymentioning

confidence: 99%

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

2018

View full text Add to dashboard Cite

show abstract

“…Soon after this, transient BBB opening was safely achieved by low‐intensity FUS combined with an ultrasound contrast agent (microbubbles) in rabbits, rodents, and primates . The potential of FUS BBB opening for targeted delivery of therapeutic agents, chemotherapy, immunotherapy, gene therapy, viral vectors, neural stem cells, and others is being tested extensively in animal models …”

Section: Bbb Opening To Halt Nigrostriatal Neurodegenerationmentioning

confidence: 99%

“…Thus, MRI‐guided FUS delivered at high intensity produces a focal increase of temperature that can be used for thermal ablation of the targeted brain tissue . On the other hand, MRI‐guided FUS delivered at low intensity combined with ultrasound contrast agents (ie, microbubbles) produces focally controlled mechanical stresses on the capillary walls that can temporarily open the blood–brain barrier (BBB), allowing for targeted delivery of therapeutic agents that would not otherwise move across the BBB in therapeutic quantity …”

mentioning

confidence: 99%

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

et al. 2019

View full text Add to dashboard Cite

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease‐modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood–brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease‐modifying therapy in very‐early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood–brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies—subthalamotomy and putaminal blood–brain barrier opening—could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society

show abstract

“…Intravenously delivered ligand-receptor based delivery schemes are attractive due to their targeting potential, but such vehicles are limited in their specificity, affinity and overall ability to deliver sufficient quantities of therapeutic agent through active transport mechanisms 1. BBB disruption using intravenously administered microbubbles stimulated with focused ultrasound (FUS) is an attractive noninvasive approach for permeabilizing the BBB due to its transient effect on vasculature 2-4, as well as its ability to target specific brain regions utilizing stereotaxic coordinates 5 and image guidance 6. Of particular interest, FUS-targeted gene delivery to the brain has been demonstrated with intravenously injected microbubbles and adeno-associated viral vectors 7-11.…”

Section: Introductionmentioning

confidence: 99%

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

et al. 2017

View full text Add to dashboard Cite

Focused ultrasound with microbubbles is being developed to transiently, locally and noninvasively open the blood-brain barrier (BBB) for improved pharmaceutical delivery. Prior work has demonstrated that, for a given concentration dose, microbubble size affects both the intravascular circulation persistence and extent of BBB opening. When matched to gas volume dose, however, the circulation half-life was found to be independent of microbubble size. In order to determine whether this holds true for BBB opening as well, we independently measured the effects of microbubble size (2 vs. 6 µm diameter) and concentration, covering a range of overlapping gas volume doses (1-40 µL/kg). We first demonstrated precise targeting and a linear dose-response of Evans Blue dye extravasation to the rat striatum for a set of constant microbubble and ultrasound parameters. We found that dye extravasation increased linearly with gas volume dose, with data points from both microbubble sizes collapsing to a single line. A linear trend was observed for both the initial sonication (R 2 =0.90) and a second sonication on the contralateral side (R 2 =0.68). Based on these results, we conclude that microbubble gas volume dose, not size, determines the extent of BBB opening by focused ultrasound (1 MHz, ~0.5 MPa at the focus). This result may simplify planning for focused ultrasound treatments by constraining the protocol to a single microbubble parameter -gas volume dose -which gives equivalent results for varying size distributions. Finally, using optimal parameters determined for Evan Blue, we demonstrated gene delivery and expression using a viral vector, dsAAV1-CMV-EGFP, one week after BBB disruption, which allowed us to qualitatively evaluate neuronal health.

show abstract

Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound

Cited by 120 publications

References 170 publications

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound

Contact Info

Product

Resources

About