Simulation and in vivo validation of craniotomies in rats for the disruption of the blood brain barrier with focused ultrasound for drug delivery

2017 ◽  
Author(s):  
D. A. Hernandez ◽  
M. I. Gutierrez ◽  
A. Vera ◽  
D. Martinez-Fong ◽  
L. Leija
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Blood Brain ◽  
In Vivo Validation

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

2019 ◽  
Author(s):  
Megan C. Rich ◽  
Jennifer Sherwood ◽  
Aundrea F. Bartley ◽  
Quentin A. Whitsitt ◽  
W.R. Willoughby ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Rat Brain ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Temporal Specificity ◽  
Blood Brain ◽  
Barrier Opening ◽  
Blood Brain Barrier Opening

AbstractThere is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation.Graphical Abstract

scholarly journals Enhanced Delivery and Bioactivity of the Neurturin Neurotrophic Factor through Focused Ultrasound—Mediated Blood—Brain Barrier Opening in vivo

2015 ◽  
Vol 35 (4) ◽  
pp. 611-622 ◽  
Author(s):  
Gesthimani Samiotaki ◽  
Camilo Acosta ◽  
Shutao Wang ◽  
Elisa E Konofagou
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurotrophic Factor ◽  
Focused Ultrasound ◽  
Direct Injection ◽  
Brain Barrier ◽  
Injection Technique ◽  
Nigrostriatal Pathway ◽  
Blood Brain

The blood—brain barrier (BBB) constitutes a major obstacle in brain drug delivery. Focused ultrasound (FUS) in conjunction with microbubbles has been shown to open the BBB noninvasively, locally, and transiently to allow large molecules diffusion. Neurturin (NTN), a member of the glial-derived neurotrophic factor (GDNF) family, has been demonstrated to have neuroprotective and regenerative effects on dopaminergic neurons in vivo using invasive drug delivery methods. The brain's ascending nigrostriatal pathway is severely damaged in Parkinson's disease (PD), and therefore the substantia nigra (SN) and striatal caudoputamen (CP) were selected as the target areas. The objective of the study was to investigate whether safe and efficient NTN delivery can be achieved through FUS-induced BBB opening via intravenous administration, and thus trigger the neuroregeneration cascade in the nigrostriatal pathway. After the optimization of FUS parameters and target locations in the murine brain, NTN bioavailability and downstream signaling were detected and characterized through immunostaining. FUS significantly enhanced the delivery of NTN compared with the direct injection technique, whereas triggering of the signaling cascade was detected downstream to the neuronal nuclei. These findings thus indicate the potential of the FUS method to mediate transport of proteins through the blood—brain barrier in a PD animal model.

scholarly journals Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood–brain barrier opening

2016 ◽  
Vol 37 (4) ◽  
pp. 1236-1250 ◽  
Author(s):  
Carlos Sierra ◽  
Camilo Acosta ◽  
Cherry Chen ◽  
Shih-Ying Wu ◽  
Maria E Karakatsani ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Targeted Drug Delivery ◽  
Focused Ultrasound ◽  
Brain Barrier ◽  
Inertial Cavitation ◽  
Blood Brain ◽  
Targeted Drug ◽  
Cavitation Detection

Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood–brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood–brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

The Blood-Brain Barrier and Brain Drug Delivery

2006 ◽  
Vol 6 (9) ◽  
pp. 2712-2735 ◽  
Author(s):  
J. M. Koziara ◽  
P. R. Lockman ◽  
D. D. Allen ◽  
R. J. Mumper
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Present Report ◽  
Drug Carriers ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Anatomy And Physiology ◽  
Brain Drug Delivery ◽  
Blood Brain

The present report encompasses a thorough review of drug delivery to the brain with a particular focus on using drug carriers such as liposomes and nanoparticles. Challenges in brain drug delivery arise from the presence of one of the strictest barriers in vivo—the blood-brain barrier (BBB). This barrier exists at the level of endothelial cells of brain vasculature and its role is to maintain brain homeostasis. To better understand the principles of brain drug delivery, relevant knowledge of the blood-brain barrier anatomy and physiology is briefly reviewed. Several approaches to overcome the BBB have been reviewed including the use of carrier systems. In addition, strategies to enhance brain drug delivery by specific brain targeting are discussed.

scholarly journals Blood-brain barrier opening for facilitating drug delivery in neurological and neurodegenerative diseases in non-human primates

2018 ◽  
Author(s):  
Elisa E. Konofagou
Keyword(s):  
Neurodegenerative Diseases ◽  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Neurological Diseases ◽  
Brain Barrier ◽  
Blood Brain ◽  
Therapeutic Molecules ◽  
After Cancer ◽  
Large Animals

After cancer and heart disease, neurodegenerative diseases, such as Alzheimer's, Parkinson's, multiple sclerosis (MS), amythrophic lateral sclerosis (ALS), and neurological diseases take more lives each year than any other illness. Although great progress has been made in recent years toward understanding of central nervous system (CNS) diseases, few effective treatments and no cures are currently available. This is mainly because the blood-brain barrier (BBB) limits the delivery of the vast majority of systemically-administered drugs available to treat those diseases. The underlying hypothesis of this study is that delivery of therapeutic molecules is safe and effective through the blood-brain barrier (BBB) using Focused Ultrasound (FUS) in large animals in vivo. Our preliminary results have shown that the FUS technique can induce BBB opening entirely noninvasively, selectively and be monitored with MRI at sub-millimeter resolution in vivo. The specific aims are therefore to: 1) build a MRcompatible system for FUS targeting and monitoring in the MRI system; 2) test and demonstrate delivery of neurotrophic factors to the hippocampus and putamen of monkeys; 3) test and demonstrate delivery of inhibitors to the visual cortex of monkeys; and 4) assess the safety of the FUS method in monkeys.

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