Remote spatiotemporally controlled and biologically selective permeabilization of blood-brain barrier.
The blood-brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system.
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Xiaobing
X
Xiong
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Yao
Y
Sun
Comprehensive Cancer Center, Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Anirudh
A
Sattiraju
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA; Comprehensive Cancer Center, Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem 27157, USA; Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Youngkyoo
Y
Jung
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA; Comprehensive Cancer Center, Brain Tumor Center of Excellence, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Akiva
A
Mintz
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA; Department of Biostatistics Sciences, Wake Forest School of Medicine, Winston-Salem 27157, USA.
Satoru
S
Hayasaka
Department of Radiology, Wake Forest School of Medicine, Winston-Salem 27157, USA. Electronic address: kingli@wakehealth.edu.
King C P
KC
Li
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002478:Cells, Cultured; D015870:Gene Expression; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006358:Hot Temperature; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D010539:Permeability; D011923:Rats, Nude; D013234:Stem Cells; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014464:Ultrasonic Therapy
D018840:HSP70 Heat-Shock Proteins; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D008156:Luciferases
Blood–brain barrier; Gadopentetate dimeglumine (PubChem CID: 55466); HSP70; High intensity focused ultrasound; Image guided drug delivery; Luciferin (PubChem CID: 5484207); MRI; Poly (lactide-co-glycolide) (PubChem CID: 23111554); Stem cells