Nanoparticle delivery to the brain--By focused ultrasound and self-assembled nanoparticle-stabilized microbubbles

Andreas K O Åslund; Sigrid Berg; Sjoerd Hak; Ýrr Mørch; Sverre H Torp; Axel Sandvig; Marius Widerøe; Rune Hansen; Catharina de Lange Davies

doi:10.1016/j.jconrel.2015.10.047

Nanoparticle delivery to the brain--By focused ultrasound and self-assembled nanoparticle-stabilized microbubbles

J Control Release. 2015 Dec 28;220(Pt A):287-294. doi: 10.1016/j.jconrel.2015.10.047. Epub 2015 Oct 28.

Authors

Andreas K O Åslund¹, Sigrid Berg², Sjoerd Hak³, Ýrr Mørch⁴, Sverre H Torp⁵, Axel Sandvig⁶, Marius Widerøe³, Rune Hansen², Catharina de Lange Davies⁷

Affiliations

¹ Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway. Electronic address: andreas.aslund@ntnu.no.
² SINTEF Technology and Society, P.O. box 4760 Sluppen, 7465 Trondheim, Norway; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
³ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁴ SINTEF Materials and Chemistry, P.O. box 4760 Sluppen, 7465 Trondheim, Norway.
⁵ Department of Pathology and Medical Genetics, St.Olavs University Hospital, Trondheim, Norway; Department of Neuroscience, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
⁶ Department of Neuroscience, Norwegian University of Science and Technology, 7491 Trondheim, Norway; Division of Pharmacology and Clinical Neuroscience, Department of Neurosurgery, Umeå University Hospital, Umeå, Sweden.
⁷ Department of Physics, Norwegian University of Science and Technology, 7491 Trondheim, Norway.

PMID: 26518721
DOI: 10.1016/j.jconrel.2015.10.047

Abstract

The blood-brain barrier (BBB) constitutes a significant obstacle for the delivery of drugs into the central nervous system (CNS). Nanoparticles have been able to partly overcome this obstacle and can thus improve drug delivery across the BBB. Furthermore, focused ultrasound in combination with gas filled microbubbles has opened the BBB in a temporospatial manner in animal models, thus facilitating drug delivery across the BBB. In the current study we combine these two approaches in our quest to develop a novel, generic method for drug delivery across the BBB and into the CNS. Nanoparticles were synthesized using the polymer poly(butyl cyanoacrylate) (PBCA), and such nanoparticles have been reported to cross the BBB to some extent. Together with proteins, these nanoparticles self-assemble into microbubbles. Using these novel microbubbles in combination with focused ultrasound, we successfully and safely opened the BBB transiently in healthy rats. Furthermore, we also demonstrated that the nanoparticles could cross the BBB and deliver a model drug into the CNS.

Keywords: Blood–brain barrier; Drug delivery; Focused ultrasound; Microbubble; Nanoparticle; PBCA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood-Brain Barrier / metabolism*
Capillary Permeability*
Drug Carriers*
Drug Compounding
Enbucrilate / chemistry*
Female
Fluorescent Dyes / chemistry
Fluorescent Dyes / metabolism*
Magnetic Resonance Imaging
Microbubbles*
Nanoparticles*
Nanotechnology
Oxazines / chemistry
Oxazines / metabolism*
Rats, Sprague-Dawley
Ultrasonics / methods*

Substances

Drug Carriers
Fluorescent Dyes
Oxazines
Enbucrilate
nile red