Abstract
The blood–brain barrier (BBB) is a major obstacle that prevents therapeutic drugs or genes from being delivered to the central nervous system. Therefore, it is important to develop methods to enhance the permeability of the BBB. We have developed echo-contrast gas (C3F8) entrapping liposomes (Bubble liposomes, BLs) that can work as a gene delivery tool in combination with ultrasound (US) exposure. Here, we studied whether the permeability of the BBB can be enhanced by the combination of BLs and high-intensity focused ultrasound (HIFU). Mice were intravenously injected with Evans blue (EB). BLs were subsequently injected, and the right hemispheres were exposed to HIFU. As a result, the accumulation of EB in the HIFU-exposed brain hemispheres was increased over that observed in the non-HIFU-exposed hemispheres, depending on the intensity and the duration of the HIFU. Similarly, the combination of BLs and HIFU allowed fluorescent-labeled antisense oligonucleotides to be delivered into the HIFU-exposed left hemispheres of the treated mice. Furthermore, a firefly luciferase-expressing plasmid DNA was delivered to the brain by the combination method of BLs and HIFU, which resulted in the increased gene expression in the brain at the focused-US exposure site. These results suggest that the method of combining BLs and HIFU together serves as a useful means for accelerating the permeability of BBB and thereby enabling antisense oligonucleotides or genes to be delivered to the focused brain site.
Highlights
In today’s rapidly aging society, there is an urgent need for the development of breakthrough treatments for refractory central nervous system (CNS) diseases such as Alzheimer’s disease or Parkinson’s disease
We examined whether the permeability of the blood–brain barrier (BBB) can be enhanced by the combination of Bubble Liposomes (BLs) and high-intensity focused ultrasound (HIFU), thereby enabling the delivery of nucleic acids or plasmid DNA expressing the luciferase gene into the brain at a focused US exposure site
Mice were intravenously injected with Evans blue dye (EB), BLs were subsequently injected, and the right hemispheres were exposed to HIFU
Summary
In today’s rapidly aging society, there is an urgent need for the development of breakthrough treatments for refractory central nervous system (CNS) diseases such as Alzheimer’s disease or Parkinson’s disease. The gene expression in CNS tissues by the local gene delivery with viral-vectors or non-viral vectors via intracranial injection has been demonstrated, but their gene expressions are shown in limited brain regions [2,3,4,5]. These direct injection methods are highly invasive, and the risk increases when the treatments are repeated. We examined whether the permeability of the BBB can be enhanced by the combination of BLs and high-intensity focused ultrasound (HIFU), thereby enabling the delivery of nucleic acids (e.g., antisense oligonucleotide) or plasmid DNA expressing the luciferase gene into the brain at a focused US exposure site
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