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. 2022 Apr 14:13:786475.
doi: 10.3389/fphar.2022.786475. eCollection 2022.

Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy

Gaetano Barbato  1   2 , Robert Nisticò  2   3 , Viviana Triaca  4
Affiliations

Exploiting Focused Ultrasound to Aid Intranasal Drug Delivery for Brain Therapy

Gaetano Barbato et al. Front Pharmacol. .

Abstract

Novel effective therapeutic strategies are needed to treat brain neurodegenerative diseases and to improve the quality of life of patients affected by Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral sclerosis (ALS) as well as other brain conditions. At present no effective treatment options are available; current therapeutics for neurodegenerative diseases (NDs) improve cognitive symptoms only transiently and in a minor number of patients. Further, most of the amyloid-based phase III clinical trials recently failed in AD, in spite of promising preclinical and phase I-II clinical trials, further pinpointing the need for a better knowledge of the early mechanisms of disease as well as of more effective routes of drug administration. In fact, beyond common pathological events and molecular substrates, each of these diseases preferentially affect defined subpopulations of neurons in specific neuronal circuits (selective neuronal vulnerability), leading to the typical age-related clinical profile. In this perspective, key to successful drug discovery is a robust and reproducible biological validation of potential new molecular targets together with a concomitant set up of protocols/tools for efficient and targeted brain delivery to a specific area of interest. Here we propose and discuss Focused UltraSound aided drug administration as a specific and novel technical approach to achieve optimal concentration of the drug at the target area of interest. We will focus on drug delivery to the brain through the nasal route coupled to FUS as a promising approach to achieve neuroprotection and rescue of cognitive decline in several NDs.

Keywords: brain circuit vulnerability; clinical trials; drug delivery; focused ultrasound; neurodegenerative diseases.

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Conflict of interest statement

Author BG is employed by Inno-Sol Srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of terminal capillaries targeted by the FUS stream. In the absence of FUS-induced cavitation, an intact BBB of a living animal (No FUS) with flowing red blood cells and peripherally (tail vein) injected microbubbles is depicted. Upon FUS stimulation and depending on the specific combination of acoustic pressure and frequency applied, a controlled stable cavitation with a balanced microbubbles expansion and compression or an inertial cavitation with a wide range of microbubbles diameters may be achieved by the operator at specific brain point locations. Both mechanisms leading to stretching of tight junctions in the endothelial cells of the final capillary allowing a 15′-12 h window of BBB opening and drugs delivery to adjacent brain parenchyma. In case of stable cavitation conditions microbubbles induce the opening of the capillary walls mainly through push-and-pull mechanisms and/or local microstreaming of the blood flow. If inertial cavitation takes place, microbubbles become unstable and collapse emitting high energy microjets or more rarely explode (fragmentation), in both cases facilitating the drug passage through the BBB, however often resulting in local inflammation/oxidative insult.
FIGURE 2
FIGURE 2
Brain target engagement by FUS-aided delivery of drugs in NDs therapy. A two steps experimental paradigm with the intranasal or systemic administration of the drug of choice, followed by FUS-driven local brain stimulation allowing non-invasive, targeted, and transient opening of the BBB at the region of interest for therapeutic purposes.
FIGURE 3
FIGURE 3
FUS-aided, non-invasive brain delivery of novel or repurposed drugs, as possible therapeutic application in three devastating neurodegenerative diseases of the human central nervous system, namely AD, PD and HD. Specific target regions are identified and selectively reached for FUS-aided drug delivery in neuroprotective/therapeutic approaches: hippocampus (HP) for AD, Substantia nigra (SN) for PD, and Caudate Putamen (CPu) for HD. NGF and BDNF in AD, L-Dopa or dopaminergic drugs in PD, and gene therapy or currently unknown molecules are proposed for intranasal FUS-aided therapy.
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