Focused ultrasound – a new way of enhancing drug delivery?

Original article: Blood–Brain Barrier Opening With Focused Ultrasound in Experimental Models of Parkinson’s Disease, Movement Disorders: July 30, 2019.

The takeaway

Focused ultrasound (FUS) represents a promising new area of investigation into improving the delivery of drugs and neurotrophic factors.

Why is it important?

The efficacy of any therapeutic is highly dependent on it reaching the neurons whose function it is designed to target, in the right concentration, and form. FUS offers promise in this respect.

Background

The neurons and non-neuronal glial cells that make up the brain are protected from potentially harmful toxins and other substances carried by the blood by what is known as the blood brain barrier, or BBB. The BBB can be thought of as a layered wall, consisting of the surface of the blood vessel, the glial cell and the outer surface of the neuron itself, which allows the selective passage of very small molecules.

It is this wall that therapeutics taken orally, for example, must get through. The effectiveness of any given therapeutic depends on the amount of it that manages to cross the BBB, the form in which it needs to be in order to do so, as well as our ability to deliver it to the right part of the brain which is affected by Parkinson’s.

This review piece presents the existing preclinical evidence supporting a potential role for focused ultrasound (FUS), as a method of selectively and reversibly disrupting the BBB for the effective delivery of therapeutics.

The details

In addition to oral administration, targeted methods to deliver drug directly into the brain have so far included transcranial injections or infusions, or delivery through the nose, which are either highly invasive and carry a significant risk of complications, or are not targeted enough to guarantee success.

Ultrasound coupled with the delivery of microbubbles has been proposed as the only non-invasive technique to temporarily, locally, and reversibly disrupt the BBB. The microbubbles are effectively made to enlarge or reduce in size depending on the frequency of the ultrasound and, in this way, create reversible gaps in the BBB. This method creates a window in time and space in which therapeutic molecules can be helped to enter the delicate brain tissue.

The authors review a number of animal studies in which this method has been used to deliver brain derived neurotrophic factor (BDNF), as well as glial derived neurotrophic factor (GDNF) and neurturin (NTN) which support neuronal growth, directly into the regions which are affected by Parkinson’s.

Using this method, higher levels of GDNF as well as neurturin were achieved in different animal models across a broader area compared with injections directly into the brain. Another animal study delivered BDNF through the nostrils to mice, along with FUS to the striatum on one side, a movement related area affected by Parkinson’s.

The researchers found a higher amount of bioavailable BDNF on the side of the striatum that had been subjected to ultrasound. In addition, a study addressing the effects of an alpha synuclein antibody in transgenic mice found that when this was delivered along with focused ultrasound, the treated animals had a 1.5 fold reduction in alpha synuclein compared to those which hadn’t received the ultrasound treatment.

Next steps

There are still many open questions and inconsistencies between sonification protocols: how many sessions and what frequencies are optimal, and which regions should be targeted, represent some of the important open questions.

More experimental evidence in suitable animal models is needed in order to develop the clinical applications of this promising technology. 

Related work and trials

Original article: Karakatsani ME, Blesa J, Konofagou EE. July 20, 2019. Blood–Brain Barrier Opening With Focused Ultrasound in Experimental Models of Parkinson’s Disease

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