An On-Demand Drug Delivery System for Control of Epileptiform Seizures

Abstract

Drug delivery systems have the potential to deliver high concentrations of drug to target areas on demand, while elsewhere and at other times encapsulating the drug, to limit unwanted actions. Here we show proof of concept in vivo and ex vivo tests of a novel drug delivery system based on hollow-gold nanoparticles tethered to liposomes (HGN-liposomes), which become transiently permeable when activated by optical or acoustic stimulation. We show that laser or ultrasound simulation of HGN-liposomes loaded with the GABAA receptor agonist, muscimol, triggers rapid and repeatable release in a sufficient concentration to inhibit neurons and suppress seizure activity. In particular, laser-stimulated release of muscimol from previously injected HGN-liposomes caused subsecond hyperpolarizations of the membrane potential of hippocampal pyramidal neurons, measured by whole cell intracellular recordings with patch electrodes. In hippocampal slices and hippocampal–entorhinal cortical wedges, seizure activity was immediately suppressed by muscimol release from HGN-liposomes triggered by laser or ultrasound pulses. After intravenous injection of HGN-liposomes in whole anesthetized rats, ultrasound stimulation applied to the brain through the dura attenuated the seizure activity induced by pentylenetetrazol. Ultrasound alone, or HGN-liposomes without ultrasound stimulation, had no effect. Intracerebrally-injected HGN-liposomes containing kainic acid retained their contents for at least one week, without damage to surrounding tissue. Thus, we demonstrate the feasibility of precise temporal control over exposure of neurons to the drug, potentially enabling therapeutic effects without continuous exposure. For future application, studies on the pharmacokinetics, pharmacodynamics, and toxicity of HGN-liposomes and their constituents, together with improved methods of targeting, are needed, to determine the utility and safety of the technology in humans.

Ultrasound-Mediated Blood–Brain Barrier Disruption for Drug Delivery: A Systematic Review of Protocols, Efficacy, and Safety Outcomes from Preclinical and Clinical Studies

“…A minimally invasive strategy that has been employed to achieve this is via the application of ultrasound. The use of transcranial ultrasound for enhancing drug delivery in the CNS also extends beyond BBB disruption, including in functioning as an external trigger to initiate drug release from nanoparticles [4] at targeted areas of the BBB in diseases such as epilepsy [5]. While the use of ultrasound in disrupting the BBB was first described in the 1950s [6], it is within the last 20 years [7] that this technique has garnered significant research interest in improving drug delivery to the brain.…”

Harnessing Ultrasound for Targeting Drug Delivery to the Brain and Breaching the Blood–Brain Tumour Barrier

“…Given that ultrasound is a generally well-tolerated, non-radioactive, accessible and less invasive method of energy transmission into the body, sono-responsive drug delivery systems have been the subject of much research in controlled and selective drug delivery [ 14 , 142 , 143 ]. Drug carrier systems can be formulated to be sensitive to the mechanical and/or thermal biomechanisms of ultrasound, thereby allowing drug release from drug carriers in the selected region of interest on ultrasound stimulus exposure.…”

Brain-Targeted Drug Delivery

“…Focusing on intravenous administration for brain-targeted drug delivery, Nakano et al developed hollow-gold nanoparticles tethered to liposomes (HGN-liposomes) loaded with muscimol to be released by laser or ultrasound stimulation and to inhibit neurons and suppress epileptiform seizures [7]. The combination of ultrasound stimulation and intravenous administration of HGN-liposomes suppressed seizure activity in the hippocampus, demonstrating the therapeutic potential of HGN-liposomes for controlling epileptiform seizures without continuous exposure.…”