Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

Ozdas, Mehmet S.; Shah, Aagam S.; Johnson, Paul M.; Patel, Nisheet; Marks, Markus; Yaşar, Tansel Baran; Stalder, Urs; Bigler, Laurent; Behrens, Wolfger von der; Sirsi, Shashank R.; Yanik, Mehmet Fatih

doi:10.1038/s41467-020-18059-7

Cited by 53 publications

(31 citation statements)

References 70 publications

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“…On the other hand, focused US can be transmitted through the skull and brain tissue. Recent work has demonstrated the feasibility of US-stimulated release of drugs from liposomes in vivo [2]. We have also shown that in vitro, US can evoke multiple release events of a constant amount over 25 individual applications [6].…”

Section: Discussionmentioning

confidence: 75%

“…For diseases with episodic, paroxysmal expres-sion, another way to limit side-effects is to reduce exposure to active drugs inside the body by delivering the drug only when and where it is needed [1]. Time-selective focal triggering of drug release has the potential to reduce side-effects by limiting drug exposure to the specific time period and location at which therapeutic effects occur [2]. Such a possibility requires the development of on-demand drug delivery devices that sequester drugs so that they remain inert until required, and trigger release when necessary.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…FUS devices are constantly developed to be more suitable for clinical practice. Using nanoparticles that specifically target drugs in specific brain areas have been used as mediators to improve the targetability of FUS (Ozdas et al, 2020 ; Hou et al, 2021 ). FUS has been used effectively and safely for neuromodulation in small animals, non-human primates, and humans (Legon et al, 2018 ; Folloni et al, 2019 ; Baek et al, 2020 ) and is compatible with MRI and CT imaging techniques, showing considerable potential as a neuromodulation method for disabling neurological disorders.…”

Section: Focused Ultrasoundmentioning

confidence: 99%

Review of Noninvasive or Minimally Invasive Deep Brain Stimulation

Liu

Qiu

Hou

et al. 2022

Front. Behav. Neurosci.

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Brain stimulation is a critical technique in neuroscience research and clinical application. Traditional transcranial brain stimulation techniques, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS) have been widely investigated in neuroscience for decades. However, TMS and tDCS have poor spatial resolution and penetration depth, and DBS requires electrode implantation in deep brain structures. These disadvantages have limited the clinical applications of these techniques. Owing to developments in science and technology, substantial advances in noninvasive and precise deep stimulation have been achieved by neuromodulation studies. Second-generation brain stimulation techniques that mainly rely on acoustic, electronic, optical, and magnetic signals, such as focused ultrasound, temporal interference, near-infrared optogenetic, and nanomaterial-enabled magnetic stimulation, offer great prospects for neuromodulation. This review summarized the mechanisms, development, applications, and strengths of these techniques and the prospects and challenges in their development. We believe that these second-generation brain stimulation techniques pave the way for brain disorder therapy.

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“…This group used focused ultrasound energy to inertially cavitate bubbles to trigger drug release [ 32 ]. More recently, Ozdas et al demonstrated that low-intensity radiation-fragmentation pulses applied to liposome loaded-microbubbles could enhance targeted delivery of an encapsulated GABA A receptor agonist (muscimol) without compromising the blood–brain barrier integrity [ 33 ]. However, short physiological half-lives of the bubbles, limited drug-loading capacity on the shell, and incomplete drug release are challenges that remain unaddressed.…”

Section: Introductionmentioning

confidence: 99%

Improving Release of Liposome-Encapsulated Drugs with Focused Ultrasound and Vaporizable Droplet-Liposome Nanoclusters

et al. 2021

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Active targeted delivery of small molecule drugs is becoming increasingly important in personalized therapies, especially in cancer, brain disorders, and a wide variety of other diseases. However, effective means of spatial targeting and delivering high drug payloads in vivo are still lacking. Focused ultrasound combined with superheated phase-shift nanodroplets, which vaporize into microbubbles using heat and sound, are rapidly becoming a popular strategy for targeted drug delivery. Focused ultrasound can target deep tissue with excellent spatial precision and without using ionizing energy, thus can activate nanodroplets in circulation. One of the main limitations of this technology has been poor drug loading in the droplet core or the shell material. To address this need, we have developed a strategy to combine low-boiling point decafluorabutane and octafluoropropane (DFB and OFP) nanodroplets with drug-loaded liposomes, creating phase-changeable droplet-liposome clusters (PDLCs). We demonstrate a facile method of assembling submicron PDLCs with high drug-loading capacity on the droplet surface. Furthermore, we demonstrate that chemical tethering of liposomes in PDLCs enables a rapid release of their encapsulated cargo upon acoustic activation (>60% using OFP-based PDLCs). Rapid uncaging of small molecule drugs would make them immediately bioavailable in target tissue or promote better penetration in local tissue following intravascular release. PDLCs developed in this study can be used to deliver a wide variety of liposome-encapsulated therapeutics or imaging agents for multi-modal imaging applications. We also outline a strategy to deliver a surrogate encapsulated drug, fluorescein, to tumors in vivo using focused ultrasound energy and PDLCs.

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Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

Cited by 53 publications

References 70 publications

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

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

Review of Noninvasive or Minimally Invasive Deep Brain Stimulation

Improving Release of Liposome-Encapsulated Drugs with Focused Ultrasound and Vaporizable Droplet-Liposome Nanoclusters

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