Ultrasound-sensitive nanodroplets achieve targeted neuromodulation

Habenula as a Neural Substrate for Aggressive Behavior

“…Focused ultrasound is being intensively investigated as a novel non-invasive tool for neuromodulation that could be used to deliver pharmacological agents to localized brain areas, without the need of a systemic distribution ( 77 ). By repurposing a commercially available ultrasound contrast, Lea-Banks and colleagues fabricated an ultrasound-sensitive nanodroplet loaded with or without anesthetic drug, that was injected intravenously and then vaporized in a discrete brain target using focused ultrasound ( 78 , 79 ). The authors showed that the use of the unloaded nanodroplets increased local neuronal activity, while drug-loaded nanodroplets suppressed ( 78 , 79 ).…”

“…By repurposing a commercially available ultrasound contrast, Lea-Banks and colleagues fabricated an ultrasound-sensitive nanodroplet loaded with or without anesthetic drug, that was injected intravenously and then vaporized in a discrete brain target using focused ultrasound ( 78 , 79 ). The authors showed that the use of the unloaded nanodroplets increased local neuronal activity, while drug-loaded nanodroplets suppressed ( 78 , 79 ). Considering that the Hb is involved in the regulation of monoamines, such as those modulated by drug therapy, and the current evidence on the possibility of reducing the reward value of aggressive behavior by increasing neuronal firing in the LHb, one could envision further exploring this innovative technique to selectively deliver nanodroplets to the LHb and modulate its activity, to reduce aggressive behavior in patients with psychiatric disorders that do not present adequate response to conventional therapy.…”

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

“…For example, our data show that PFP-based nanoparticles not exposed to ultrasound (0 MPa datapoint in Figure 4) have twice the rate of spontaneous release compared with PFOB. Further, low boiling point PFCs can form persistent microbubbles after vaporization by ultrasound (Rapoport, 2016; Rapoport et al, 2009; Lea-Banks et al, 2021). In fact, with respect to PFC safety, the FDA has thus far approved PFCs with a high boiling point for large-scale use in humans—PFOB in particular.…”

“…When exposed to ultrasound, the PFC core has been hypothesized to change phase from liquid to gas, greatly expanding in volume, and thus mediating drug release (Sheeran et al, 2013; Doinikov et al, 2014; Shpak et al, 2014; Rapoport, 2016; Kripfgans et al, 2000). Harnessing this understanding, a majority of previous studies used nanoparticles with PFC boiling points below body temperature (Rapoport et al, 2007; Rapoport et al, 2009; Rapoport et al, 2011; Sheeran et al, 2012; Rapoport et al, 2015; Rapoport, 2016; Airan et al, 2017; Airan et al, 2017; Wang et al, 2018; Zhong et al, 2019; Wu et al, 2018; Lea-Banks and Hynynen, 2021; Lea-Banks et al, 2021). From safety perspective, however, the use of PFCs with higher boiling point is preferable to prevent a risk of embolism.…”

Predicting initial nucleation events occurred in a metastable nanodroplet during acoustic droplet vaporization

“…Upon external ultrasound stimulation above a certain threshold, these nanodroplets can be vaporized into microbubbles in situ , a process known as acoustic droplet vaporization (ADV) [1] , [2] , [3] , [4] . It can significantly enhance the ultrasound imaging in the tumor region for treatment guidance/monitoring [6] , [7] , meanwhile, can also perform therapeutic actions such as on-demand drug release [8] , [9] , cell sonoporation [10] , [11] , HIFU sensitization [12] , [13] , and targeted neuromodulation [14] , etc. For these theranostic applications, the PFC nanodroplets are expected to be reliable and effective only if they do not spontaneously vaporize or dissolve after intravenous injection in vivo , and also can be vaporized in situ with a low enough threshold to avoid adverse effects, hence requiring a trade-off between in vivo stability and ADV threshold [2] , [4] .…”