Polymeric perfluorocarbon nanoemulsions are ultrasound-activated wireless drug infusion catheters

Abstract

Author Contributions QZ and RDA designed the experiments. QZ performed the chemistry of nanoparticle production and physicochemical characterization, carried out the pharmacokinetics study and in vivo biodistribution of the nanoparticles, and performed the in vitro/in vivo ultrasonic drug uncaging experiments, with guidance from MA and assistance from JBW and AK. Cryo-TEM imaging was performed by MAB, RHC, and NHN. QZ and BCY performed the ultrasound imaging and ultrasonic nicardipine uncaging experiments and their analysis. TI and KFW designed and performed the ultra-high-speed optical imaging and passive cavitation detection of the nanoemulsions. QZ, BCY, and RDA prepared the figures and wrote the manuscript, with input and edits from all the authors.

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

“…As the local propofol concentration required for inhibition is miniscule (tens of nanograms 56 ), this suggests that most of the propofol content of the nanoemulsions must be released nonspecifically to the rest of the brain, which is in fact a large quantity. Indeed, the authors observe significant propofol levels in the blood plasma (in the jugular vein) immediately following FUS treatment of frontal cortex 55 , which likely has nonspecific effects. Such systemic plasma levels are nearly half of the systemic propofol levels necessary to observe anesthetic effects 57 .…”

“…Therefore, for use in chronic treatments of many brain disorders, it is vital to achieve FUS-mediated drug release without compromising BBB as we demonstrated here. Recent studies by Airan et al 24,54,55 suggested that FUSsensitive perfluoropentane (PFP) nanoemulsions (instead of the microbubbles+liposomes used here) can allow delivery of lipophilic-only compounds to the brain without opening BBB. While highly interesting, these methods require extremely large amounts of encapsulated drug to be injected to observe any effects (nanoemulsions containing 1 mg kg −1 propofol need to be injected to show similar effects to systemic injection of only 2 mg kg −1 propofol).…”

Focused Ultrasound for Noninvasive, Focal Pharmacologic Neurointervention

“…The hydrophilic component of the surfactant faces the aqueous medium, whereas the hydrophobic component binds the drug payload and emulsifies the perfluorocarbon droplet. Our group has found that this platform is generalizable to a wide range of hydrophobic drugs, with similar release characteristics and nanoparticle properties regardless of the drug's identity (Zhong et al, 2019). This criterion allows encapsulation of virtually any drug that is small and hydrophobic, and therefore most drugs of neuropsychiatric interest, as these are the chemical features of drugs that can cross the intact BBB (Norinder and Haeberlein, 2002;Weksler et al, 2005;Geldenhuys et al, 2015).…”

“…Other potential uses for ultrasonic drug uncaging include focal treatment of vascular pathologies. Calcium channel blockers such as nicardipine have been encapsulated successfully in these nanoparticles and have been shown to be able to selectively dilate parts of the aorta based on where the uncaging ultrasound transducer was placed (Zhong et al, 2019). Budding applications of this work include the treatment of cerebral vasospasm, a common highly morbid complication of subarachnoid hemorrhage after cerebral aneurysm rupture (Condette-Auliac et al, 2001).…”

Nanosized Phase‐Changeable “Sonocyte” for Promoting Ultrasound Assessment

“…[14] There is growing interest in the development of PFC-based ultrasound contrast agents, and especially different shell materials were used to stabilize PFC nanodroplets. [14][15][16] However, most shell materials significantly affect the Laplace pressure and the vaporization threshold of nanodroplets, which prevent the tendency of PFC phase transition, leading to insensitivity to ultrasound stimulation. [17][18][19] Although low boiling point PFC (<30 °C) has been applied to overcome this main issue in ultrasound imaging due to its low acoustic activation threshold, it is challenging to produce stable PFC nanodroplets to avoid rapid evaporation.…”