No abstract

Focused ultrasound (FUS) with microbubbles can temporally open the blood-brain barrier (BBB), and the cavitation activities of microbubbles play a key role in the BBB-opening process. Previous attempts used contrast-enhanced magnetic resonance imaging (CE-MRI) to correlate the mechanical index (MI) with the scale of BBB-opening, but MI only partially gauged acoustic activities, and CE-MRI did not fully explore correlations of pharmacodynamic/pharmacokinetic behaviors. Recently, the cavitation index (CI) has been derived to serve as an indicator of microbubble-ultrasound stable cavitation, and may also serve as a valid indicator to gauge the level of FUS-induced BBB opening. This study investigates the feasibility of gauging FUS-induced BBB opened level via the two indexes, MI and CI, through dynamic contrast-enhanced (DCE)-MRI analysis as well as passive cavitation detection (PCD) analysis. Pharmacodynamic/pharmacokinetic parameters derived from DCE-MRI were characterized to identify the scale of FUS-induced BBB opening. Our results demonstrated that DCE-MRI can successfully access pharmacodynamic/pharmacokinetic BBB-opened behavior, and was highly correlated both with MI and CI, implying the feasibility in using these two indices to gauge the scale of FUS-induced BBB opening. The proposed finding may facilitate the design toward using focused ultrasound as a safe and reliable noninvasive CNS drug delivery.

Microbubbles have been widely studied as ultrasound contrast agents for diagnosis and as drug/gene carriers for therapy. However, their size and stability (lifetime of 5-12min) limited their applications. The development of stable nanoscale ultrasound contrast agents would therefore benefit both. Generating bubbles persistently in situ would be one of the promising solutions to the problem of short lifetime. We hypothesized that bubbles could be generated in situ by providing stable air nuclei since it has been found that the interfacial nanobubbles on a hydrophobic surface have a much longer lifetime (orders of days). Mesoporous silica nanoparticles (MSNs) with large surface areas and different levels of hydrophobicity were prepared to test our hypothesis. It is clear that the superhydrophobic and porous nanoparticles exhibited a significant and strong contrast intensity compared with other nanoparticles. The bubbles generated from superhydrophobic nanoparticles sustained for at least 30min at a MI of 1.0, while lipid microbubble lasted for about 5min at the same settings. In summary MSNs have been transformed into reliable bubble precursors by making simple superhydrophobic modification, and made into a promising contrast agent with the potentials to serve as theranostic agents that are sensitive to ultrasound stimulation.

This study investigated the acoustic droplet vaporization (ADV) of perfluoropentane (PFP) droplets in single droplet-loaded macrophages (DLMs) by insonation with single three-cycle ultrasound pulses. Transient responses of intracellular ADV within a single DLM were observed with synchronous high-speed photography and cavitation detection. Ultrasound B-mode imaging was further applied to demonstrate the contrast enhancement of ADV-generated bubbles from a group of DLMs. The PFP droplets incorporated in a DLM can be liberated from the cell body after being vaporized into gas bubbles. Inertial cavitation can be simultaneously induced at the same time that bubbles appear. The coalescence of bubbles occurring at the onset of vaporization may facilitate gas embolotherapy and ultrasound imaging. Macrophages can be potential carriers transporting PFP droplets to avascular and hypoxic regions in tumors for ultrasound-controlled drug release and ADV-based tumor therapies.

Nanoscale gas bubbles residing on a macroscale hydrophobic surface have a surprising long lifetime (on the order of days) and can serve as cavitation nuclei for initiating inertial cavitation (IC). Whether interfacial nanobubbles (NBs) reside on the infinite surface of a hydrophobic nanoparticle (NP) and could serve as cavitation nuclei is unknown, but this would be very meaningful for the development of sonosensitive NPs. To address this problem, we investigated the IC activity of polytetrafluoroethylene (PTFE) NPs, which are regarded as benchmark superhydrophobic NPs due to their low surface energy caused by the presence of fluorocarbon. Both a passive cavitation detection system and terephthalic dosimetry was applied to quantify the intensity of IC. The IC intensities of the suspension with PTFE NPs were 10.30 and 48.41 times stronger than those of deionized water for peak negative pressures of 2 and 5MPa, respectively. However, the IC activities were nearly completely inhibited when the suspension was degassed or ethanol was used to suspend PTFE NPs, and they were recovered when suspended in saturated water, which may indicates the presence of interfacial NBs on PTFE NPs surfaces. Importantly, these PTFE NPs could sustainably initiate IC for excitation by a sequence of at least 6000 pulses, whereas lipid microbubbles were completely depleted after the application of no more than 50 pulses under the same conditions. The terephthalic dosimetry has shown that much higher hydroxyl yields were achieved when PTFE NPs were present as cavitation nuclei when using ultrasound parameters that otherwise did not produce significant amounts of free radicals. These results show that superhydrophobic NPs may be an outstanding candidate for use in IC-related applications.