Development of Acoustically Active Nanocones Using the Host–Guest Interaction as a New Histotripsy Agent

Abstract

Histotripsy is a noninvasive and nonthermal ultrasound ablation technique, which mechanically ablates the tissues using very short, focused, high-pressured ultrasound pulses to generate dense cavitating bubble cloud. Histotripsy requires large negative pressures (≥28 MPa) to generate cavitation in the target tissue, guided by real-time ultrasound imaging guidance. The high cavitation threshold and reliance on real-time image guidance are potential limitations of histotripsy, particularly for the treatment of multifocal or metastatic cancers. To address these potential limitations, we have recently developed nanoparticle-mediated histotripsy (NMH) where perfluorocarbon (PFC)-filled nanodroplets (NDs) with the size of ∼200 nm were used as cavitation nuclei for histotripsy, as they are able to significantly lower the cavitation threshold. However, although NDs were shown to be an effective histotripsy agent, they pose several issues. Their generation requires multistep synthesis, they lack long-term stability, and determination of PFC concentration in the treatment dose is not possible. In this study, PFC-filled nanocones (NCs) were developed as a new generation of histotripsy agents to address the mentioned limitations of NDs. The developed NCs represent an inclusion complex of methylated β-cyclodextrin as a water-soluble analog of β-cyclodextrin and perfluorohexane (PFH) as more effective PFC derivatives for histotripsy. Results showed that NCs are easy to produce, biocompatible, have a size <50 nm, and have a quantitative complexation that allows us to directly calculate the PFH amount in the used NC dose. Results further demonstrated that NCs embedded into tissue-mimicking phantoms generated histotripsy cavitation “bubble clouds” at a significantly lower transducer amplitude compared to control phantoms, demonstrating the ability of NCs to function as effective histotripsy agents for NMH.

Review on Acoustic Droplet Vaporization in Ultrasound Diagnostics and Therapeutics

“…The cavitation threshold of nanodroplet-mediated histotripsy is determined by the incident PNP [101], the frequency [102], and the elasticity of the surrounding medium [103]. For all studies involved, the cavitation threshold was significantly lower in NMH compared to conventional histotripsy [16, 102, 104], which would considerably reduce the risk of damaging healthy tissue outside the region of interest.…”

“…Third, the concentration of PFP is vital for the cavitation threshold. Rehman et al [16] have recently developed a novel type of nanocone (NC) made out of methylated β -cyclodextrin and filled with PFP. The NCs have a size smaller than 50 nm, which make them suitable for diffusion into the tumor intertissue.…”

“…The NCs have a size smaller than 50 nm, which make them suitable for diffusion into the tumor intertissue. They are also made by mixing two commercially available and FDA approved substances in a simple manner [16]. Khirallah et al [17] showed that the cavitation threshold decreases, when the concentration of these NC increases.…”

“…By benefiting from the broad potentials of ADV in medical applications, with consideration of its capability in localized noninvasive energy exposure, it is possible to utilize its effect in targeted drug delivery [4, 5], embolotherapy [6], ultrasound imaging [7–10], transdermal noninvasive drug delivery [11], theranostics [12, 13], thermal therapy [14, 15], and histotripsy [16, 17].…”

Bubble Cloud Behavior and Ablation Capacity for Histotripsy Generated from Intrinsic or Artificial Cavitation Nuclei

“…More recently, nanoparticle-mediated histotripsy (NMH) has been developed as a targeted ablation method that combines fluid-filled nanoparticles with histotripsy pulsing modalities (Vlaisavljevich et al 2013a;Yuksel Durmaz et al 2014;Aydin et al 2016;Khirallah et al 2019). Nanoparticles used in NMH can consist of perfluorocarbon (PFC) nanodroplets (NDs, »200À400 nm) (Yuksel Durmaz et al 2014;Vlaisavljevich et al 2015aVlaisavljevich et al , 2016a or recently developed PFC nanocones (NCs, »30À50 nm) (Rehman et al 2019). Unlike MBs, which lower the cavitation threshold by directly providing gas nuclei for seeding cavitation, NDs and NCs reduce the cavitation threshold for histotripsy because of the lower nucleation threshold of the PFC fluid inside the particles, matching the predictions of classic nucleation theory (Arvengas et al 2011;Vlaisavljevich et al 2016b;Miles et al 2018).…”