Transluminal Approach with Bubble-Seeded Histotripsy for Cancer Treatment with Ultrasonic Mechanical Effects

Abstract

Bubble-seeded histotripsy (BSH) is a newly developed ultrasound-based mechanical fractionation technique using locally injected phase change nanodroplets (PCNDs) as sensitizers. The PCNDs are a kind of microbubble precursor compressed into submicron-size in droplets form, which were designed for local administration and will expand into microbubbles under ultrasound exposure. Previously, we reported that a combination of PCNDs injection and pulsed high-intensity focused ultrasound (pHIFU) with an acoustic intensity as low as about 3 kW/cm at 1.1 MHz, which is similar to the acoustic intensity of currently available HIFU coagulation therapy, was enough to induce tissue fractionation after significant antitumor effects in an in vivo study. Toward therapeutic application of BSH to deep-seated tissues such as the pancreas, the transluminal approach, using endoscopic ultrasound was thought to be ideal. Therefore, for a preliminary examination, we developed a new transducer with a small aperture (20- × 20-mm square) and long focal length (35 mm), operating at 2.1 MHz that could be attached to an EUS-mimicking probe. With the newly developed transducer and locally injected PCNDs, predictable tissue mechanical fractionation was observed in both ex vivo and in vivo studies at acoustic intensities that were too low to induce any significant bioeffects (around 4 kW/cm) without using PCNDs. For in situ monitoring of the treatment site during a procedure, the degree of attenuation of microbubble motions after exposing the microbubbles to pHIFU was monitored, using ultrafast echographic imaging. Microbubble movements were observed to be largest at 25-30 s after pHIFU exposure. On the contrary, after 40 s, the movement of microbubbles decreased to the same level as at the start of the procedure, suggesting that an overdose of pHIFU exposure causes coagulation attributable to the thermal effect caused by absorption of the energy. Those results were promising for expanding the application of BSH for a transluminal approach, using a small transducer under real-time monitoring.

Experimental and Computational Investigation of Clustering Behavior of Cyclodextrin–Perfluorocarbon Inclusion Complexes as Effective Histotripsy Agents

“…Nanodroplets (NDs) were developed as the first nanoparticles for nanoparticle-mediated histotripsy (NMH) as they successfully showed a decrease in the cavitation threshold. ,, Due to the challenging synthetic routes of NDs and indeterminacy of the quantity of perfluorocarbons (PFCs) loaded in the nanoparticle, next-generation nanoparticles were researched, , revealing the complexation potential of low-degree methylated βCD (LMβCD) as a host molecule incorporating perfluorohexane (PFH) into its core as a guest, resulting in an inclusion complex, namely, “nanocone (NC),” having a size of <50 nm for histotripsy applications. These agents contain PFCs as acoustically active compounds that can undergo phase transition through acoustic droplet vaporization (ADV) to generate and maintain the cavitation bubble cloud for ablation. , Perfluoropentane (PFP) and PFH are the most commonly used PFC derivatives for histotripsy because of their low boiling points (29 and 56 °C, respectively). − In addition, PFCs are chemically inert because they have strong fluorine–carbon bonds and are not metabolized in the body …”

Selective intracellular delivery of perfluorocarbon nanodroplets for cytotoxicity threshold reduction on ultrasound‐induced vaporization

“…Although cytotoxic threshold reduction occurred under in vitro conditions, further investigations are imperative to determine whether this effect occurs in vivo and whether adequate PCNDs can be delivered to extravascular tumor sites to induce internalization and aggregation. In particular, in cases where PCNDs are locally injected at tumor tissue sites, higher concentration of PCNDs could potentially be achieved . Moreover, use of low–boiling point PFCs as internal composites of droplets and application of increased ultrasound frequency would reduce the vaporization threshold.…”

A theoretical framework for acoustically produced luminescence: From thermometry to ultrasound pressure field mapping

“…New developments are constantly broadening the application range of US. For instance, the introduction of microbubbles for therapeutic use in recent years has shown potential for single cell therapy, gene therapy, blood-brain barrier opening, local drug delivery and histotripsy [5][6][7][8][9]. Moreover, the development of high-speed plane wave imaging over the past decade has opened the door for different branches of ultrasonic research in testing [10,11], microscopy [12,13], super localization and functional imaging [4,[14][15][16], particle manipulation [17][18][19][20][21][22] and non-linear US [2,10,23].…”