title: Noninvasive Ablation of Prostate Cancer Spheroids Using Acoustically-Activated Nanodroplets.
abstract: We have developed acoustically activated nanodroplets (NDs) using an amphiphilic triblock copolymer, which self-assembles and encapsulates different perfluorocarbons including perfluoropentane (PFP) and perfluorohexane (PFH). Applying histotripsy pulses (i.e., short, high pressure, ultrasound pulses) to solutions of PFP- and PFH-NDs generated bubble clouds at a significantly reduced acoustic pressure compared to the cavitation pressure observed for histotripsy treatment alone. In this report, we summarize the results of combining histotripsy at low frequency (345 and 500 kHz) with PFP-NDs and PFH-NDs on the ablation of PC-3 and C4-2B prostate cancer cells. Using custom built histotripsy transducers coupled to a microscope and a high speed recording camera, we imaged the generation of a cavitation bubble cloud in response to different ultrasound regimes in solution and in tissue-mimicking gel phantoms. We quantified the associated ablation of individual cancer cells and 3D spheroids suspended in solution and embedded in tissue phantoms to compare the ablative capacity of PFP-NDs and PFH-NDs. Results show that histotripsy pulses at high acoustic pressure (26.2 MPa) ablated 80% of prostate cancer spheroids embedded in tissue-mimicking gel phantoms. In comparison, combining histotripsy pulses at a dramatically lower acoustic pressure (12.8 MPa) with PFP-NDs and PFH-NDs caused an ablation of 40% and 80% of the tumor spheroid volumes, respectively. These results show the potential of acoustically activated NDs as an image-guided ablative therapy for solid tumors and highlight the higher ablative capacity of PFH-NDs, which correlates with the boiling point of the encapsulated PFH and the stability of the formed bubble cloud.
authors.affiliation: Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Omer
authors.initials: O
authors.lastname: Aydin
authors.affiliation: Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Eli
authors.initials: E
authors.lastname: Vlaisavljevich
authors.affiliation: Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.|Department of Biomedical Engineering, School of Engineering and Natural Sciences, Istanbul Medipol University , Beykoz, Istanbul, 34810, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Yuksel Durmaz
authors.affiliation: Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.|Division of Pediatric Cardiology, Department of Pediatrics and Communicable Diseases, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.|Macromolecular Science and Engineering Program, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Mohamed E H
authors.initials: ME
authors.lastname: ElSayed
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D005466:Fluorocarbons / Q000737:chemistry* / Q000528:radiation effects; D057086:High-Intensity Focused Ultrasound Ablation / Q000379:methods*; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D019047:Phantoms, Imaging; D011108:Polymers / Q000737:chemistry* / Q000528:radiation effects; D011471:Prostatic Neoplasms / Q000628:therapy*; D018874:Spheroids, Cellular / Q000473:pathology / Q000528:radiation effects*; D014407:Tumor Cells, Cultured; D010420:Pentanes
chemical_list: D005466:Fluorocarbons; D011108:Polymers; C008806:perfluoropentane; D010420:Pentanes
keywords: acoustically activated nanodroplets; cavitation bubble cloud; histotripsy; perfluorocarbon; targeted cell ablation