Quantification of Vaporised Targeted Nanodroplets

G. Zhang, S. Lin, C.H. Leow, K. Tian Pang, J. Hernández-Gil, N. J.Long, R. J. Eckersley, T. Matsunaga, and M.X. Tang, “Quantification of Vaporised Targeted Nanodroplets Using High-Frame-Rate Ultrasound and Optics

Accepted by Ultrasound in Medicine & Biology


DOI: https://doi.org/10.1016/j.ultrasmedbio.2019.01.009


Affiliation

G. Zhang, S. Lin, C. H. Leow, and M.-X. Tang are with the Ultrasound Laboratory for Imaging and Sensing Group, Department of Bioengineering, Imperial College London, London, SW7 2AZ, U.K. (email: mengxing.tang@imperial.ac.uk)

K. Tian Pang is with the Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.

J. Hernández-Gil and N. J. Long are with Department of Chemistry, Imperial College London, London, SW7 2AZ, U.K.

R. J. Eckersley is with the Division of Imaging Sciences, Biomedical Engineering Department, King’s College   London, London, SE1 7EH, U.K.

T. Matsunaga is with the Department of Medical Imaging, University of Arizona, United States of America.



Abstract:

Molecular targeted nanodroplets, promising to extravasate beyond the vascular space, have great potential to improve tumor detection and characterization. High frame rate ultrasound, on the other hand, is an emerging tool for imaging at a frame rate 1-2 orders of magnitude higher than common existing ultrasound operating systems. In this study, we used high frame rate ultrasound combined with optics to study the acoustic response and size distribution of Folate Receptor (FR) – targeted versus Non-Targeted (NT)-nanodroplets in vitro with MDA-MB-231 breast cancer cells immediately after ultrasound activation. A flow velocity mapping technique, Stokes’ theory, and optical microscopy were used to estimate the size of both floating and attached vaporized nanodroplets immediately after activation. It was found that the size of floating vaporized nanodroplets was on average more than 7 times larger than the size of vaporized nanodroplets attached to the cells. The results also showed that the acoustic signal of vaporized FR-nanodroplets was persistent after activation, with 70% of the acoustic signals still present 1 second after activation, compared to the vaporized NT-nanodroplets where only 40% of the acoustic signal remains. The optical microscopic images showed on average 6 times more vaporized FR-nanodroplets generated with a wider range of diameters (from 4 to 68 µm) that still attach to the cells compared to vaporized NT-nanodroplets (from 1 to 7 µm) with non-specific binding after activation. It was also found that the mean size of attached vaporized FR-nanodroplets was on average about 3-fold larger than that of attached vaporized NT-nanodroplets. The study offers an improved understanding of the vaporization of the targeted nanodroplets in terms of their sizes and acoustic response in comparison with non-targeted ones, taking advantage of high-frame-rate contrast-enhanced ultrasound and optical microscopy. Such understanding would help design optimized methodology for imaging and therapeutic applications.



Supporting Bodies:

The research was partially funded by the UK EPSRC under Grants EP/N015487/1, EP/N014855/1 and EP/M011933/1, and the CRUK Multidisciplinary Project Award (C53470/A22353).



Ultrasound imaging of Opticell chamber before and after activation. Two layers can be visualized in the video. The top layer is the top plane of the Opticell chamber. The bottom layer is the bottom plane of the Opticell chamber with the MDA-MB-231 breast cancer cells grown on it. As can be seen from the video that, after the ultrasonic activation, the bottom layer with folate receptor (FR)-targeted nanodroplets shows a higher contrast signal compared to the non-targeted (NT)-nanodroplets.

Flow velocity mapping of activated nanodroplets within the Opticell chamber

After ultrasonic activation, the folate-receptor targeted (FR)-nanodroplets show a wider distribution in terms of diameter compared to the non-targeted (NT)-nanodroplets.