Opening of endothelial cell-cell contacts due to sonoporation

JOURNAL OF CONTROLLED RELEASE

卷:322

Article

Beekers, Ines¹  Vegter, Merel¹  Lattwein, Kirby R.¹  Mastik, Frits¹  Beurskens, Robert¹  van der Steen, Antonius F. W.^1,2  de Jong, Nico^1,2  Verweij, Martin D.^1,2  Kooiman, Klazina¹ 

[1] Erasmus MC, Dept Biomed Engn, Thoraxctr, Off Ee2302,POB 2040, NL-3000 CA Rotterdam, Netherlands

[2] Delft Univ Technol, Dept Imaging Phys, Lab Med Imaging, Bldg 22,Room D218,Lorentzweg 1, NL-2628 CJ Delft, Netherlands

关键词: Drug delivery;    Microbubbles;    Ultrasound;    Sonoporation;    Cell-cell contact opening;    High-speed imaging;   

DOI  :  10.1016/j.jconrel.2020.03.038

来源: Elsevier

【 摘 要 】

Ultrasound insonification of microbubbles can locally increase vascular permeability to enhance drug delivery. To control and optimize the therapeutic potential, we need to better understand the underlying biological mechanisms of the drug delivery pathways. The aim of this in vitro study was to elucidate the microbubbleendothelial cell interaction using the Brandaris 128 ultra-high-speed camera (up to 25 Mfps) coupled to a custom-built Nikon confocal microscope, to visualize both microbubble oscillation and the cellular response. Sonoporation and opening of cell-cell contacts by single alpha(V)beta(3)-targeted microbubbles (n = 152) was monitored up to 4 min after ultrasound insonification (2 MHz, 100-400 kPa, 10 cycles). Sonoporation occurred when microbubble excursion amplitudes exceeded 0.7 mu m. Quantification of the influx of the fluorescent model drug propidium iodide upon sonoporation showed that the size of the created pore increased for larger microbubble excursion amplitudes. Microbubble-mediated opening of cell-cell contacts occurred as a cellular response upon sonoporation and did not correlate with the microbubble excursion amplitude itself. The initial integrity of the cell-cell contacts affected the susceptibly to drug delivery, since cell-cell contacts opened more often when cells were only partially attached to their neighbors (48%) than when fully attached (14%). The drug delivery outcomes were independent of nonlinear microbubble behavior, microbubble location, and cell size. In conclusion, by studying the microbubble-cell interaction at nanosecond and nanometer resolution the relationship between drug delivery pathways and their underlying mechanisms was further unraveled. These novel insights will aid the development of safe and efficient microbubble-mediated drug delivery.

【 授权许可】

Free