Ultrasound-Mediated Targeted Drug Delivery – SOUNDELIVERY

The proposed project must answer the following questions. What is the sonoporation mechanism: the formation of transient micropores in the cell membrane or other phenomenon such as stimulation of endocytosis? What are the physical effects generated by ACUs that trigger the process of sonoporation? How does a cell membrane repsond to an ultrasound and microbubbles excitation? What are the conditions for making a non-lethal sonoporation? How to identify and distinguish the acoustic signatures of microbubbles necessary for the permeabilization of biological barriers?

Theoretical models describing the behavior of contrast microbubbles have been developed to predict the acoustic phenomena of sonoporation.

Experimental validation

1. A. Doinikov; A. Bouakaz, “Microstreaming generated by two acoustically induced gas bubbles”, (2016), Journal of fluid mechanics, vol. 796
2. A. Doinikov ; A. Bouakaz, “Interaction of an ultrasound-activated contrast microbubble with a wall at arbitrary separation distances”, Phys. Med. Biol. 60 (2015) 7909–7925
3. A. Doinikov, A. Bouakaz, « Theoretical model for coupled radial and translational motion of two bubbles at arbitrary separation distances”, PHYSICAL REVIEW E 92, 043001 (2015)
4. A. Zeghimi, J.M. Escoffre, A. Bouakaz « Role of endocytosis in sonoporation-mediated membrane permeabilization and uptake of small molecules: a electron microscopy study, Phys. Biol, (2015), Nov 24; 12.

Targeted gene and drug delivery (delivery of a compound to a strictly localized site in the human body) is one of the most ambitious goals of modern therapy. Although a great amount of work is conducted worldwide on the research of various targeted gene and drug delivery systems, this goal still remains unachievable yet. In recent years, new promising possibilities for targeted delivery have been discovered based on the combination ultrasound and contrast agents (UCAs). UCAs are micron-sized encapsulated gas bubbles for an improved medical diagnosis. Besides, they can carry drugs and selectively adhere to specific sites in the human body. This capability, in combination with the effect known as sonoporation, provides great possibilities for localized gene and drug delivery. Sonoporation is a process in which ultrasonically activated UCAs, pulsating nearby biological barriers (cell membrane or endothelial layer), increase their permeability and thereby boost the penetration of external substances. In this way drugs and genes can be delivered inside individual cells without serious consequences for the cell viability. In addition, this delivery system promises to be a low-cost technology like other ultrasound technologies. However, the mechanisms of sonoporation are still today unknown.
The aim of the proposed project is to determine the physical and cellular mechanisms responsible for cell membrane permeabilization caused by sonoporation, investigating theoretically and experimentally the interaction between ultrasound waves, contrast agent microbubbles and cell membranes. In the present project, it is first planned to unite all the problems related to sonoporation and to solve them jointly using complementary disciplines such as ultrasound physics, microbubble dynamics, cell biology and molecular dynamics simulations.