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Local drug delivery through ultrasound

Therapeutic application of ultrasound contrast agents

Researchers:   Joop Kouijzer , Gonzalo Collado Lara, Simone Langeveld, Sara Zullino, Kirby LattweinInes BeekersNico de JongKlazina Kooiman

Ultrasound contrast agents
Ultrasound contrast agents (UCA) are routinely used in perfusion imaging in cardiology as well as radiology. UCA contain gas microbubbles that are surrounded by a shell made from lipid, protein, sugar or polymer. The diameter of the microbubbles is in the range of 1 to 10 µm. Although UCA were initially developed to enhance diagnostic imaging, their potential as local drug delivery systems is now widely recognized and their use continues to expand. For more information on UCA, click here.

Local drug delivery
The aim is to achieve a specific pharmacological response of a therapeutic agent at a particular diseased site in the body using UCA. The benefits of locally delivered drugs are a more controlled biodistribution of the therapeutic agent which will not only reduce side-effects, but also improve therapeutic efficacy. A unique feature of ultrasound is local insonification which can be used to trigger drug release from an UCA-based drug delivery system only at the region of interest. In addition, ultrasound imaging will aid the guidance and monitoring of therapy. Given the presence of microvascular networks in nearly all tissues, local drug delivery using an UCA-based drug delivery system provides extensive possibilities for treating pathological tissues, including the treatment of vascular structures themselves.

UCA-based drug delivery systems
In general, two UCA-based drug delivery systems are distinguished. In the first system, the therapeutic agent is co-administered with the UCA so that the UCA circulates through the bloodstream alongside the therapeutic agent. When ultrasound is applied locally, endothelial cell membrane permeability will locally and transiently increase and the therapeutic agent will be taken up by the cell or tissue. This method is also referred to as sonoporation.

In the second system, the therapeutic agent is attached to or incorporated into the microbubbles. Microbubbles of different composition have been designed to carry hydrophilic as well as lipophilic therapeutic agents. When ultrasound is applied locally, these microbubbles are triggered to locally release their payload.

Research within the group of Dr. Klazina Kooiman is focused on the therapeutic use of ultrasound contrast agents.

Present Projects:

Dr. Kooiman received a prestigious Erasmus MC fellowship in 2015. The focus within this project is treating infective endocarditis, a bacterial infection of the native heart valve, using UCA. In 2016 Dr. Kooiman received a grant from the Phospholipid Research Center in Germany to produce and characterize an innovative phospholipid-coated microbubble for theranostic (combination of therapy and diagnostic) use. In 2018 Dr. Kooiman received the highly prestigious European Research Council (ERC) starting grant for the BUBBLE CURE project. The acronym stands for "Targeted microbubble vibrations to accurately diagnose and treat cardiac device-related bacterial biofilm infections".

Past Projects:

The BURST (Bubbles for UltRaSound and Therapy) project started in November 2004 and successfully finished in November 2008. It was a collaboration between our department, Philips Research Eindhoven, University of Twente, and University of Wageningen. Within this project polymer-shelled microbubbles were developed and characterized that were partly oil-filled.
We also successfully finished the European FP7 project Sonodrugs, a collaboration of 15 European partners. The focus in this project was on co-administration of microbubbles and drugs as well as developing new ultrasound contrast agents specific for drug delivery. We were also successfully in the NanoNextNL project, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners. The focus within this project was on ultrasound contrast agents for imaging and therapy. In the spring of 2018 Dr. Kooiman successfully finished her prestigious Veni personal grant from NWO, the Dutch Scientific Organization, division TTW (Applied and Engineering Sciences). She started this project entitled 'Treatment in sight through sound' in 2014. Within the project unique technology was created by coupling the Brandaris 128 ultra-high speed camera to a custom-built confocal microscope, see also The Brandaris 128..