Theranostic phospholipid-coated ultrasound contrast agents: response on demand

Assoc. Prof. Dr. K. Kooiman1), Erasmus MC University, Medical Center Rotterdam/The Netherlands

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Associate Prof. Dr. Klazina KooimanTherapeutic Ultrasound Contrast Agent Group, Department of Biomedical Engineering, Thoraxcenter, Erasmus Medical Center, Ee2302, P.O.Box 2040, 3000 CA Rotterdam, The Netherlands

People involved

Simone A.G. Langeveld, MSc (PhD fellow sponsored by the PRC) – Erasmus Medical Center, Rotterdam, The Netherlands (


Ultrasound contrast agents are comprised of phospholipid-coated gas microbubbles, 1-10 μm in size, that vibrate (expand and compress) in response to ultrasound. However, the vibration of current microbubbles is unpredictable and thus a huge problem for the new theranostic applications of microbubbles: ultrasound molecular imaging and drug delivery.1)2)3)4)5)6)

The aim of this proposal is to produce an innovative phospholipid-coated microbubble that does respond on demand, controlled by ultrasound. Three innovative steps must be taken to achieve this goal: 1. selection of phospholipids, 2. production of the microbubbles, and 3. characterization with state-of-the-art techniques like unique high-speed optical imaging (15 million frames per s recordings) to assess the microbubble’s vibration and 4Pi confocal microscopy to asses lipid miscibility and phase.

The new theranostic microbubbles will be evaluated in vitro and in vivo for their therapeutic drug delivery and diagnostic properties using up-to-date marker drugs and ultrasound scanner machines. This multi-disciplinary innovative project is expected to result in a breakthrough in the predictable response of theranostic microbubbles in an ultrasound field. This proposal brings two large research areas together which were up to now largely separated, namely the world of microbubbles as theranostics and the world of phospholipid research. The knowledge gained will greatly advance diagnoses and augment drug delivery. As a result, cancer and cardiovascular disease patients will benefit.

Benefit for the community

Most importantly, patients suffering from cardiovascular disease and cancer will benefit because of improved ultrasound molecular imaging and local drug uptake using microbubbles that respond predictable and on demand to ultrasound. In addition, this improvement will have an enormous impact on the quality of life during treatment and by that having a big social impact.

Visit the supervisors lab


van Rooij T, Daeichin V, Skachkov I, de Jong N, Kooiman K, 2015
Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy
Int. J. Hyperthermia 31, 90-106
Kooiman K, Kokhuis TJA, van Rooij T, Skachkov I, Nigg A, Bosch JG, van der Steen AFW, van Cappellen WA, de Jong N, 2014
DSPC or DPPC as main shell component influences ligand distribution and binding area of lipid-coated targeted microbubbles
Eur. J. Lipid Sci. Tech. 116, 1217-1227
Kooiman K, Vos HJ, Versluis M, de Jong N, 2014
Acoustic behavior of microbubbles and implications for drug delivery
Adv. Drug Deliv. Rev. 72, 28-48
Segers T, Versluis M, 2014
Acoustic bubble sorting for ultrasound contrast agent enrichment
Lab Chip 14, 1705-1714
Garg S, Thomas AA, Borden MA, 2013
The effect of lipid monolayer in-plane rigidity on in vivo microbubble circulation persistence
Biomaterials 34, 6862-6870
Kaya M, Feingold S, Hettiarachchi K, Lee AP, Dayton PA, 2010
Acoustic responses of monodisperse lipid-encapsulated microbubble contrast agents produced by flow focusing
Bubble Sci. Eng. Technol. 2, 33-40
Publications derived from the project:
Langeveld SAG, Schwieger C, Beekers I, Blaffert J, van Rooij T, Blume A, Kooiman K, 2020
Ligand Distribution and Lipid Phase Behavior in Phospholipid-Coated Microbubbles and Monolayers
Langmuir 36, 3221-3233
Kooiman K, Roovers S, Langeveld SAG, Kleven RT, Dewitte H, O'Reilly MA, Escoffre JM, Bouakaz A, Verweij MD, Hynynen K, Lentacker I, Stride E, Holland CK, 2020
Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery
Ultrasound Med. Biol. 46, 1296-1325
Beekers I, Lattwein KR, Kouijzer JJP, Langeveld SAG, Vegter M, Beurskens R, Mastik F, Verduyn Lunel R, Verver E, van der Steen AFW, de Jong N, Kooiman K, 2019
Combined Confocal Microscope and Brandaris 128 Ultra-High-Speed Camera
Ultrasound Med. Biol. 45, 2575-2582
Langeveld SAG, Beekers I, Collado-Lara G, van der Steen AFW, de Jong N, Kooiman K, 2021
The Impact of Lipid Handling and Phase Distribution on the Acoustic Behavior of Microbubbles
Pharmaceutics 13, 119
Langeveld SAG, Meijlink B, Kooiman K, 2021
Phospholipid-coated targeted microbubbles for ultrasound molecular imaging and therapy
Curr. Opinion Chem. Biol. 63, 171-179
Langeveld SAG, Meijlink B, Beekers I, Olthof M, van der Steen AFW, de Jong N, Kooiman K, 2022
Theranostic Microbubbles with Homogeneous Ligand Distribution for Higher Binding Efficacy
Pharmaceutics 14, 311
Beekers I, Langeveld SAG, Meijlink B, van der Steen AFW, de Jong N, Verweij MD, Kooiman K, 2022
Internalization of targeted microbubbles by endothelial cells and drug delivery by pores and tunnels
J. Controlled Release 347, 460-475
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