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Ultrasound-mediated delivery enhances therapeutic efficacy of MMP sensitive liposomes


To improve therapeutic efficacy of nanocarrier drug delivery systems, it is essential to improve their uptake and
penetration in tumour tissue, enhance cellular uptake and ensure efficient drug release at the tumour site. Here
we introduce a tumour targeting drug delivery system based on the ultrasound-mediated delivery of enzyme
sensitive liposomes. These enzyme sensitive liposomes are coated with cleavable poly(ethylene glycol) (PEG)
which will be cleaved by two members of the enzyme matrix metalloproteinase family (MMP-2 and MMP-9).
Cleavage of the PEG coat can increase cellular uptake and will destabilize the liposomal membrane which can
result in accelerated drug release. The main aim of the work was to study the effect of focused ultrasound and
microbubbles on the delivery and therapeutic efficacy of the MMP sensitive liposome. The performance of the
MMP sensitive liposome was compared to a non-MMP sensitive version and Doxil-like liposomes. In vitro, the
cellular uptake and cytotoxicity of the liposomes were studied, while in vivo the effect of ultrasound and microbubbles
on the tumour accumulation, biodistribution, microdistribution, and therapeutic efficacy were investigated.
For all tested liposomes, ultrasound and microbubble treatment resulted in an improved tumour
accumulation, increased extravasation, and increased penetration of the liposomes from blood vessels into the
extracellular matrix. Surprisingly, penetration depth was independent of the ultrasound intensity used.
Ultrasound-mediated delivery of free doxorubicin and the Doxil-like and MMP sensitive liposome resulted in a
significant reduction in tumour volume 28 days post the first treatment and increased median survival. The MMP
sensitive liposome showed better therapeutic efficacy than the non-MMP sensitive version indicating that
cleaving the PEG-layer is important. However, the Doxil-like liposome outcompeted the MMP and non-MMP
sensitive liposome, both with and without the use of ultrasound and microbubbles.


Academic article


  • Research Council of Norway (RCN) / 262228
  • Liaison Committee between the Central Norway Regional health Authority (RHA) and the Norwegian University of Science and Technology (NTNU) / 90270600




  • Marieke Olsman
  • Viktoria Sereti
  • Kristine Andreassen
  • Sofie Snipstad
  • Annemieke van Wamel
  • Rasmus Eliasen
  • Sigrid Berg
  • Andrew J. Urquhart
  • Thomas L. Andresen
  • Catharina de Lange Davies


  • Norwegian University of Science and Technology
  • Technical University of Denmark
  • St. Olavs Hospital, Trondheim University Hospital
  • SINTEF Industry / Biotechnology and Nanomedicine
  • SINTEF Digital / Health Research



Published in

Journal of Controlled Release






121 - 134

View this publication at Cristin