Image-Controlled Ultrasound-Induced Drug Delivery

Welcome to the Sonodrugs website

Sonodrugs was an integrated project (IP), partly funded by the NMP program of the European Commission's 7th Framework (FP7 NMP-4-LA-2008-213706). Sonodrugs started November 1st, 2008 and ran for four years, ending October 31, 2012.

A Public Summary of the project and the obtained results is available here


Sonodrugs final year conference.

April 2012 we presented the topic of Image-Controlled Ultrasound Induced Drug Delivery and our results at the 12th European Symposium on Controlled Drug Delivery. Sonodrugs organized one of the afternoon sessions at the ESCDD. See Events.

Aim of the project.

The demographic changes in Europe towards an aging society will coincide with increasing morbidity of the population. European citizens need improved access to state-of-the-art medical care especially in oncology and cardiology, while keeping expenditures on healthcare affordable. New therapeutic options such as externally triggered local drug release at the diseased area hold promise to solve urgent medical needs: improved treatment with reduced side effects, fewer burdens to the patient and faster recovery after intervention. Nanomedicine, the application of nanomaterials and nanotechnology to healthcare, will enable breakthroughs in clinical practice.

Sonodrugs addressed clinical needs by developing novel drug delivery technologies for localized treatment of cardiovascular disease and cancer. Within Sonodrugs drug delivery concepts have been developed where drug release can be triggered by focused ultrasound induced pressure or temperature stimuli within the diseased tissue. New drug loaded nanocarriers have been designed for tailored drug delivery systems that respond to either of the two stimuli. Medical imaging, i.e. magnetic resonance imaging and ultrasound imaging is used to guide, follow and quantify the drug delivery process. Therapy efficacy using different drug delivery systems has been assessed in vitro and subsequently in preclinical studies. Starting from research on a broad range of materials and drugs, two nanocarriers have been finally selected, optimized, produced on lab-scale and thoroughly assessed in combination with image-guided delivery tools and methods.

Sonodrugs combined expertise in materials research (Philips Research Eindhoven, Eindhoven University of Technology, Ghent University, Nanobiotix, Aalto University); material production (Nanobiotix, Lipoid); clinical knowledge in oncology (University of Tours, University of Cyprus) and cardiology (University of Muenster); in vitro and preclinical validation (University of Tours, Erasmus Medical Center, University of Cyprus, University of Muenster, University of Bordeaux/University Medical Centre Utrecht, Philips Research Eindhoven, Eindhoven University of Technology); research on imaging techniques (University of Cyprus, Philips Healthcare, Philips Research Hamburg, University Bordeaux/University Medical Centre Utrecht, Philips Research Eindhoven); and pharmacokinetics, toxicology and biodistribution (University of London, Eindhoven University of Technology).

Final obtained results of Sonodrugs

The following final results have been achieved:

  • Knowhow on nanocarrier preparation and optimization for polymer microbubbles, (targeted) drug-loaded microbubbles and dDrug-loaded temperature-sensitive liposomes with and without MR contrast agents.
  • Preclinical proof-of-concepts for three approaches of US mediated drug delivery.
  • Therapeutic efficacy shown for two approaches so far.
  • Methods for MR-HIFU hyperthermia and drug delivery: Triggering of nanocarriers, tracking of nanocarriers, temperature mapping for controlled hyperthermia induction, treatment monitoring and monitoring of drug release, and integration of these methods.
  • Temporal window for sonoporation.
  • Two-step delivery method.
  • Knowhow on custom-made US transducer production.
  • In vitro set-up to study the effect of HIFU induced hyperthermia on nanocarriers.
  • Scientific dissemination resulting in an increased interest in US mediated drug delivery, which is now a very hot topic. It has been added to the roadmap of several organizations and clinical trials (the next step towards clinical and commercial adoption) are coming up.

Progress in period 3 (November 2011 to October 2012)

The main objectives of the last 12-month review period of Sonodrugs were to finalize the in vitro and in vivo evaluations of the developed nanocarriers for ultrasound-mediated drug delivery under image guidance. Focus was on in vivo studies to assess toxicology and to determine therapeutic efficacy in preclinical models of disease. Furthermore, as this was the final period, we wrapped up the project.

Related to these objectives the following results have been obtained:

The final optimization for several nanocarriers has been performed based on the feedback from in vitro and in vivo evaluations. These include antibody-targeted microbubbles for US pressure activated local therapy, as well as liposomes with improved drug release properties for US hyperthermia activated local therapy. Initial steps for a pilot scale-up production have been made.

The co-administration approach that has been validated with doxorubicin before was now found to be applicable also for irinotecan, both on cell lines as in preclinical tumour models. Great progress has also been made for plasmid DNA gene delivery via co-administration with pressure-sensitive microbubbles, although the definite break-through has not been achieved yet. Using a new two-compartment setup, in vitro drug release from temperature sensitive materials could now also be investigated using hyperthermia induced by focussed ultrasound, showing rapid and high release of the encapsulated drugs. Finally, the mechanism of action for ultrasound mediated drug delivery was investigated in vitro, examining the release of drugs from the nanocarriers and uptake of the payload drug in cells. Novel insights were obtained by high-speed optical imaging, confocal microscopy and electron microscopy, showing e.g. that formation of pores in the cell membrane allows for direct entry of the drug in the target cells during sonoporation.

Toxicity of the developed methods was found to be low. Both ultrasound treatment of cells, incubation of endothelial cells with the nanocarriers, and preclinical in vivo studies assessing long-term toxicity of injected materials by histology, all showed no significant adverse effects. Pharmacokinetics and biodistribution was studied further in this period; in vivo uptake of drugs from liposomes was shown by SEPCT/CT imaging. Moreover the pharmacokinetic data of doxorubicin delivery from temperature-sensitive liposomes obtained throughout the project was collated in a kinetic model that can be interrogated via a java program.

Methods have been optimized for imaging of the nanocarriers and monitoring of the triggering. Optimal settings for use in preclinical studies were established. Novel methods for therapy monitoring have been developed, and initial steps towards clinical translation were made. Finally, the therapeutic efficacy of enhanced ultrasound-mediated drug delivery was shown in four studies. Co-administration was successful for preclinical delivery of irinotecan to tumours, siRNA to cardiac muscle, and siRNA to liver. In the latter case a dose-dependent effect was observed, with ultrasound-mediated drug delivery able to lower the effective dose by a factor of 100. Additionally, MR-HIFU treatment with temperature-sensitive liposomes was shown to slow tumour development by a factor of 3. In this case, the liposomes contained both an MR contrast agent and doxorubicin, and the MR imaging signal changes during treatment correlated very nicely to the observed therapeutic effect, a prime example of image-guided therapy.

Dissemination of our results was done by the publication of 15 peer-reviewed manuscripts, and 23 oral and 23 poster presentations at conferences in this period. Moreover, we organized a Sonodrugs conference in the form of an “Ultrasound Mediated Drug Delivery” afternoon at the European Symposium on Controlled Drug Delivery, April 2012. In order to wrap up the project, we compiled an overview and evaluation of all developed nanocarrier systems, drafted a Public Summary, and finalized the Exploitation plan, which contains the market position and exploitation activities (commercial and academic) of all partners.


Progress in period 2 (May 2010 to October 2011)

The main objectives of the second 18-month review period of Sonodrugs were the continued development of new and optimized nanocarriers for ultrasound (US) mediated drug delivery, their in vitro evaluation and initial in vivo testing of biodistribution and local delivery. Furthermore, the co-administration approach was to be evaluated, and two newly developed materials from WP1 would be selected for scaled up production to allow for larger scale in vivo studies with uniform material.

Related to these objectives the following results have been obtained: Nanocarriers have been developed for US pressure activated local therapy (both using the co-administration approach as well as the drug-loaded microbubble approach) and US hyperthermia activated local therapy (using temperature-sensitive liposomes). The formulation of these nanocarriers has been optimized based on the feedback from in vitro and in vivo evaluations.

The blood circulation half-time and biodistribution of microbubbles for co-administration and liposomal nanocarriers was determined, by traditional methods as well as by non-invasive imaging techniques. The drug loaded microbubbles were extensively tested for optimal US activation conditions, and the behavior of these nanocarriers under US stimulation was established by US imaging as well as by ultra-fast optical imaging.

In addition hardware, settings and protocols for US activation of nanocarriers by pressure and hyperthermia were developed. Preclinical proof-of-concept of enhanced local delivery of compounds was achieved for the co-administration and hyperthermia approaches, and for a combination approach.

FP7

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Sonodrugs is a 48 month research project, partly funded by the NMP priority
of the European 7th Framework Program.

© the Sonodrugs project, 2008-2012.