Targeted Drug Delivery by Focused Ultrasound under MR-guidance
NANOPORATION sets out to explore specific solutions to overcome the current challenges of drug delivery to cancer cells. The project seeks to use Focused Ultrasound Surgery under Magnetic Resonance Image-guidance (MRgFUS)to release drugs from various encapsulation formulae, and enhance delivery to tissue and cells, with low level heating and cavitation effects. Ultrasound can be used to cavitate micro bubbles for increased cell permeability and to open drug loaded nano-capsules, releasing proven active cancer drugs directly to the tumour cell population,thus avoiding the adverse side-effect associated with systemic dosage. The Project involves research centres at the UNIVERSITY of DUNDEE - IMSaT (Institute for Medical Science and Technology), Engineering and Bio-Physics, Surgical and Molecular Oncology, Nano Materials Laboratory and two companies, INSIGHTEC and CAPSUTECH. InSightec is the world leading vendor of clinical MRgFUS devices. CapsuTech produces a thermally sensitive polymer nano-capsule that encapsulates and passivates anti-cancer drugs.
MRgFUS (ExAblate2000 and ExAblate2100) assisted experiments to assess the enhancement of drug uptake into cancer cells due to sonoporation with microbubbles.
1)ExAblate 2000 in-vitro setup.
2) Cavitation acoustic signature at 0.575MHz for a transmitting frequency of 1.15MHz.
3a) Sonication effect on cells with Sonovue micro-bubbles.
3b) Sonicated cells no microbubbles. 3c) Control sample with microbubbles, no sonication.
3d) Control sample without microbubbles, no sonication.
The project aims to overcome the current challenges of cancer chemotherapy by development of:
- Targeted low energy, focused ultrasound insonation protocols, which will concurrently release active drug from nano-capsules and other drug carriers (Nanoporation) and increase the permeability (Sonoporation) and hence uptake by cancer cells.
Controlled cavitation can play an important role in sonoporation. Above: High speed-camera image sequence of cavitation clouds developing in the proximity of a Mylar substrate on which cancer cells are attaché.
- Nano-capsule based drug carrier systems or formulations, which do not involve covalent binding of the cytotoxic drugs with the carrier polymer(s) and release loaded drugs when modulated with focussed ultrasound.
- Nanoparticles, micro-bubbles, liposomes will be investigated for targeting drug to cancer site using focused ultrasound under MRI guidance to increase focal effective concentration and reducing systemic side effects.
Top: AFM images of a) non-magnetic liposomes, b) magneto-liposomes (cysteamine coated Fe3O4 NPs) c)magneto-liposomes (FePt NPs) showing increased size and altered surface morphology.
Bottom: SEM images of a) simple liposomes b) FePt liposomes, c) cysteamine-coated Fe3O4 NPs containing liposomes showing different encapsulations (black arrows-lipid bilayer) and (red arrow- magnetic NPs )
- Novel MRI compatible ultrasound and micro-bubble technology enhancement (several orders of magnitude) of the uptake of known anti-cancer agents following systemic administration and affecting this increased uptake only to targeted tumour cell populations.
The programme focuses on exchange of expertise in MRI guided focussed ultrasound, drug nano-capsules, nano-scale sonication research, cell biology and pre-clinical oncology research for targeted delivery of existing chemotherapy drugs. The training and skills development of early stage and experienced researchers from inside and outside the partnership by trainers and senior experienced researchers from both academia and industry is a key objective of NANOPORATION.The benefits of the joint research activities proposed by this inter-disciplinary IAPP include development of a new integrated treatment protocol, characterised by reduced systemic dosage (and associated side effects) of existing anti-cancer drugs, with more effective tumour cell uptake and hence enhanced objective tumour response.The establishment of this exchange of knowledge and expertise between the three partners and external researchers through this IAPP will lead to substantial clinical and industrial benefits and enhanced research and development capacity in a growing interdisciplinary area of research.
Operational objectives of the project
- Creation of a core group of researchers competent to establish a successful career in this rapidly developing scientific field by providing multi-disciplinary training in cutting-edge methodologies for novel drug delivery
- Development of low energy ultrasound, focussed, targeted focal sonication protocols that will increase the membrane permeability of cancer cells, and release active drug from nanocapsules and other drug carriers.
- Significant (several orders of magnitude) enhancement of the uptake of known anti-cancer agents following systemic administration and limiting this increased uptake only to the tumour cell population using novel ultrasound based MRI compatible technology