Bubble Therapy: a New Paradigm for Targeted Drug Delivery by Ultrasound
Lead Research Organisation:
University of Oxford
Department Name: Engineering Science
Abstract
High amplitude ultrasound waves propagating through tissue have been recently reported to induce a range of potentially beneficial phenomena, such as rapid tissue heating, increased permeability of cells to large drug molecules (sonoporation) or enhanced activity of drugs. These bioeffects are heavily correlated with the ultrasound-induced nucleation and subsequent excitation of micron-sized bubbles, yielding two types of acoustic cavitation activity: (1) inertial cavitation, which dramatically increases the energy transfer to tissue and can cause rapid heating and mechanical damage, and (2) stable cavitation, whereby bubbles act as micropumps that dramatically enhance the local mixing and transport length scales of drug molecules. In cancer treatment, local heating combined with chemotherpay will render cancer cells more sensitive to treatment, whilst local micropumping of the drug can help overcome delivery problems arising from the highly complex tumour structure. In the context of breaking down blood clots for stroke therapy, cavitation-enhanced mixing will promote delivery of the drug to a site of low blood flow and greatly increase the diffusion of the thombolyic drug across the clot surface.However, the nucleation of cavitating microbubbles and subsequent interaction with cells in biologically relevant media remain poorly understood. The objectives of the proposed research therefore are (i) to investigate the potential of cell- and site-specific cavitation nucleation using commercially available targeted nanoparticles currently being developed for molecular imaging; (ii) to understand and optimize the mechanism by which ultrasound and cavitation can enhance local drug delivery and drug activity across inaccessible interfaces such as tumours or blood clots; (iii) to develop clinically relevant means of monitoring cavitation activity and exploit them for real-time monitoring of drug delivery and (iv) to test the optimized drug delivery and treatment monitoring protocols in a clinically relevant organ model.It is hoped that the proposed resarch will pave the road for widespread clinical uptake of cavitaiton-enhanced targeted drug delivery by ultrasound. Particular advantages of this technique will include the ability to locally enhance drug activity, thus reducing the necessary drug dosages and their side effects, and to monitor therapy in real time. The outcomes of the proposed research are expected to be directly transferable to many other novel therapeutic ultrasound applications, such as non-invasive tissue ablation by High-Intensity Focussed Ultrasound (HIFU), acoustic haemostasis and ultrasound-induced opening of the blood-brain barrier for transcranial drug delivery.
People |
ORCID iD |
Constantin Coussios (Principal Investigator) |
Publications
Arvanitis CD
(2011)
Cavitation-enhanced extravasation for drug delivery.
in Ultrasound in medicine & biology
Bazan-Peregrino M
(2012)
Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model.
in Journal of controlled release : official journal of the Controlled Release Society
Bazan-Peregrino M
(2013)
Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound
in Journal of Controlled Release
Carlisle R
(2013)
Targeting of liposomes via PSGL1 for enhanced tumor accumulation.
in Pharmaceutical research
Carlisle R
(2013)
Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound.
in Journal of the National Cancer Institute
Carlisle R
(2013)
Mechanical approaches to oncological drug delivery
in Therapeutic Delivery
Carlisle R.
(2014)
Improving Delivery of Oncolytic Viruses to Solid Tumours
in HUMAN GENE THERAPY
Choi JJ
(2012)
Spatiotemporal evolution of cavitation dynamics exhibited by flowing microbubbles during ultrasound exposure.
in The Journal of the Acoustical Society of America
Choi JJ
(2014)
Non-invasive and real-time passive acoustic mapping of ultrasound-mediated drug delivery.
in Physics in medicine and biology
Coussios C
(2008)
Applications of Acoustics and Cavitation to Noninvasive Therapy and Drug Delivery
in Annual Review of Fluid Mechanics
Coussios C
(2010)
Passive mapping for real-time monitoring of ultrasound therapy.
in The Journal of the Acoustical Society of America
Feiszthuber H
(2015)
Cavitation-enhanced delivery of insulin in agar and porcine models of human skin.
in Physics in medicine and biology
Graham SM
(2014)
Inertial cavitation to non-invasively trigger and monitor intratumoral release of drug from intravenously delivered liposomes.
in Journal of controlled release : official journal of the Controlled Release Society
Gyöngy M
(2010)
Passive spatial mapping of inertial cavitation during HIFU exposure.
in IEEE transactions on bio-medical engineering
Gyöngy M
(2010)
Passive cavitation mapping for localization and tracking of bubble dynamics.
in The Journal of the Acoustical Society of America
Jensen CR
(2013)
Real-time temperature estimation and monitoring of HIFU ablation through a combined modeling and passive acoustic mapping approach.
in Physics in medicine and biology
Jensen CR
(2012)
Spatiotemporal monitoring of high-intensity focused ultrasound therapy with passive acoustic mapping.
in Radiology
Kwan J
(2013)
Inertial cavitation at the nanoscale
in The Journal of the Acoustical Society of America
Kwan J
(2016)
Ultrahigh-Speed Dynamics of Micrometer-Scale Inertial Cavitation from Nanoparticles
in Physical Review Applied
Mo S
(2015)
Increasing the density of nanomedicines improves their ultrasound-mediated delivery to tumours.
in Journal of controlled release : official journal of the Controlled Release Society
Mo S
(2012)
Ultrasound-enhanced drug delivery for cancer.
in Expert opinion on drug delivery
Myers R
(2018)
Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines.
in International journal of nanomedicine
Myers R
(2016)
Polymeric Cups for Cavitation-mediated Delivery of Oncolytic Vaccinia Virus.
in Molecular therapy : the journal of the American Society of Gene Therapy
Myers R
(2018)
Ultrasound-mediated cavitation does not decrease the activity of small molecule, antibody or viral-based medicines.
in International journal of nanomedicine
Mylonopoulou E
(2013)
A non-exothermic cell-embedding tissue-mimicking material for studies of ultrasound-induced hyperthermia and drug release.
in International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
Mylonopouloua E
(2010)
Ultrasonic Activation of Thermally Sensitive Liposomes
Rifai B
(2010)
Cavitation-enhanced delivery of macromolecules into an obstructed vessel.
in The Journal of the Acoustical Society of America
Robert C. Carlisle (Author) ,
(2012)
Cavitation-enhanced delivery of a self-amplifying oncolytic adenovirus for tumour-selective cancer therapy
Sacha D. Nandlall (Author)
(2010)
Real-time passive acoustic monitoring of tissue damage during thermal ablation by high-intensity focused ultrasound.
Stride EP
(2010)
Cavitation and contrast: the use of bubbles in ultrasound imaging and therapy.
in Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine
Description | This research has led to three key findings: (I) ultrasound-induced inertial cavitation is capable of delivering drugs very deep into tumours, to distances considerably greater than the peak distance between a cancer cell and the nearest blood vessel (ii) a novel ultrasound-based technique, baptised Passive Acoustic Mapping, can be used to map inertial cavitation in real-time and in 3D and provide real-time information as to where and when a drug has been successfully delivered (iii) thermal, rather than cavitational, effects of ultrasound can also be successfully used to achieve targeted drug release of drugs from thermosensitive liposomes. Thermal mechanisms also offer significant advantages in terms of drug distribution in tumours. |
Exploitation Route | On the basis of this research, a first-in-man clinical trial of ultrasound-enhanced drug delivery from thermosensitive liposomes has been initiated at the Cancer Centre in Oxford (Churchill Hospital) under NIHR funding. The trial is expected to be completed by 2015. A spin-out company is being formed to exploit the unique drug delivery and real-time treatment monitoring technology developed as part of this Challenging Engineering award. |
Sectors | Healthcare |
URL | http://www.ibme.ox.ac.uk/bubbl |
Description | First-in-man clinical trial of ultrasound-mediated drug delivery to liver tumours |
First Year Of Impact | 2014 |
Sector | Healthcare |
Impact Types | Societal Economic |
Title | MAPPING AND CHARACTERIZATION OF CAVITATION ACTIVITY |
Description | Apparatus for locating bubbles in a subject comprises a plurality of pressure wave detectors arranged to operate as passive detectors to generate output signals in response to the receipt of pressure waves generated at a source comprising at least one bubble, and processing means arranged to receive signals from the detectors and to determine from the signals the position of the source. |
IP Reference | WO2010052494 |
Protection | Patent application published |
Year Protection Granted | 2010 |
Licensed | Yes |
Impact | Incorporated within a new medical device being developed by the licensee |
Title | ULTRASOUND SYSTEMS |
Description | An ultrasound system comprises a transducer, a controller arranged to generate control signals arranged to control the transducer to generate pressure waves directed at a target volume, and sensing means arranged to sense cavitation in the target volume. The controller is arranged to receive sensing signals from the sensing means and to vary the control signals in response to the sensing signals thereby to control the cavitation. |
IP Reference | WO2011036475 |
Protection | Patent application published |
Year Protection Granted | 2011 |
Licensed | Yes |
Impact | Incrorporated into a a clinical system currently being developed by the licensee. |
Title | TarDox |
Description | Non-invasive targeted doxorubicin delivery from thermosensitive liposomes using high-intensity focussed ultrasound in cancer patients with metastases to the liver. This is a first-in-man trial enabled by the work carried out under my Challenging Engineering award and supported by the Oxford Centre for Drug Delivery Devices (OxCD3) and the Oxford BRC (NIHR) . |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2014 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Ten patients were successfully treated between 2016 and 2018 and the outputs of the trial were reported in Lancet Oncology (2018) and Radiology (2019) |
URL | https://clinicaltrials.gov/ct2/show/NCT02181075 |
Company Name | OxSonics |
Description | OxSonics has developed ultrasound technology to deliver drugs to treat cancers and chronic lower back pain. |
Year Established | 2013 |
Impact | The company successfully raised £1m of external investor capital and recently received a further £1.2m Primer Award from Innovate UK to develop a clinical prototype. |
Website | http://www.oxsonics.com |
Company Name | OxSonics |
Description | OxSonics has developed ultrasound technology to deliver drugs to treat cancers and chronic lower back pain. |
Year Established | 2013 |
Impact | The company received a £2.5m Innovate UK early stage award in 2014 to enable pre-clinical development of the ultrasound device, associated ultrasound transducer and GMP manufacture of the sonosensitive particles. |
Website | http://www.oxsonics.com |