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.

Publications

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Arvanitis CD (2011) Cavitation-enhanced extravasation for drug delivery. in Ultrasound in medicine & biology

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Bazan-Peregrino M (2013) Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound. in Journal of controlled release : official journal of the Controlled Release Society

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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

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Carlisle R (2013) Targeting of liposomes via PSGL1 for enhanced tumor accumulation. in Pharmaceutical research

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Carlisle R (2013) Mechanical approaches to oncological drug delivery. in Therapeutic delivery

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Carlisle R. (2014) Improving Delivery of Oncolytic Viruses to Solid Tumours in HUMAN GENE THERAPY

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Coussios C (2010) Passive mapping for realtime monitoring of ultrasound therapy. in The Journal of the Acoustical Society of America

 
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 pluraity 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 2008
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 2009
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 www.orthoson.com 
Description Therapeutic ultrasound technologies for minimally invasive orthopaedic and particularly spinal surgery 
Year Established 2016 
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.orthoson.com