Exploiting Non-Linear Acoustics for Enhanced Molecular Delivery

Lead Research Organisation: University of Dundee
Department Name: Electronic Engineering and Physics

Abstract

RNAi is a new form of therapy that allows faulty genes to be switched off in a wide range of genetic diseases and in cancer. The barrier to applying this revolutionary new form of medicine is how to deliver it into the body, since the molecules involved are larger than normal drugs and so cells require some help in taking this material up so it can have its beneficial effect. The main aim of this project is to revolutionise the delivery of these new therapeutics into the skin, as a test organ system by exploiting the penetrating effect of ultrasound activated microbubbles. Skin has the advantage of being on the outside of the body for easy access, and excess human skin from cosmetic surgery (breast reductions and tummy tucks) is readily available for experimentation to optimise delivery of RNAi molecules. In pursuit of this, we will develop an innovative new tool combining chemistry, ultrasound and arrays of microscopic painless needles for fast, effective and reliable delivery into skin at high coverage rates. Once optimised for skin diseases, this hand-held device will be readily adapted for use on internal organs using keyhole surgery methods, so that the potential applications of this device across all branches of medicine are huge. The team assembled in Dundee brings together a leading molecular biologist with a physicist, but supported by further international collaborators with diverse skills across many different fields, in order to piece together elements of technology in ways that have never been done before. The estimated market for solving the therapy delivery problem being tackled here is in the order of 10s of billions of dollars per year.
Ultrasound, as prescribed in the manner presented, looks like a very promising route to achieving that goal.

Technical Summary

RNA-interference (RNAi) has revolutionised biomedical sciences as a research tool and has enormous potential for treatment a host of genetic diseases and cancer. In 2004, the projected market for this new class of therapeutics was estimated at $25 billion in the USA alone. The major limiting factor preventing RNAi technology from clinical application is effective delivery. The skin is an attractive target organ for delivery development due its accessibility but the stratum corneum, the impermeable barrier layer at the epidermal surface, is difficult to cross. Here we have assembled a multidisciplinary team consisting of a molecular biologist with expertise in genetic skin disease and an physicist highly active in design of microfabrication of new medical devices for ultrasonic delivery of molecules (sonoporation), all based in a new translational research division within the 5* research environment at the University of Dundee. The team is supported by collaborators that include a clinical dermatologist, the CEO of a siRNA biopharma start-up and the leading experts in use of sonoporation for skin delivery and in use of microneedles for trans-stratum corneum delivery. The overarching objective for this project is to revolutionise the delivery of molecular therapeutics across the stratum corneum and into the underlying living tissue. This will be achieved by marrying the latest cutting edge findings drawn from ultrasound driven micro-fluid mechanics, with state-of-the-art RNAi biotechnology. Here, we make a quantum leap in procedures by coupling the initial penetrative passage through the stratum corneum with an active mode of subsequent dispersal into the viable dermis using ultrasound activated microbubbles that contain the siRNA. Delivery testing will involve use of human skin biopsy material. This scientific method, and the hardware developed in support of it are unique, and have not been attempted before.

Publications

10 25 50
 
Description Basic Technology Translation Award
Amount £964,449 (GBP)
Funding ID EP/H045368/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description MRC Milstein Award
Amount £625,000 (GBP)
Funding ID G0801742 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2009 
End 08/2012
 
Title Dedicated Cell BioPhysics facility 
Description Access to instrumentation funded by the MRC grant that has divisional impact on a rota basis - training on the kit. 
Type Of Material Improvements to research infrastructure 
Year Produced 2010 
Provided To Others? Yes  
Impact Developing pilot research with other PIs for future grant funding proposals 
 
Description MRC Milstein Award 
Organisation University of Dundee
Department Division of Molecular Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Exploitation of microfluidics expertise to create prototype microbubble generator that will contain our siRNA of choice. Utilisation of high speed imaging infrastructure to prove concept of the novel microfluidics chip.
Collaborator Contribution Consolidation of pilot work and infrastructural development with the injection of a new jointly supervised multidisciplinary team
Impact 1. Patents under preparation for microfluidics chip now that concept proved. This work has been multidisciplinary involving physics and optical engineeing to develop control the microfluidics, fluid mechanics/computational physics to design the chip in the first instance, and in tandem, the inclusion of specialist microbubble formulations (pharmaceutical/biotech/chemical engineering) to ensure longevity of the microbubbles and also their suitability for in vitro use and eventually clinical implementation. 2. Conference paper presented at ICHSIP in Morioka, Japan, highlighting the proof of concept and extended paper under preparation for the journal Optics Express
Start Year 2009
 
Description Group Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact 10 members of the public came for a tour of the group and wider division.

Interesting connections with historical figures associated with the University developed.
Year(s) Of Engagement Activity 2010
URL http://www.cicass.net
 
Description Public Engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 35 members of the public attended a talk I gave as part of Cafe Scientifique -at the Q & A stage, which lasted over 30 minutes, topics such as ethics in research and the cost of NHS were embraced

I was invited to give the keynote address at the Scottish Science Education Conference 2011, and have also been invited to assist with the development of the Scottish Qualifications Agency's Advanced Higher (A' Level) practical elements.
Year(s) Of Engagement Activity 2010
URL http://www.cicass.net
 
Description Public Lecture (British Association for the Advancement of Science) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact "Are you thick skinned enough? Dermatology Discoveries in Dundee". Audience of about 60 people, all from the Tayside region general public. 60 min lecture plus 30 min discussion.
Year(s) Of Engagement Activity 2017
 
Description Public Lecture, Comber Rotary Club, County Down, Northern Ireland. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public talk hosted by a Rotary Club. "Studying inherited skin disease through thick and thin". Audience of about 30-40 Rotarians and interested public. 30 min lecture plus 15 min discussion.
Year(s) Of Engagement Activity 2017