An acoustic wavelet technology for delivering smart imaging probes to the brain
Lead Research Organisation:
Imperial College London
Department Name: Bioengineering
Abstract
Aim of the PhD Project:
Create an acoustic wavelet technology that delivers imaging probes across the blood-brain barrier.
Synthesise new and existing single- and dual-modality imaging probes.
Image the delivered imaging probes using MRI and fluorescence experiments.
Project Description / Background:
Molecular imaging probes have the potential to transform neuroimaging. Whereas CT and conventional MRI provide structural and anatomic information of the brain, molecular probes can identify processes that are specific to a disease and its stage. This could allow doctors to classify the disease earlier and more accurately, and match it with the best therapeutic option (i.e., personalised medicine). Some important unmet needs include locating hidden cancer cells after surgical removal of a glioblastoma tumour; and identifying Alzheimer's disease early so that the correct treatments can be initiated.
However, molecular imaging probes cannot enter the brain, because of the blood-brain barrier, and thus remain impractical. Thus, at the moment, molecular imaging targets are constrained to intravascular targets, such as receptors on endothelial cells, which are unlikely to be direct indicators of the disease. We would like to widen the scope of molecular imaging probes to all extravascular targets - neurons, microglial cells, and disease processes in the extracellular space (e.g., ABeta plaques in Alzheimer's disease).
Dr. Choi's lab has developed an acoustic wavelet technology that can deliver drugs across the blood-brain barrier. Acoustic wavelets are short, low-pressure ultrasound pulses. Meanwhile, Prof. Long's lab specialises in creating molecular imaging probes. In this PhD project, we would like to combine the wavelet technology with these imaging probes to create a platform for imaging specific disease processes using MRI or other imaging modalities.
To enable the use of molecular imaging probes by wavelet delivery, it must not damage the blood-brain barrier and brain tissue. We have developed an acoustic wavelet sequence for blood-brain barrier opening (Fig. 1). In a recent publication Radiology (2019), we have shown the following:
Diffuse delivery of drugs to parenchyma
Delivery into cells
Short duration BBB permeability change (< 20 min)
Size-selective BBB permeability change
Create an acoustic wavelet technology that delivers imaging probes across the blood-brain barrier.
Synthesise new and existing single- and dual-modality imaging probes.
Image the delivered imaging probes using MRI and fluorescence experiments.
Project Description / Background:
Molecular imaging probes have the potential to transform neuroimaging. Whereas CT and conventional MRI provide structural and anatomic information of the brain, molecular probes can identify processes that are specific to a disease and its stage. This could allow doctors to classify the disease earlier and more accurately, and match it with the best therapeutic option (i.e., personalised medicine). Some important unmet needs include locating hidden cancer cells after surgical removal of a glioblastoma tumour; and identifying Alzheimer's disease early so that the correct treatments can be initiated.
However, molecular imaging probes cannot enter the brain, because of the blood-brain barrier, and thus remain impractical. Thus, at the moment, molecular imaging targets are constrained to intravascular targets, such as receptors on endothelial cells, which are unlikely to be direct indicators of the disease. We would like to widen the scope of molecular imaging probes to all extravascular targets - neurons, microglial cells, and disease processes in the extracellular space (e.g., ABeta plaques in Alzheimer's disease).
Dr. Choi's lab has developed an acoustic wavelet technology that can deliver drugs across the blood-brain barrier. Acoustic wavelets are short, low-pressure ultrasound pulses. Meanwhile, Prof. Long's lab specialises in creating molecular imaging probes. In this PhD project, we would like to combine the wavelet technology with these imaging probes to create a platform for imaging specific disease processes using MRI or other imaging modalities.
To enable the use of molecular imaging probes by wavelet delivery, it must not damage the blood-brain barrier and brain tissue. We have developed an acoustic wavelet sequence for blood-brain barrier opening (Fig. 1). In a recent publication Radiology (2019), we have shown the following:
Diffuse delivery of drugs to parenchyma
Delivery into cells
Short duration BBB permeability change (< 20 min)
Size-selective BBB permeability change
Planned Impact
Strains on the healthcare system in the UK create an acute need for finding more effective, efficient, safe, and accurate non-invasive imaging solutions for clinical decision-making, both in terms of diagnosis and prognosis, and to reduce unnecessary treatment procedures and associated costs. Medical imaging is currently undergoing a step-change facilitated through the advent of artificial intelligence (AI) techniques, in particular deep learning and statistical machine learning, the development of targeted molecular imaging probes and novel "push-button" imaging techniques. There is also the availability of low-cost imaging solutions, creating unique opportunities to improve sensitivity and specificity of treatment options leading to better patient outcome, improved clinical workflow and healthcare economics. However, a skills gap exists between these disciplines which this CDT is aiming to fill.
Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.
- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.
- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.
- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.
We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.
Consistent with our vision for the CDT in Smart Medical Imaging to train the next generation of medical imaging scientists, we will engage with the key beneficiaries of the CDT: (1) PhD students & their supervisors; (2) patient groups & their carers; (3) clinicians & healthcare providers; (4) healthcare industries; and (5) the general public. We have identified the following areas of impact resulting from the operation of the CDT.
- Academic Impact: The proposed multidisciplinary training and skills development are designed to lead to an appreciation of clinical translation of technology and generating pathways to impact in the healthcare system. Impact will be measured in terms of our students' generation of knowledge, such as their research outputs, conference presentations, awards, software, patents, as well as successful career destinations to a wide range of sectors; as well as newly stimulated academic collaborations, and the positive effect these will have on their supervisors, their career progression and added value to their research group, and the universities as a whole in attracting new academic talent at all career levels.
- Economic Impact: Our students will have high employability in a wide range of sectors thanks to their broad interdisciplinary training, transferable skills sets and exposure to industry, international labs, and the hospital environment. Healthcare providers (e.g. the NHS) will gain access to new technologies that are more precise and cost-efficient, reducing patient treatment and monitoring costs. Relevant healthcare industries (from major companies to SMEs) will benefit and ultimately profit from collaborative research with high emphasis on clinical translation and validation, and from a unique cohort of newly skilled and multidisciplinary researchers who value and understand the role of industry in developing and applying novel imaging technologies to the entire patient pathway.
- Societal Impact: Patients and their professional carers will be the ultimate beneficiaries of the new imaging technologies created by our students, and by the emerging cohort of graduated medical imaging scientists and engineers who will have a strong emphasis on patient healthcare. This will have significant societal impact in terms of health and quality of life. Clinicians will benefit from new technologies aimed at enabling more robust, accurate, and precise diagnoses, treatment and follow-up monitoring. The general public will benefit from learning about new, cutting-edge medical imaging technology, and new talent will be drawn into STEM(M) professions as a consequence, further filling the current skills gap between healthcare provision and engineering.
We have developed detailed pathways to impact activities, coordinated by a dedicated Impact & Engagement Manager, that include impact training provision, translational activities with clinicians and patient groups, industry cooperation and entrepreneurship training, international collaboration and networks, and engagement with the General Public.
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/S022104/1 | 01/10/2019 | 31/03/2028 | |||
| 2442183 | Studentship | EP/S022104/1 | 01/10/2020 | 30/09/2024 | William Lim Kee Chang |
| Description | The blood-brain barrier poses a major obstacle to the diagnosis and treatment of brain diseases as it prevents most agents in the blood from reaching pathological sites in the brain. We have recently demonstrated the use of a rapid short-pulse ultrasound sequence with circulating microbubbles to disrupt the blood-brain barrier and deliver a peptide-sized, 3-nm-diameter model agent to mouse brains. Using this sequence, an even delivery distribution of the agent was achieved with little to no compromise on the dose delivered, when compared with a long-pulse sequence commonly used for this method of agent delivery to the brain. A good safety profile was also evidenced, with no leakage of red blood cells and minimal to no leakage of blood proteins into brain tissue detected after treatment with the rapid short-pulse sequence, whilst the blood-brain barrier was found to close within 10 minutes. We have now successfully applied the rapid short-pulse ultrasound sequence to the delivery of model agents up to 8-11 nm in diameter. Larger agents, such as 98-nm-diameter liposomes, can be delivered using a higher acoustic pressure. This work has demonstrated the versatility of this sequence in delivering a range of sizes of therapeutic and imaging agents to mouse brains, with minimal adverse bioeffects. However, at fixed acoustic parameters, we observed increasingly uneven delivery distributions with increasing agent size and reduced doses delivered up to a size threshold, at which no agent delivery was observed. This study also provided insights into the influence of short-pulses on the mechanism of ultrasound and microbubble-assisted blood-brain barrier disruption. Short-pulses appear to induce milder microbubble activity at increased sites across the vasculature, leading to gentler stimulation of the vasculature and increased numbers of sites at which agents can cross into the brain. Insights into the influence of agent size on the route of blood-brain barrier crossing were also gained. In agreement with studies using long-pulse ultrasound sequences, 8-11-nm-diameter agents and smaller appear to predominantly enter the brain through the gaps between cells lining the vasculature, having been widened by ultrasound-driven microbubble activity. |
| Exploitation Route | Researchers developing imaging agents and therapeutics towards the diagnosis and treatment of brain diseases may use this agent delivery system to evaluate their agents through in vivo studies. Demonstrating the versatility and safety of ultrasound-mediated drug delivery of various agents to the brain will also enable researchers more freedom in enhancing properties without compromising on blood-brain barrier permeability, potentially expediting clinical translation. Treatments and diagnostic methods previously thought to be unfeasible due to constraints provided by the blood-brain barrier may also be revisited as a result. Insights into the effect of varying ultrasound parameters and agent size on both adverse bioeffects and delivery outcomes will also contribute to fundamental research in ultrasound enhanced drug delivery to the brain. These findings are expected to inform researchers and aid in the refinement of ultrasound-mediated drug delivery systems towards clinical applications. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |