Pump Prime Awards
Workshop on drug delivery to the brain – 27th February 2020
On Thursday 27th February 2020, we held our second workshop on drug delivery to the brain. As part of this day in Edinburgh, we awarded three pump prime awards, to Julia Benzel, Nicola Farrer and Peter Harvey. Read more about their projects below.
Julia Benzel, KiTZ / DKFZ, Germany
Monitoring drug-induced tumour responses in real-time
Treatment responses and direct effects of drug exposures at site of action are difficult to estimate. Usually, biopsies are necessary to study direct effects of therapies.
This leads us to the research question: How can we measure in real-time drug concentrations and metabolites as well as drug-induced responses (e.g. cytokines) in the tumour tissue of interest?
The method cerebral microdialysis allows us not only to measure drug concentrations in tumour or healthy tissue in real-time, but also to simultaneously measure drug-induced tumour responses (e.g. cytokines). This enables us to measure drug penetration over the blood-brain barrier and drug-induced early tumour responses without the necessity of repeated biopsies.
Update June 2021
In (pre)clinical studies, researchers often use tissue biopsies to estimate treatment responses and direct effects of drug exposures in brain tumours. An alternative approach is cerebral microdialysis for measuring drug concentrations in tumour or healthy tissue in real-time. This enables monitoring of drug penetration over the blood-brain barrier (BBB), and potentially drug-induced early tumour-responses, without being dependent on repeated biopsies.
In this project, we are using supratentorial ependymomas harbouring ZFTA/C11orf95 fusions as a model system. These aggressive brain tumours occur in children. Systemic chemotherapeutic or targeted therapies have not been found to be effective so far. However, recently p53 reactivation and inhibition of nuclear protein shuttling have been identified as promising therapeutic approaches.
It has previously been shown that low-dose dactinomycin can successfully re-establish p53 function in tumor cells in vitro. In this study, using cerebral microdialysis we are analysing actual penetration of the drug across the BBB. Our results so far looking at tissue homogenates from preclinical models that were treated with dactinomycin, indicate that the drug most probably does penetrate the BBB.
Nicola Farrer, University of Oxford, UK
Acetylene cross-linking for improved platinum(IV) prodrug retention in liposomes
The childhood cancer Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of death from brain cancer in children and is currently fatal; new approaches and new treatments are urgently needed.
Platinum complexes are currently in use for treating DIPG; we are investigating packaging up new platinum complexes, which should be less reactive than the established platinum drugs, so that they are less toxic at the point of injection. This project will seek to improve how the platinum complexes are packaged.
Update June 2021
We have been investigating the liposomal encapsulation of the platinum(IV) prodrug iproplatin using active loading strategies, monitoring prodrug leakage by HPLC. ICP-MS analysis scheduled to be performed over the summer will enable us to quantify the leakage, and we aim to then progress to cross-linking strategies with Professor Steve Evans in Leeds as and when COVID-19 permits.
Peter Harvey, University of Nottingham, UK
Monitoring Lipophilic Drug Delivery with Lipophilic MRI Contrast Agents
Delivery of drugs to particular regions of the body is key to treating disease. This delivery is particularly difficult in the brain, due to the blood-brain barrier. Unfortunately, we are limited in our ability to track drugs as they pass through the body.
Our solution is to use imaging compounds that can report on the position of drugs by magnetic resonance imaging (MRI). We will use imaging compounds that resemble drugs in their physical properties and cage them inside nanoparticles in order for the imaging readout to be directly linked to the drug positioning.
Update June 2021
A key issue in delivering drugs to the brain is not only in the difficulty of transporting drugs into the brain, but also in determining whether the delivery has occurred and where the drug may subsequently have spread. MRI contrast agents are often used as model compounds for drugs to image these properties, but the chemistry of these contrast agents is wildly different to a typical chemotherapeutic, particularly in terms of lipophilicity.
The aim of our pump-prime award is to use lipophilic MRI contrast agents to provide a more detailed outlook on the delivery of lipophilic drugs to the brain. To this aim, we have so far investigated a few different angles. Firstly, new lipophilic contrast agents are being synthesised both at Nottingham and at MIT. Progress is going well, and these compounds should be ready for further testing over the summer. Nanoparticle composites of existing fluorinated chemotherapeutics have been created and measured, with a view to using self-contained MR signals as the imaging marker. Ex vivo MRI studies have also been carried out following in vivo spinal delivery of contrast agents to the brain. The remainder of the award will focus on combining the initial work on the separate branches of the project – contrast agents, therapeutic nanoparticles, & MR imaging - towards our overall aim.