Rethinking repurposing: Developing cryogel technology to address glioblastoma recurrence through year-long local delivery of repurposed therapeutics
Lead Research Organisation:
CARDIFF UNIVERSITY
Department Name: Welsh School of Pharmacy
Abstract
Repurposing existing drugs to treat brain cancer.
Repurposing drugs (also known as repositioning) is the process of taking an existing medicine that is already authorised for human use in one disease/condition, and then using it to treat another condition. This is an attractive strategy for new medical treatments as the drug development and regulatory approval process is long, costly and high-risk.
Unfortunately, for brain cancers such as the highly aggressive glioblastoma, this repurposing idea is severely hampered because most drugs cannot pass from the bloodstream to the brain. The blood-brain barrier, which protects our brains in normal life, hinders their passage to the tumour. Consequently, current drugs that may be highly effective against brain cancer cells in the laboratory, can't reach their target in a human.
Glioblastoma patients have a poor prognosis - typically around 14 months survival. Despite surgical removal of the tumour (in most cases), followed by radiotherapy and chemotherapy with a single drug, some cancer cells remain. These cells come in many guises meaning that one drug is unlikely to kill them all. Unfortunately, the remaining cells ultimately cause tumour recurrence, most commonly near the original tumour site. Hence new therapeutic strategies are desperately needed.
For this project we have assembled a team of scientists with a variety of research backgrounds to answer these three key questions:
1) How can we deliver repurposed drugs to the tumour?
2) Which drug or drug combinations would be best to deliver?
3) How can we work out how far the delivered drug penetrates into the surrounding brain tissue to mop up those residual cells?
1) How to deliver multiple drugs safely?
We propose to make a set of soft, sponge-like materials, where each be loaded with a different repurposed drug. These sponges (called cryogels) could be inserted into the cavity left behind during surgery. They are easily handled by surgeons and are so soft that they compress very easily to fill the cavity without putting headache-causing pressure on the brain. By having a set of sponges (each sponge loaded with a different drug), the surgical team can choose combinations of this modular system specifically for the best outcomes in that patient (all cancers are slightly different). Our preliminary system can deliver drugs for far longer (6 months) than other systems in development (days or weeks). Furthermore, our technology would be the first that can be refillable, giving the surgical team even greater flexibility as recurrence is slowed and patients live longer.
2) How to select drugs and combinations?
Until now this has been done very arbitrarily, with some very poor drug selection. Our team would systematically screen thousands of potential drugs to find:
- Those most suited for the delivery system,
- Those that cause the most harm to the glioblastoma cancer cells, but least harm to the healthy brain.
We hope that the results of this screen will completely change how we think about drug repurposing for brain cancers.
3) How to visualise drug penetration into the brain?
This is a key question that researchers have little answer for, as it is technically very challenging. Our team has recently developed a new technique (first in the UK) for imaging drug penetration in tissue, which will transform our understanding of what happens once the drug is delivered, allowing much better translation of animal data to the large human brain.
Whilst glioblastoma is a clear target for this work, we are sure our findings will be highly applicable to other cancers, giving researchers the technological innovation required to deliver drugs directly to the target site.
Repurposing drugs (also known as repositioning) is the process of taking an existing medicine that is already authorised for human use in one disease/condition, and then using it to treat another condition. This is an attractive strategy for new medical treatments as the drug development and regulatory approval process is long, costly and high-risk.
Unfortunately, for brain cancers such as the highly aggressive glioblastoma, this repurposing idea is severely hampered because most drugs cannot pass from the bloodstream to the brain. The blood-brain barrier, which protects our brains in normal life, hinders their passage to the tumour. Consequently, current drugs that may be highly effective against brain cancer cells in the laboratory, can't reach their target in a human.
Glioblastoma patients have a poor prognosis - typically around 14 months survival. Despite surgical removal of the tumour (in most cases), followed by radiotherapy and chemotherapy with a single drug, some cancer cells remain. These cells come in many guises meaning that one drug is unlikely to kill them all. Unfortunately, the remaining cells ultimately cause tumour recurrence, most commonly near the original tumour site. Hence new therapeutic strategies are desperately needed.
For this project we have assembled a team of scientists with a variety of research backgrounds to answer these three key questions:
1) How can we deliver repurposed drugs to the tumour?
2) Which drug or drug combinations would be best to deliver?
3) How can we work out how far the delivered drug penetrates into the surrounding brain tissue to mop up those residual cells?
1) How to deliver multiple drugs safely?
We propose to make a set of soft, sponge-like materials, where each be loaded with a different repurposed drug. These sponges (called cryogels) could be inserted into the cavity left behind during surgery. They are easily handled by surgeons and are so soft that they compress very easily to fill the cavity without putting headache-causing pressure on the brain. By having a set of sponges (each sponge loaded with a different drug), the surgical team can choose combinations of this modular system specifically for the best outcomes in that patient (all cancers are slightly different). Our preliminary system can deliver drugs for far longer (6 months) than other systems in development (days or weeks). Furthermore, our technology would be the first that can be refillable, giving the surgical team even greater flexibility as recurrence is slowed and patients live longer.
2) How to select drugs and combinations?
Until now this has been done very arbitrarily, with some very poor drug selection. Our team would systematically screen thousands of potential drugs to find:
- Those most suited for the delivery system,
- Those that cause the most harm to the glioblastoma cancer cells, but least harm to the healthy brain.
We hope that the results of this screen will completely change how we think about drug repurposing for brain cancers.
3) How to visualise drug penetration into the brain?
This is a key question that researchers have little answer for, as it is technically very challenging. Our team has recently developed a new technique (first in the UK) for imaging drug penetration in tissue, which will transform our understanding of what happens once the drug is delivered, allowing much better translation of animal data to the large human brain.
Whilst glioblastoma is a clear target for this work, we are sure our findings will be highly applicable to other cancers, giving researchers the technological innovation required to deliver drugs directly to the target site.
Technical Summary
New therapeutic strategies are urgently needed for glioblastoma patients. Reviewing ~2000 papers on pre-clinical work in this area, showed that emerging local drug delivery technologies fail to deliver a drug at a therapeutic dose for the sustained periods required for clinical efficacy. In addition, these systems often require technical expertise, are difficult to manufacture/store/sterilise and offer no flexibility in the therapeutic regimen (i.e., combinations of drugs delivered).
Drug selection, for use with the delivery system, is currently arbitrary in nature due to a lack of data on the specificity of drug action.
Key research questions for this project:
1) How to deliver combinations of drugs to brain tumours at therapeutically relevant doses for extended time periods?
2) How to select drugs with the highest "on target" specificity score (i.e., maximal effect with minimum cytotoxicity to healthy cells)?
3) How to determine drug penetration into the brain parenchyma?
Hypothesis:
Soft, macroporous cryogel scaffolds can be developed to safely deliver repurposed drugs for one year. A glioblastoma specificity screen will allow previously unexplored drugs and drug combinations to be explored for glioblastoma therapeutics.
Methodology:
Un-biased in silico selection and patient tissue ex vivo screening will determine drugs with highest specificity for glioblastoma cells. We will develop cryogels that load these drugs by electrostatic attraction rather than internal encapsulation, allowing sustained delivery and subsequent refilling (assessed in vitro). Combinations of these will be delivered to glioblastoma spheroid cultures in vitro via the cryogels. The most efficacious drug/cryogel partnership will be analysed in a rat resection glioma model, using Orbi-SIMS technology to determine drug distribution in the brain for further funding acquisition.
Our team has the unique skill sets to bring about this paradigm shift in local drug delivery.
Drug selection, for use with the delivery system, is currently arbitrary in nature due to a lack of data on the specificity of drug action.
Key research questions for this project:
1) How to deliver combinations of drugs to brain tumours at therapeutically relevant doses for extended time periods?
2) How to select drugs with the highest "on target" specificity score (i.e., maximal effect with minimum cytotoxicity to healthy cells)?
3) How to determine drug penetration into the brain parenchyma?
Hypothesis:
Soft, macroporous cryogel scaffolds can be developed to safely deliver repurposed drugs for one year. A glioblastoma specificity screen will allow previously unexplored drugs and drug combinations to be explored for glioblastoma therapeutics.
Methodology:
Un-biased in silico selection and patient tissue ex vivo screening will determine drugs with highest specificity for glioblastoma cells. We will develop cryogels that load these drugs by electrostatic attraction rather than internal encapsulation, allowing sustained delivery and subsequent refilling (assessed in vitro). Combinations of these will be delivered to glioblastoma spheroid cultures in vitro via the cryogels. The most efficacious drug/cryogel partnership will be analysed in a rat resection glioma model, using Orbi-SIMS technology to determine drug distribution in the brain for further funding acquisition.
Our team has the unique skill sets to bring about this paradigm shift in local drug delivery.
