James Dixon - Acidosis-inducible drug and label delivery as a breast cancer therapeutic 2021 Pilot Grant
Lay abstract
Background: When breast tumours develop, they form acidic cores. This distinguishes them from normal tissues. The acidity could be used to trigger drug delivery systems to preferentially kill disease tissue, while sparing normal breast tissue. Being able to engineer effective ways to target this microenvironmental difference in tumour verses normal tissue would be very valuable and minimise side effects and treat tumours effectively.
Aims: To confirm a drug-delivery system can be modified to target breast cancers. This involves showing that the drug-delivery system can deliver labels that can be tracked. Once validated we will test if we can deliver drugs to preferentially target and kill breast cancer cells but leave non-acidic normal cells/tissue unaffected.
Techniques and methodology: We have engineered versions of a drug delivery system that is sensitive to relevant acidity levels seen in tumours. We will show uptake in cancer cells at these relevant acidities and also engineered 3D tissues which will generate their own acidic cores. We will initially show fluorescent labels can penetrate these tissues. Ultimately, we will deliver a drug using this approach to demonstrate that we can kill tumour cells in the acidic cores of 3D tumours we engineer.
Impact on breast cancer research: If we can efficiently target acidic conditions generated inside tumours, we could deliver drugs/therapies to target tumours preferentially. This would be transformative as the technology. This could provide a valuable way to label disease tissue and track it and deliver toxic drugs more specifically to breast cancers. Ultimately this will improve the outcomes of breast cancer patients.
Scientific Abstract
Background: When breast tumours develop, they form acidic cores which distinguishes them from normal tissues. The acidity can be used to trigger drug delivery systems to preferentially kill disease tissue, while sparing normal breast tissue. Being able to engineer effective ways to target this microenvironmental difference in tumour verses normal tissue would be very valuable to minimise side effects and generate the most efficacious treatments.
Aims: To confirm a drug-delivery system (called GET-5-7) can be modified to allow breast cancer targeting. This involves showing that labels that can be tracked and drugs (peptide based) can be used to preferentially target and kill breast cancer cells but leave normal cells/tissue unaffected.
Techniques and methodology: We have already engineered versions of GET that respond to the acidic pHs (pH5.5-6.5) found in tumours. We will show uptake in cancer cells at these lower pHs also engineered tissues (spheroids) which generate their own acidic cores. We will initially show fluorescent labels can bind and penetrate these spheroids and ultimately, we will deliver a peptide drug to demonstrate that we can initiate the death of the acidic pH cores of tumours spheroids.
Impact on breast cancer research: If we can efficiently target these acidic conditions generated inside tumours, we could deliver drugs/therapies to tumours preferentially. This would be transformative as the technology could be a valuable way to either label disease tissue and track it, and for the delivery of toxic drugs more specifically to breast cancer tissue. This will ultimately improve the outcomes of breast cancer patients.