Poster Presentation 32nd Lorne Cancer 2020

Bifunctional aptamer-doxorubicin conjugate crosses blood brain barrier and selectively delivers payload to Epithelial Cell Adhesion Molecule positive tumour cells. (#348)

Joanna Macdonald 1 2 , Justin Henri 1 , Adelaide Jamieson 1 , Delphine Denoyer 3 4 , Ingrid Burvenich 4 5 , Normand Pouliot 3 4 6 , Sarah Shigdar 1 2
  1. School of Medicine, Deakin University, Geelong, VIC, Australia
  2. Centre for Molecular and Medical Research, Deakin University, Geelong, VIC, Australia
  3. Matrix Microenvironment and Metastasis Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Vic, Australia
  4. School of Cancer Medicine, La Trobe University, Melbourne, Vic, Australia
  5. Tumour Targeting Laboratory, Olivia Newton John Cancer Research Institute, Melbourne, Vic, Australia
  6. Department of Pathology and University of Melbourne, Melbourne, Vic, Australia

Prognosis for breast cancer patients diagnosed with brain metastases is poor, with survival time measured merely in months. This can largely be attributed to the limited treatment options capable of reaching the tumour as a result of the highly restrictive blood-brain barrier. While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and non-specific, leading to severe neurotoxic side effects. A novel approach to address these issues is the development of therapeutics targeting receptor mediated transport mechanisms on the blood-brain barrier endothelial cell membranes. Using this approach, we intercalated doxorubicin into a bifunctional aptamer targeting the transferrin receptor on the blood brain barrier and epithelial cell adhesion molecule on the metastatic cancer cells. The ability of the doxorubicin loaded aptamer to transcytose the blood brain barrier and selectively deliver the payload to epithelial cell adhesion molecule-positive tumours was evaluated in an in vitro model and confirmed for the first time in vivo using the MDA-MB-231 breast cancer metastasis model (MDA-MB-231Br). We show that co-localised aptamer and doxorubicin are clearly detectable within the brain lesions 75 minutes post administration. Collectively, the results from this study demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for the specific targeting of epithelial cell adhesion molecule-positive brain metastases.