macdonald-bifunctionalaptamer-2020.pdf (1.01 MB)
Bifunctional aptamer-doxorubicin conjugate crosses the blood-brain barrier and selectively delivers Its payload to EpCAM-positive tumor cells
journal contribution
posted on 2020-03-01, 00:00 authored by Joanna MacdonaldJoanna Macdonald, Delphine Denoyer, Justin Liam Henri, A Jamieson, I J G Burvenich, N Pouliot, Sarah ShigdarSarah ShigdarThe 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 tumor as a result of the highly restrictive blood-brain barrier (BBB). While methods of overcoming this barrier have been developed and employed with current treatment options, the majority are highly invasive and nonspecific, 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 BBB endothelial cell membranes. Using this approach, we intercalated doxorubicin (DOX) into a bifunctional aptamer targeting the transferrin receptor on the BBB and epithelial cell adhesion molecule (EpCAM) on metastatic cancer cells. The ability of the DOX-loaded aptamer to transcytose the BBB and selectively deliver the payload to EpCAM-positive tumors 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 colocalized aptamer and DOX are clearly detectable within the brain lesions 75 min postadministration. Collectively, results from this study demonstrate that through intercalation of a cytotoxic drug into the bifunctional aptamer, a therapeutic delivery vehicle can be developed for specific targeting of EpCAM-positive brain metastases.
History
Journal
Nucleic acid therapeuticsVolume
30Issue
2Pagination
117 - 128Publisher
Mary Ann LiebertLocation
New Rochelle, N.Y.Publisher DOI
Link to full text
ISSN
2159-3337eISSN
2159-3345Language
engPublication classification
C1 Refereed article in a scholarly journalUsage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC