title: Development of a Bifunctional Aptamer Targeting the Transferrin Receptor and Epithelial Cell Adhesion Molecule (EpCAM) for the Treatment of Brain Cancer Metastases.
abstract: The treatment of brain disorders is greatly hindered by the presence of the blood-brain barrier, which restricts the overwhelming majority of small molecules from entering the brain. A novel approach by which to overcome this barrier is to target receptor mediated transport mechanisms present on the endothelial cell membranes. Therefore, we fused an aptamer that binds to epithelial cell adhesion molecule-expressing cancer cells to an aptamer targeting the transferrin receptor. This generated a proof of concept bifunctional aptamer that can overcome the blood-brain barrier and potentially specifically target brain disorders. The initial fusion of the two sequences enhanced the binding affinity of both aptamers while maintaining specificity. Additionally, mutations were introduced into both binding loops to determine their effect on aptamer specificity. The ability of the aptamer to transcytose the blood-brain barrier was then confirmed in vivo following a 1 nmol injection. This study has shown that through the fusion of two aptamer sequences, a bifunctional aptamer can be generated that has the potential to be developed for the specific treatment of brain disorders.
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Joanna
authors.initials: J
authors.lastname: Macdonald
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Justin
authors.initials: J
authors.lastname: Henri
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Lynda
authors.initials: L
authors.lastname: Goodman
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Dongxi
authors.initials: D
authors.lastname: Xiang
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.affiliation: School of Medicine and ‡Centre for Molecular and Medical Research, Deakin University , Geelong, Victoria 3128, Australia.
authors.forename: Sarah
authors.identifier: 0000-0001-8084-8447
authors.initials: S
authors.lastname: Shigdar
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011990:Receptors, Transferrin; D057900:Transcytosis
chemical_list: D052157:Aptamers, Nucleotide; D000071858:Epithelial Cell Adhesion Molecule; D011990:Receptors, Transferrin
keywords: Aptamer; bifunctional; blood−brain barrier; epithelial cell adhesion molecule (EpCAM); receptor mediated transcytosis; transferrin receptor