title: Design and synthesis of mono- and multimeric targeted radiopharmaceuticals based on novel cyclen ligands coupled to anti-MUC1 aptamers for the diagnostic imaging and targeted radiotherapy of cancer.
abstract: Targeted radiopharmaceuticals offer the possibility of improved tumor imaging and radiotherapy, with reduced side effects. A variety of monoclonal antibodies and antibody fragments have previously been successfully radiolabeled and used in diagnostic imaging and targeted radiotherapy of cancer. Many such antibodies have been shown to recognize the well-characterized MUC1 tumor marker and have recently been in clinical trials. Furthermore, a number of chelators have been synthesized and are currently used as radiopharmaceuticals for imaging and therapy. We now report the synthesis of a novel, cyclen-based ligand with a sulfur-containing arm that offers increased stability of the ligand-metal complex. We have coupled this ligand with previously selected aptamers to the MUC1 tumor marker to generate a novel targeted radiopharmaceutical with improved properties. We have tested the complex against known, commercially available chelators such as MAG3 in model breast cancer systems. To improve the pharmacokinetic properties of the aptamer-based targeted radiopharmaceutical, we have generated multi-aptamer complexes around a central chelator. Such multi-aptamer complexes have increased retention of the complex in circulation, without affecting the lack of immunogenicity of the complex or altering its superior tumor penetration properties.
authors.affiliation: Chemistry Department, The Open University, Milton Keynes, UK.
authors.forename: K Eszter
authors.initials: KE
authors.lastname: Borbas
authors.forename: Catia S M
authors.initials: CS
authors.lastname: Ferreira
authors.forename: Alan
authors.initials: A
authors.lastname: Perkins
authors.forename: James I
authors.initials: JI
authors.lastname: Bruce
authors.forename: Sotiris
authors.initials: S
authors.lastname: Missailidis
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D052157:Aptamers, Nucleotide / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D000080027:Cyclams; D003952:Diagnostic Imaging; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008715:Methionine / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D018396:Mucin-1; D009077:Mucins / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013667:Technetium / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000081:Acetamides; D000951:Antigens, Neoplasm; D052157:Aptamers, Nucleotide; D014408:Biomarkers, Tumor; D002614:Chelating Agents; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D008024:Ligands; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C013874:chloroacetamide; C036827:methionine ethyl ester; D013667:Technetium; C038072:cyclen; D008715:Methionine