title: Block copolymer micelles target Auger electron radiotherapy to the nucleus of HER2-positive breast cancer cells.
abstract: Intracellular trafficking of Auger electron emitting radionuclides to perinuclear and nuclear regions of cells is critical to realizing their full therapeutic potential. In the present study, block copolymer micelles (BCMs) were labeled with the Auger electron emitter indium-111 ((111)In) and loaded with the radiosensitizer methotrexate. HER2 specific antibodies (trastuzumab fab) and nuclear localization signal (NLS; CGYGPKKKRKVGG) peptides were conjugated to the surface of the BCMs to direct uptake in HER2 expressing cells and subsequent localization in the cell nucleus. Cell uptake and intracellular distribution of the multifunctional BCMs were evaluated in a panel of breast cancer cell lines with different levels of HER2 expression. Indeed cell uptake was found to be HER2 density dependent, confirming receptor-mediated internalization of the BCMs. Importantly, conjugation of NLS peptides to the surface of BCMs was found to result in a significant increase in nuclear uptake of the radionuclide (111)In. Successful nuclear targeting was shown to improve the antipoliferative effect of the Auger electrons as measured by clonogenic assays. In addition, a significant radiation enhancement effect was observed by concurrent delivery of low-dose MTX and (111)In in all breast cancer cell lines evaluated.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
authors.forename: Bryan
authors.initials: B
authors.lastname: Hoang
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D000595:Amino Acid Sequence; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004583:Electrons; D004705:Endocytosis; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics; D007205:Indium Radioisotopes; D008727:Methotrexate / Q000493:pharmacokinetics*; D008823:Micelles; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D008727:Methotrexate; D008823:Micelles; D019913:Nuclear Localization Signals; D011091:Polyesters; D011092:Polyethylene Glycols; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C439611:methoxy poly(ethylene glycol-co-epsilon-caprolactone); C508053:ERBB2 protein, human