Article pubs.acs.org/Biomac
Block Copolymer Micelles Target Auger Electron Radiotherapy to the Nucleus of HER2-Positive Breast Cancer Cells Bryan Hoang,† Raymond M. Reilly,†,‡,∥ and Christine Allen*,†,§,⊥ †
Leslie Dan Faculty of Pharmacy, §Department of Chemistry, and ‡Department of Medical Imaging, University of Toronto, 144 College Street, Toronto, Ontario, Canada, M5S 3M2 ∥ Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada ⊥ STTARR Innovation Centre, Radiation Medicine Program, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada S Supporting Information *
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 (111In) 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 111In. 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 111In in all breast cancer cell lines evaluated.
■
the macromolecule.10−15 Additionally, nuclear translocation requires the presence of various cytosolic factors such as karyopherin and importins.16,17 In recent years there has been significant interest in the design of nanosystems such as liposomes, nanoparticles, and block copolymer micelles that facilitate delivery of cargo to the nucleus.13,18−21 Block copolymer micelles (BCMs) are nanoassemblies of amphiphilic copolymers that consist of a hydrophobic core surrounded by a hydrophilic corona.22 The core of the micelles can be used to encapsulate therapeutic agents while, the hydrophilic blocks within the corona may be labeled with radionuclides for imaging or radiotherapy.22 Micelles formed from biocompatible and biodegradable polymers such as poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) have been explored extensively for drug delivery.23−25 Recently the therapeutic potential of low energy (
