title: Multifunctional block copolymer micelles for the delivery of 111In to EGFR-positive breast cancer cells for targeted Auger electron radiotherapy.
abstract: Block copolymer micelles (BCMs) can improve the payload delivery of therapeutic agents to tumors. Our aim was to construct hEGF-modified BCMs for the delivery of 111In to tumor cells for Auger electron-emission radiotherapy of EGFR-positive breast cancer (BC). Multifunctional nanosized BCMs were prepared from MePEG(2500)-b-PCL(1200) and 111In-DTPA-PEG(3000)-b-PCL(1600) with or without hEGF-PEG(2900)-b-PCL(1400) (111In-hEGF-BCMs or 111In-BCMs). The resulting BCMs were analyzed by dynamic light scattering and transmission electron microscopy. Cellular uptake and nuclear importation were assessed in MDA-MB-468, MDA-MB-231 and MCF-7 BC cells with decreasing EGFR density. In vitro antiproliferative effects were evaluated using the WST-1 assay after 48 h with 111In-hEGF-BCMs, and the clonogenic assay was used to determine the survival fraction (SF) after a 21 h exposure. Results were compared with 111In-DTPA-hEGF, an established Auger electron-emitting radiotherapeutic that is currently in clinical development. Cell uptake and nuclear importation of 111In-hEGF-BCMs decreased in the following order: MDA-MB-468 > MDA-MB-231 > MCF-7. Cellular uptake of 111In-hEGF-BCMs was less than 111In-DTPA-hEGF (P < 0.05) but was 4-fold higher than for 111In-BCMs (P < 0.001). There was a significant growth inhibition of MDA-MB-468 cells by 111In-hEGF-BCMs (6-fold inhibition, P < 0.05) while the growth of MDA-MB-231 and MCF-7 were not significantly inhibited. The SF of MDA-MB-468 cells was decreased to 2.6% while that for MCF-7 cells was 132.7%. 111In-DTPA-hEGF reduced the SF of MDA-MB-468 cells to 0.4%. Nontargeted 111In-BCMs had minimal effect on the SF of BC cells. Therefore, the 111In-hEGF-BCMs were bound, internalized and transported to the nuclei of EGFR-positive BC cells, where the Auger electron emissions were lethal. The 111In-hEGF-BCMs are a promising delivery system for targeted radiotherapy of BC.
authors.affiliation: Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
authors.forename: Humphrey
authors.initials: H
authors.lastname: Fonge
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D016503:Drug Delivery Systems; D004583:Electrons / Q000627:therapeutic use; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000008:administration & dosage* / Q000627:therapeutic use; D008823:Micelles; D004369:Pentetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011108:Polymers; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000627:therapeutic use; D014410:Tumor Stem Cell Assay
chemical_list: C478252:111In-DTPA-human epidermal growth factor; D007205:Indium Radioisotopes; D008823:Micelles; D011108:Polymers; D019275:Radiopharmaceuticals; D004815:Epidermal Growth Factor; D004369:Pentetic Acid; D066246:ErbB Receptors