Multifunctional Block Copolymer Micelles for the Delivery of 111In to EGFR-Positive Breast Cancer Cells for Targeted Auger Electron Radiotherapy

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 In-111 to tumor cells for Auger electron-emission radiotherapy of EGFR-positive breast cancer (BC). Multifunctional nanosized BCMs were prepared from MePEG(2500)-b-PCL1200 and In-111-DTPA-PEG(3000)-b-PCL1600 with or without hEGF-PEG(2900)-b-PCL1400 (In-111-hEGF-BCMs or In-111-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 In-111-hEGF-BCMs, and the clonogenic assay was used to determine the survival fraction (SF) after a 21 h exposure. Results were compared with In-111-DTPA-hEGF, an established Auger electron-emitting radiotherapeutic that is currently in clinical development. Cell uptake and nuclear importation of In-111-hEGF-BCMs decreased in the following order: MDA-MB-468 > MDA-MB-231 > MCF-7. Cellular uptake of In-111-hEGF-BCMs was less than In-111-DTPA-hEGF (P < 0.05) but was 4-fold higher than for In-111-BCMs (P < 0.001). There was a significant growth inhibition of MDA-MB-468 cells by In-111-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%. In-111-DTPA-hEGF reduced the SF of MDA-MB-468 cells to 0.4%. Nontargeted In-111-BCMs had minimal effect on the SF of BC cells. Therefore, the In-111-hEGF-BCMs were bound, internalized and transported to the nuclei of EGFR-positive BC cells, where the Auger electron emissions were lethal. The In-111-hEGF-BCMs are a promising delivery system for targeted radiotherapy of BC.