Multifunctional block copolymer micelles for the delivery of 111In to EGFR-positive breast cancer cells for targeted Auger electron radiotherapy

Mol Pharm. 2010 Feb 1;7(1):177-86. doi: 10.1021/mp900201v.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / radiotherapy*
  • Cell Line, Tumor
  • Cell Proliferation / radiation effects
  • Drug Delivery Systems*
  • Electrons / therapeutic use
  • Epidermal Growth Factor / administration & dosage
  • ErbB Receptors / metabolism*
  • Female
  • Humans
  • Indium Radioisotopes / administration & dosage*
  • Indium Radioisotopes / therapeutic use
  • Micelles
  • Pentetic Acid / administration & dosage
  • Pentetic Acid / analogs & derivatives
  • Polymers
  • Radiopharmaceuticals / administration & dosage*
  • Radiopharmaceuticals / therapeutic use
  • Tumor Stem Cell Assay

Substances

  • 111In-DTPA-human epidermal growth factor
  • Indium Radioisotopes
  • Micelles
  • Polymers
  • Radiopharmaceuticals
  • Epidermal Growth Factor
  • Pentetic Acid
  • ErbB Receptors