Polymeric Radioimmunoconjugates for Targeted Breast Cancer Therapy

Human epidermal growth factor receptor 2 (HER2) proteins that normally regulate cell growth are over-expressed in 25-30% of breast cancer (BC) patients causing BC cells to reproduce uncontrollably resulting in metastasis. Trastuzumab is a monoclonal antibody, which targets the HER2 proteins over-expressed on the surface of the BC cells. Our goal is to synthesize a polymeric radioimmunoconjugate where trastuzumab is conjugated to a metal chelating polymer loaded with In(111). In(111) decays through electron capture emitting gamma rays (useful for imaging) and Auger electrons that are lethal to the cancer cell if In(111) is present in the cell nucleus. With a short penetration depth, Auger electrons are able to destroy the targeted BC cells leaving normal cells unharmed. Our hypothesis is that the trastuzumab will be recognized by the HER2 receptor and the radioimmunoconjuate will be taken into the BC cell by endocytosis. Subsequently, the proton sponge effect will induce endosomal release of the radioimmunoconjuate into the cytoplasm. The importin proteins on the surface of the nucleus will recognize the nuclear localization sequence (NLS) and transport the cytotoxic radionuclides into the BC cells leading to cell death. Doxorubicin can also be conjugated to the polymer either in place of or in conjunction with In(111) to induce cancer cell death. This project involves collaboration between the Winnik group and the Reilly group from the pharmacy department at the University of Toronto.