Novel Approach of an Automated Radiolabeling of Micro- and Nanoscale UiO-66 MOFs for Internal Radiotherapy of Breast Cancer.

Development of automated radiolabeling strategies for perspective materials is in huge demand to reach the large-scale production of radiopharmaceuticals with unique features under good manufacturing practice (GMP) conditions. Inherent properties of metal-organic frameworks (MOFs) such as high loading capacity, chemical stability, and biocompatibility allow to recommend them as promising radionuclide carriers for cancer therapy but this area of research is poorly investigated. Herein, we first engineered an automated procedure for radiolabeling micro- and nanoscale UiO-66-NH2 MOFs (mMOF and nMOF) with therapeutic isotope radium-223 (223Ra) for internal radiotherapy of breast cancer. It allowed us to optimize the manual protocol of radiolabeling mMOF and nMOF with 223Ra (223Ra@mMOF and 223Ra@nMOF) and further transfer it into an automated radiolabeling procedure similar to GMP conditions. The stable porous structure of UiO-66-NH2 can effectively load 223Ra isotope (> 94%) and prevent its leakage for a long-term period (> 93% for 7 d). Then, UiO-66-NH2 MOFs were labeled with fluorescent dye Cy5 and diagnostic isotope 99mTc to investigate internalization efficiency toward 4T1 cells and in vivo biodistribution on the example of 4T1 tumor-bearing mice (breast cancer). The results of in vitro studies demonstrated a high penetration efficiency of Cy5@mMOF and Cy5@nMOF to 4T1 cells. It was shown that Cy5@mMOF/99mTc@mMOF and Cy5@nMOF/99mTc@mMOF can be effectively accumulated within the tumors in vivo without any release into healthy organs. Due to this, 223Ra@mMOF and 223Ra@nMOF have remarkable antitumor effects against breast cancer, demonstrating tumor inhibition of ∼ 76% for 223Ra@mMOF and ∼83% for 223Ra@nMOF without any significant side effects. Thus, our work firstly introduced highly effective automated radiolabeling for UiO-66-NH2 with excellent isotope loading for internal radiotherapy of breast cancer.