Multi-functional micelles for the combination of chemotherapy and radiotherapy in hepatocellular carcinoma

Y-H Shih, C-L Peng, T-Y Luo, M-J Shieh
National Taiwan University, TW

Keywords: rhenium-188, doxorubicin, micelles, PCNA


Hepatocellular carcinoma is the third leading cause of cancer deaths in worldwide. In this study, multi-functional micelles loaded with doxorubicin (Dox) and labeled with the radionuclide rhenium-188 (188Re) were developed to provide the combination of chemotherapy and radiotherapy for liver cancer. We prepared Dox loaded DTPA-micelles (Dox-micelles) using DTPA-PEG-PCL by the co-solvent evaporation method. The Dox-micelles were labeled with Re-188. The mice orthotopically implanted with BNL/Luc hepatoma were randomly allocated to four groups for the following respective treatments, including control (n=4), 188Re-perrhenate (n=4), Dox micelles (n=5) and 188Re Dox-micelles (n=5). The biodsitribution and therapeutic efficacy were investigated by γ-counting and long-term therapeutic monitoring in orthotopic model. Bioluminescence imaging of BNL/Luc hepatoma showed the smallest tumor size in 188Re-Dox micelles group (p<0.05). Moreover, 188Re-Dox micelles group had more than thirty days survival, which was significantly different with 188Re-perrhenate and control (p<0.005). Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) shows that 188Re-Dox micelles inhibited the proliferation of BNL/Luc cell comparing with control and 188Re-perrhenate (p<0.001). 188Re Dox-micelles shows a significant inhibitory effect on the tumor growth and extend the survival time in mice hepatoma model. We suggested the multi-functional micelles could apply for the combined therapies of hepatocellular carcinoma.