Drug carrier-assisted combined chemo- and radionuclide therapy for tumors of diverse origins: effects of therapeutic schemes on tumor responses

Despite the promising results in cancer treatment, standard monotherapy remains insufficient for a wide range of oncological diseases. Combined therapy can significantly improve therapeutic outcomes compared to single-agent treatments. However, identifying the optimal treatment regimen for combined therapy can be a challenging task. In this work, we developed a therapeutic strategy for the treatment of three types of tumors - CT26 colorectal cancer, B16-F10 melanoma and 4T1 breast cancer using combined chemo- and radionuclide therapy. This was achieved by loading nanoparticles with radium-223 (²²³Ra-labeled NPs) and the chemotherapeutic drug doxorubicin (DOX). Each tumor model (CT26, B16-F10, 4T1) was treated using different therapeutic strategies: (i) intravenous or (ii) intratumoral administration of ²²³Ra-labeled NPs for single radionuclide therapy; (iii) intravenous injection of DOX for chemotherapy; and (iv) intratumoral injection of ²²³Ra-labeled NPs combined with intravenous administration of DOX for combined therapy. Our results demonstrated that each tumor model exhibited a distinct response to single and combined therapies. Notably, the combined chemo- and radionuclide therapy (DOX = 10 mg kg^-1 and ²²³Ra-labeled NPs = 2.7 KBq kg^-1) demonstrated a significantly higher therapeutic outcome than single therapies (DOX = 10 mg kg^-1 or ²²³Ra-labeled NPs = 2.7 KBq kg^-1). In particular, the average therapeutic response was >35% for monotherapy and >60%-80% for combined therapy. Importantly, the therapeutic effect across the three tumor types followed the order B16-F10 >4T1 >CT26. Thus, this work systematically investigated the response of three tumor types to the applicability of single chemo- or radionuclide therapy and their combination.