Chemoradiotherapy is a common treatment option for many cancers. Carfilzomib (CFZ) is an effective chemotherapeutic drug with a multitude of cellular effects. However, CFZ has yet to be studied in the context of chemoradiotherapy. To study the application of CFZ in chemoradiotherapy, we synthesized CFZ-loaded liposomes. We report a novel liposomal formulation of the proteasome inhibitor CFZ designed to enhance tumor radiosensitivity while improving drug solubility and tolerability. CFZ-loaded PEGylated liposomes were synthesized via thin-film hydration and probe sonication, achieving an average diameter of ∼127 nm and an encapsulation efficiency of 64%. In murine 4T1 breast carcinoma cells, CFZ treatment prior to irradiation significantly reduced clonogenic survival (dose enhancement factor = 1.26) and increased γ-H2AX foci retention, indicating impaired DNA double-strand break repair. In a dual-flank Balb/cJ allograft model, local intratumoral administration of CFZ followed by ionizing radiation (8 Gy × 2) markedly suppressed primary tumor growth compared with monotherapies without inducing systemic toxicity. Although a strong abscopal effect on distant tumors was not observed, the combination treatment reduced the pulmonary metastatic burden relative to controls. Collectively, these results demonstrate that liposomal carfilzomib can act as an effective radiosensitizer, functioning through perturbation of DNA repair and modulation of the tumor response to radiation. This study highlights a translationally relevant nanotherapeutic approach for enhancing chemoradiotherapy outcomes in solid malignancies.
Molinaro et al. (Mon,) studied this question.