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Human head and neck squamous cell carcinoma (HNSCC) is usually treated with chemoradiotherapy, but the therapeutic efficacy could be hampered by intrinsic radioresistance and early relapse. Repeated administrations of rhenium-188 ( 188 Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of  188 Re-liposome, the liposome-encapsulated  188 Re nanoparticles exhibited significant killing effects on HNSCC FaDu cells and SAS cells but not on OECM-1 cells. To investigate the biological and pharmaceutical responses of high  188 Re-liposomal dosage in vivo, repeated doses of  188 Re-liposome was injected into the orthotopic tumor model. FaDu cells harboring luciferase reporter genes were implanted in the buccal positions of nude mice followed by intravenous injection of  188 Re-liposome. The Cerenkov luminescence imaging (CLI) was performed to demonstrate an increased accumulation of  188 Re-liposome in the tumor lesion of nude mice with repeated doses compared to a single dose. Repeated doses also enhanced tumor growth delay and elongated the survival of tumor-bearing mice. These observations were associated with significant loss of Ki-67 proliferative marker and epithelial–mesenchymal transition (EMT) markers in excised tumor cells. The body weights of mice were not significantly changed using different doses of  188 Re-liposome, yet repeated doses led to lower blood counts than a single dose. Furthermore, the pharmacokinetic analysis showed that the internal circulation of repeated  188 Re-liposomal therapy was elongated. The biodistribution analysis also demonstrated that accumulations of  188 Re-liposome in tumor lesions and bone marrow were increased using repeated doses. The absorbed dose of repeated doses over a single dose was about twofold estimated for a 1 g tumor. Together, these data suggest that the radiopharmacotherapy of  188 Re-liposome can enhance tumor suppression, survival extension, and internal circulation without acute toxicity using repeated administrations.

cell death discovery

PEGylated liposome-encapsulated rhenium-188 radiopharmaceutical inhibits proliferation and epithelial–mesenchymal transition of human head and neck cancer cells in vivo with repeated therapy