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

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 (¹⁸⁸Re)-conjugated radiopharmaceutical has been reported to escalate the radiation doses for better control of advanced human cancers. Here we found that high dosage of ¹⁸⁸Re-liposome, the liposome-encapsulated ¹⁸⁸Re 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 ¹⁸⁸Re-liposomal dosage in vivo, repeated doses of ¹⁸⁸Re-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 ¹⁸⁸Re-liposome. The Cerenkov luminescence imaging (CLI) was performed to demonstrate an increased accumulation of ¹⁸⁸Re-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 ¹⁸⁸Re-liposome, yet repeated doses led to lower blood counts than a single dose. Furthermore, the pharmacokinetic analysis showed that the internal circulation of repeated ¹⁸⁸Re-liposomal therapy was elongated. The biodistribution analysis also demonstrated that accumulations of ¹⁸⁸Re-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 ¹⁸⁸Re-liposome can enhance tumor suppression, survival extension, and internal circulation without acute toxicity using repeated administrations.