부산대학교 도서관

Simple Summary: The fact that most endometrial cancer (EC) patients overexpress the CXCR4 receptor in tumor tissue, especially at incurable advanced stages, opens an avenue for developing novel therapies targeting CXCR4+ EC cells to add new armamentarium against this malignancy. We have generated novel CXCR4-targeted nanotoxins, T22-DITOX-H6 and T22-PE24-H6, which we here evaluate in EC mouse models. We observed a selective killing of CXCR4+ EC cells by apoptosis induction in cultured cells as well as in tumor models, which inhibit tumor growth and increase mouse survival after repeated intravenous doses. Moreover, T22-DITOX-H6 induced a significant block of metastasis dissemination without toxicity in non-tumor tissues. Therefore, both nanotoxins may become alternative therapeutics for CXCR4+ high-risk EC patients, who nowadays lack effective therapies. Patients with advanced endometrial cancer (EC) show poor outcomes. Thus, the development of new therapeutic approaches to prevent metastasis development in high-risk patients is an unmet need. CXCR4 is overexpressed in EC tumor tissue, epitomizing an unexploited therapeutic target for this malignancy. The in vitro antitumor activity of two CXCR4-targeted nanoparticles, including either the C. diphtheriae (T22-DITOX-H6) or P. aeruginosa (T22-PE24-H6) toxin, was evaluated using viability assays. Apoptotic activation was assessed by DAPI and caspase-3 and PARP cleavage in cell blocks. Both nanotoxins were repeatedly administrated to a subcutaneous EC mouse model, whereas T22-DITOX-H6 was also used in a highly metastatic EC orthotopic model. Tumor burden was assessed through bioluminescence, while metastatic foci and toxicity were studied using histological or immunohistochemical analysis. We found that both nanotoxins exerted a potent antitumor effect both in vitro and in vivo via apoptosis and extended the survival of nanotoxin-treated mice without inducing any off-target toxicity. Repeated T22-DITOX-H6 administration in the metastatic model induced a dramatic reduction in tumor burden while significantly blocking peritoneal, lung and liver metastasis without systemic toxicity. Both nanotoxins, but especially T22-DITOX-H6, represent a promising therapeutic alternative for EC patients that have a dismal prognosis and lack effective therapies. [ABSTRACT FROM AUTHOR]