Potent Anticancer Activity of CXCR4-Targeted Nanostructured Toxins in Aggressive Endometrial Cancer Models

• Published in: Cancers Vol. 15; no. 1; p. 85
• Main Authors: Medina-Gutiérrez, Esperanza, García-León, Annabel, Gallardo, Alberto, Álamo, Patricia, Alba-Castellón, Lorena, Unzueta, Ugutz, Villaverde, Antonio, Vázquez, Esther, Casanova, Isolda, Mangues, Ramon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.12.2022; MDPI
• Subjects: Animal models; Antimitotic agents; Antineoplastic agents; Antitumor activity; Apoptosis; Bioluminescence; Cancer; Cancer therapies; Care and treatment; Caspase-3; Cell culture; Chemokine receptors; Chemotherapy; Clinical trials; CXCR4 protein; Cytotoxicity; Endometrial cancer; Endometrium; Flow cytometry; Health aspects; Hematology; Intravenous administration; Ligands; Malignancy; Metastases; Metastasis; Monoclonal antibodies; Nanoparticles; Poly(ADP-ribose) polymerase; Proteins; Risk groups; Testing; Therapeutic targets; Toxicity; Toxins; Tumors; Spain; United States > US; Germany; CXCR4; targeted drug delivery; advanced endometrial cancer; bacterial toxins; metastasis; protein nanoparticles
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15010085

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 (T22-DITOX-H6) or (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.