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| Pàgina inicial > Articles > Articles publicats > A Targeted Nanotoxin Inhibits Colorectal Cancer Growth Through Local Tumor Pyroptosis and Eosinophil Infiltration and Degranulation |
(Institut de Recerca Sant Pau) (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya)) (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Centro deInvestigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER)) (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia) (Institut de Recerca Sant Pau) (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia) (Institut de Recerca Sant Pau)| Data: | 2025 |
| Resum: | Background: Colorectal cancer (CRC) has traditionally been treated with genotoxic chemotherapy to activate pro-apoptotic proteins to induce anticancer effects. However, cancer cells develop resistance to apoptosis, which leads to recurrence and poor prognosis. Moreover, this kind of therapy has been shown to be highly toxic to healthy tissues and, therefore, to patients. To overcome this issue, we developed a self-assembly tumor-targeted nanoparticle, T22-DITOX-H6, that incorporates the T22 peptide (a CXCR4 ligand) to selectively target cells overexpressing CXCR4, fused to the catalytic domain of diphtheria toxin, that exhibits a potent cytotoxic effect on these CXCR4+ cancer cells that exhibits potent cytotoxic effects on CXCR4-overexpressing cancer cells through the activation of pyroptosis, an immunogenic type of cell death. Methods: Colorectal CXCR4-expressing tumor cells (CT26-CXCR4+) were implanted subcutaneously into immunocompetent mice to study the effects of T22-DITOX-H6 treatment on tumor growth, cell death and innate immune cell recruitment to the tumor. Results: Here, we demonstrated that the T22-DITOX-H6 nanoparticle selectively activated pyroptosis, an immunogenic cell death that differs from apoptosis, leading to cell death in CXCR4-expressing cells, without affecting the viability of CXCR4-lacking cells. In addition, the nanoparticle administered to tumor-bearing mice induced a local antitumor effect due to the selective activation of pyroptosis in CXCR4+ targeted cancer cells. Biochemical analysis of plasma and histological analysis of non-tumor tissues revealed no differences between the groups. Remarkably, pyroptosis activation stimulates eosinophil infiltration into the tumor microenvironment, an effect recently reported to have an anti-tumorigenic function. Conclusion: These results highlight the dual role of CXCR4-targeted cytotoxic nanoparticle in eliminating cancer cells and boosting the self-immune response without compromising healthy organs. |
| Ajuts: | Instituto de Salud Carlos III PI18/00650 Instituto de Salud Carlos III PI20/00400 Instituto de Salud Carlos III PI23/00318 Instituto de Salud Carlos III PI21/00150 Agencia Estatal de Investigación PID2020-116174RB-I00 Agencia Estatal de Investigación PID2019-105416RB-I00 Agencia Estatal de Investigación PDC2022-133858-I00 Instituto de Salud Carlos III CB06/01/1031 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-865 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229 Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-01140 Instituto de Salud Carlos III FI19/00148 Ministerio de Ciencia e Innovación FPU18/04615 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Solid tumor ; Targeted therapy ; Innate immune response ; Protein-only nanoparticle |
| Publicat a: | International Journal of Nanomedicine, Vol. 20 (February 2025) , p. 2445-2460, ISSN 1178-2013 |
