Home > Articles > Published articles > GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases |
Date: | 2022 |
Abstract: | Colorectal cancer (CRC) remains the third cause of cancer-related mortality in Western countries, metastases are the main cause of death. CRC treatment remains limited by systemic toxicity and chemotherapy resistance. Therefore, nanoparticle-mediated delivery of cytotoxic agents selectively to cancer cells represents an efficient strategy to increase the therapeutic index and overcome drug resistance. We have developed the T22-PE24-H6 therapeutic protein-only nanoparticle that incorporates the exotoxin A from Pseudomonas aeruginosa to selectively target CRC cells because of its multivalent ligand display that triggers a high selectivity interaction with the CXCR4 receptor overexpressed on the surface of CRC stem cells. We here observed a CXCR4-dependent cytotoxic effect for T22-PE24-H6, which was not mediated by apoptosis, but instead capable of inducing a time-dependent and sequential activation of pyroptotic markers in CRC cells in vitro. Next, we demonstrated that repeated doses of T22-PE24-H6 inhibit tumor growth in a subcutaneous CXCR4 CRC model, also through pyroptotic activation. Most importantly, this nanoparticle also blocked the development of lymphatic and hematogenous metastases, in a highly aggressive CXCR4 SW1417 orthotopic CRC model, in the absence of systemic toxicity. This targeted drug delivery approach supports for the first time the clinical relevance of inducing GSDMD-dependent pyroptosis, a cell death mechanism alternative to apoptosis, in CRC models, leading to the selective elimination of CXCR4 cancer stem cells, which are associated with resistance, metastases and anti-apoptotic upregulation. |
Grants: | Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-229 Agència de Gestió d'Ajuts Universitaris i de Recerca 2018FI_B2_00051 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-865 Ministerio de Economía y Competitividad FI16/00017 Instituto de Salud Carlos III PI18/00650 Instituto de Salud Carlos III PI21/00150 Ministerio de Economía y Competitividad PIE15/00028 Agencia Estatal de Investigación PID2019-105416RB-I00 Agencia Estatal de Investigación I00/AEI/10.13039/501100011033 |
Rights: | 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, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Published in: | Drug Delivery, Vol. 29 Núm. 1 (2022) , p. 1384-1397, ISSN 1521-0464 |
15 p, 3.9 MB |