GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases. (31st December 2022)

• Record Type: Journal Article
• Authors: Sala, Rita; Rioja-Blanco, Elisa; Serna, Naroa; Sánchez-García, Laura; Álamo, Patricia; Alba-Castellón, Lorena; Casanova, Isolda; López-Pousa, Antonio; Unzueta, Ugutz; Céspedes, María Virtudes; Vázquez, Esther; Villaverde, Antonio; Mangues, Ramon
• Is Part Of: Drug delivery. Volume 29:Number 1(2022)
• Page Start: 1384
• Page End: 1397
• Publication Date: 2022-12-31
• Subjects: Metastasis -- CXCR4 -- colorectal cancer -- targeted nanoparticle -- PE24 exotoxin -- GSDMD -- pyroptosis; Drug delivery systems -- Periodicals; Drug targeting -- Periodicals; 615.05
• DOI: 10.1080/10717544.2022.2069302
• Languages: English
• ISSNs: 1071-7544

Abstract

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.