GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases.

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.

• Authors: Rita Sala, Elisa Rioja-Blanco, Naroa Serna, Laura Sánchez-García, Patricia Álamo, Lorena Alba-Castellón, Isolda Casanova, Antonio López-Pousa, Ugutz Unzueta, María Virtudes Céspedes, Esther Vázquez, Antonio Villaverde, Ramon Mangues
• Journal: Drug delivery (Drug Deliv) Vol. 29 Issue 1 Pg. 1384-1397 (Dec 2022) ISSN: 1521-0464 [Electronic] England
• PMID: 35532120 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CXCR4 protein, human
• GSDMD protein, human
• Phosphate-Binding Proteins
• Pore Forming Cytotoxic Proteins
• Receptors, CXCR4

Topics

• Antineoplastic Agents (pharmacology)
• Colorectal Neoplasms (drug therapy)
• Drug Delivery Systems
• Humans
• Neoplasm Metastasis (prevention & control)
• Phosphate-Binding Proteins (metabolism)
• Pore Forming Cytotoxic Proteins (metabolism)
• Pyroptosis
• Receptors, CXCR4 (metabolism, therapeutic use)
• Signal Transduction