학술논문
GSDMD-dependent pyroptotic induction by a multivalent CXCR4-targeted nanotoxin blocks colorectal cancer metastases.
Document Type
Academic Journal
Author
Sala R; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; Rioja-Blanco E; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; Serna N; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Departament de Genètica I de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Sánchez-García L; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Departament de Genètica I de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Álamo P; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; Alba-Castellón L; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; Casanova I; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; López-Pousa A; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Department of Medical Oncology, Hospital de la Santa Creu I Sant Pau, Barcelon, Spain.; Unzueta U; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Josep Carreras Research Institute, Barcelona, Spain.; Céspedes MV; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; Vázquez E; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Departament de Genètica I de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Villaverde A; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Institut de Biotecnologia I de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Departament de Genètica I de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Mangues R; Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.; CIBER en Bioingeniería, Biomateriales Y Nanomedicina (CIBER-BBN), Madrid, Spain.; Josep Carreras Research Institute, Barcelona, Spain.
Source
Publisher: Taylor & Francis Country of Publication: England NLM ID: 9417471 Publication Model: Print Cited Medium: Internet ISSN: 1521-0464 (Electronic) Linking ISSN: 10717544 NLM ISO Abbreviation: Drug Deliv Subsets: MEDLINE
Subject
Language
English
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.