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Pàgina inicial > Articles > Articles publicats > Engineering secretory amyloids for remote and highly selective destruction of metastatic foci |
Data: | 2020 |
Resum: | Functional amyloids produced in bacteria as nanoscale inclusion bodies are intriguing but poorly explored protein materials with wide therapeutic potential. Since they release functional polypeptides under physiological conditions, these materials can be potentially tailored as mimetic of secretory granules for slow systemic delivery of smart protein drugs. To explore this possibility, bacterial inclusion bodies formed by a self-assembled, tumor-targeted Pseudomonas exotoxin (PE24) are administered subcutaneously in mouse models of human metastatic colorectal cancer, for sustained secretion of tumor-targeted therapeutic nanoparticles. These proteins are functionalized with a peptidic ligand of CXCR4, a chemokine receptor overexpressed in metastatic cancer stem cells that confers high selective cytotoxicity in vitro and in vivo. In the mouse models of human colorectal cancer, time-deferred anticancer activity is detected after the subcutaneous deposition of 500 µg of PE24-based amyloids, which promotes a dramatic arrest of tumor growth in the absence of side toxicity. In addition, long-term prevention of lymphatic, hematogenous, and peritoneal metastases is achieved. These results reveal the biomedical potential and versatility of bacterial inclusion bodies as novel tunable secretory materials usable in delivery, and they also instruct how therapeutic proteins, even with high functional and structural complexity, can be packaged in this convenient format. |
Ajuts: | Ministerio de Ciencia e Innovación BIO2016-76063-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-229 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-865 Agència de Gestió d'Ajuts Universitaris i de Recerca 2018FI_B2_00051 Agència de Gestió d'Ajuts Universitaris i de Recerca 2019FI_B_00352 Ministerio de Ciencia e Innovación FPU18/04615 Instituto de Salud Carlos III PI15/00272 Instituto de Salud Carlos III PIE15/00028 Instituto de Salud Carlos III PI18/00650 Instituto de Salud Carlos III FI16/00017 |
Nota: | Altres ajuts: to EU COST Action CA 17140 |
Drets: | Tots els drets reservats. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió acceptada per publicar |
Publicat a: | Advanced materials, Vol. 32, Issue 7 (February 2020) , art. 1907348, ISSN 1521-4095 |
Postprint 38 p, 2.2 MB |