Journal
ADVANCED MATERIALS
Volume 32, Issue 7, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.201907348
Keywords
drug release; metastatic cancer; protein materials; secretory amyloids; self-assembly
Categories
Funding
- Fondo Europeo de Desarrollo Regional (FEDER) (AEI/FEDER, UE) [BIO2016-76063-R]
- AGAUR [2017SGR-229, 2018FI_B2_00051, 2019FI_B_00352]
- CIBER-BBN (project NANOPROTHER)
- CIBER-BBN project 4NanoMets
- CIBER-BBN project NANOREMOTE
- ISCIII [PI15/00272, PIE15/00028, PI18/00650]
- EU COST Action [CA 17140]
- VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions
- Instituto de Salud Carlos III
- European Regional Development Fund
- ICREA ACADEMIA award
- Miguel Servet contract
- ISCIII
- ISCIII PFIS fellowship [FI16/00017]
- Ministerio de Ciencia, Innovacion y Universidades [FPU18/04615]
- PERIS program from the Health Department of la Generalitat de Catalunya
- [2017SGR-865 GRC]
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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 mu g 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.
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