Engineering secretory amyloids for remote and highly selective destruction of metastatic foci

MARIA VIRTUDES CESPEDES; OLIVIA CANO-GARRIDO; ÁLAMO, PATRICIA; SALA, RITA; GALLARAN, A; SERNA, NAROA; AÏDA FALGÀ,; VOLTA DURAN, E; ISOLDA CASANOVA,; SÁNCHEZ-CHARDI, ALEJANDRO; HECTOR LOPEZ LAGUNA; LAURA SÁNCHEZ-GARCIA; J. M. SANCHEZ; UNZUETA, UGUTZ; VAZQUEZ, ESTHER; MANGUES, RAMÓN; VILLAVERDE, ANTONIO

ADVANCED MATERIALS

WILEY-V C H VERLAG GMBH

Lugar: Weinheim; Año: 2019

0935-9648

Functional amyloids produced in bacteria as nanoscale inclusion bodies are intriguing but poorly explored protein materials with wide therapeutic potential. Since under physiological conditions they release functional polypeptides, these materials could 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) have been administered subcutaneously in mouse models of human metastatic colorectal cancer, for sustained secretion of therapeutic nanoparticles targeted to tumor cells. These proteins are functionalized with a peptidic ligand of CXCR4, a chemokine receptor overexpressed in metastatic cancer stem cells that confers high selective cytotoxicity both in vitro and in vivo. In 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 absence of detectable 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 for use in drug delivery, and they also instruct how therapeutic proteins, even with high functional and structural complexity, can be packaged in this convenient format.