Targeting Nanomaterials to Head and Neck Cancer Cells Using a Fragment of the Shiga Toxin as a Potent Natural Ligand

Autores de IDIVAL

• 

  Juan Carlos Villegas Sordo

  Autor

  villegaj@unican.es

• 

  Rafael Valiente Barroso

  Autor

  valientr@unican.es

• 

  Mónica López Fanarraga

  Autor

  monica.lopez@unican.es

Autores ajenos al IDIVAL

• Navarro-Palomares, E
• Garcia-Hevia, L
• Padin-Gonzalez, E
• Banobre-Lopez, M

Abstract

Simple Summary: To mimic natural ligand-specific cell entry mechanisms, we have reproduced the molecular cues found in the Shiga toxin to target nanomaterials into head and neck cancer (HNC) cells bearing the globotriaosylceramide receptor (known as GB3 or CD77). This is a globoside typically found in immature endothelial cells of the intestine, also present on the surfaces of many cancerous/precancerous cells of the digestive tract such as HNC. To achieve functional biomimicry, we have coated nanoparticles with a recombinant chimera protein containing the innocuous B domain of the Shiga toxin genetically fused to a nanomaterial-binding sequence. Our results demonstrate that nanomaterials functionalized with this ligand recognize GB3+ve cells reproducing the cellular responses activated by the full-length toxin to sneak into the cellular cytoplasm. These results show how custom biofunctionalization methods can transform inert nanomaterials into hybrid nanosystems capable of identifying specific receptors predictably triggering specific cellular responses as dictated by the proteins in their coating. Head and Neck Cancer (HNC) is the seventh most common cancer worldwide with a 5-year survival from diagnosis of 50%. Currently, HNC is diagnosed by a physical examination followed by an histological biopsy, with surgery being the primary treatment. Here, we propose the use of targeted nanotechnology in support of existing diagnostic and therapeutic tools to prevent recurrences of tumors with poorly defined or surgically inaccessible margins. We have designed an innocuous ligand-protein, based on the receptor-binding domain of the Shiga toxin (ShTxB), that specifically drives nanoparticles to HNC cells bearing the globotriaosylceramide receptor on their surfaces. Microscopy images show how, upon binding to the receptor, the ShTxB-coated nanoparticles cause the clustering of the globotriaosylceramide receptors, the protrusion of filopodia, and rippling of the membrane, ultimately allowing the penetration of the ShTxB nanoparticles directly into the cell cytoplasm, thus triggering a biomimetic cellular response indistinguishable from that triggered by the full-length Shiga toxin. This functionalization strategy is a clear example of how some toxin fragments can be used as natural biosensors for the detection of some localized cancers and to target nanomedicines to HNC lesions.

Keywords

• nanotechnology; oral cancer; recombinant ligand-protein; toxin

Proyectos asociados

• Contrato Predoctoral Elena Maria Navarro Palomares
• Contrato Predoctoral Esperanza Padin Gonzalez
• Desarrollo de un dispositivo endoscópico para el tratamiento de cáncer de cabeza-cuello mediante hipertermia fotoinducida con nanopartículas multifuncionales
• Diseño de herramientas de precisión nanoteranósticas foto-activables contra el cáncer basadas en nanotubos de carbono
• Diseño y producción de pseudo-cápsides nanoteranósticas dirigidas al sistema nervioso
• Desarrollo de un virus sintético SARS-CoV-2 basado en nanobiotecnología para el testado de fármacos y sistemas de detección del COVID-19