Engineering a Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells

• Published in: ACS applied materials & interfaces 2020-02, Vol.12 (5), p.5381-5388
• Main Authors: Pesarrodona, Mireia, Sánchez-García, Laura, Seras-Franzoso, Joaquin, Sánchez-Chardi, Alejandro, Baltá-Foix, Ricardo, Cámara-Sánchez, Patricia, Gener, Petra, Jara, José Juan, Pulido, Daniel, Serna, Naroa, Schwartz, Simó, Royo, Miriam, Villaverde, Antonio, Abasolo, Ibane, Vazquez, Esther
• Format: Article
• Language: English
• Subjects: ADP Ribose Transferases - chemistry; ADP Ribose Transferases - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Bacterial Toxins - chemistry; Bacterial Toxins - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Drug Carriers - chemistry; Exotoxins - chemistry; Exotoxins - pharmacology; Female; Humans; Nanostructures - chemistry; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Pseudomonas aeruginosa - metabolism; Pseudomonas aeruginosa Exotoxin A; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Virulence Factors - chemistry; Virulence Factors - pharmacology
• ISSN: 1944-8244; 1944-8252
• DOI: 10.1021/acsami.9b15803

Five peptide ligands of four different cell surface receptors (nucleolin, CXCR1, CMKLR1, and CD44v6) have been evaluated as targeting moieties for triple-negative human breast cancers. Among them, the peptide F3, derived from phage display, promotes the fast and efficient internalization of a genetically fused green fluorescent protein (GFP) inside MDA-MB-231 cancer stem cells in a specific receptor-dependent fashion. The further engineering of this protein into the modular construct F3-RK-GFP-H6 and the subsequent construct F3-RK-PE24-H6 resulted in self-assembling polypeptides that organize as discrete and regular nanoparticles. These materials, 15–20 nm in size, show enhanced nucleolin-dependent cell penetrability. We show that the F3-RK-PE24-H6, based on the Pseudomonas aeruginosa exotoxin A (PE24) as a core functional domain, is highly cytotoxic over target cells. The combination of F3, the cationic peptide (RK) n , and the toxin domain PE24 in such unusual presentation appears as a promising approach to cell-targeted drug carriers in breast cancers and addresses selective drug delivery in otherwise difficult-to-treat triple-negative breast cancers.