Recombinant Synthesis of Hybrid Lipid–Peptide Polymer Fusions that Self‐Assemble and Encapsulate Hydrophobic Drugs

• Published in: Angewandte Chemie Vol. 129; no. 45; pp. 14167 - 14172
• Main Authors: Luginbuhl, Kelli M., Mozhdehi, Davoud, Dzuricky, Michael, Yousefpour, Parisa, Huang, Fred C., Mayne, Nicholas R., Buehne, Kristen L., Chilkoti, Ashutosh
• Format: Journal Article
• Language: English; German
• Published: Weinheim Wiley Subscription Services, Inc 06.11.2017
• Subjects: Chemical synthesis; Chemistry; Cores; Cytotoxicity; Doxorubicin; Drugs; E coli; Elastin; Encapsulation; Hydrophobicity; Intravenous administration; Lipidierung; Lipids; Myristinsäure; Myristoylation; N-Myristoyltransferase; Paclitaxel; Polypeptides; Post-translation; Posttranslationale Modifikationen; Selbstorganisation; Self-assembly; Wirkstofftransport; Yeast
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201704625

Inspired by biohybrid molecules that are synthesized in Nature through post‐translational modification (PTM), we have exploited a eukaryotic PTM to recombinantly synthesize lipid–polypeptide hybrid materials. By co‐expressing yeast N‐myristoyltransferase with an elastin‐like polypeptide (ELP) fused to a short recognition sequence in E. coli, we show robust and high‐yield modification of the ELP with myristic acid. The ELP's reversible phase behavior is retained upon myristoylation and can be tuned to span a 30–60 °C. Myristoylated ELPs provide a versatile platform for genetically pre‐programming self‐assembly into micelles of varied size and shape. Their lipid cores can be loaded with hydrophobic small molecules by passive diffusion. Encapsulated doxorubicin and paclitaxel exhibit cytotoxic effects on 4T1 and PC3‐luc cells, respectively, with potencies similar to chemically conjugated counterparts, and longer plasma circulation than free drug upon intravenous injection in mice. Von der Natur inspiriert: Die Einführung eines eukaryotischen myristoylierenden Enzyms in E. coli ermöglicht die rekombinante Synthese von micellbildenden Lipid‐Peptid‐Hybridmaterialien. Myristoylierte Micellen, die mit Antitumorwirkstoffen beladen sind, sind cytotoxisch gegen Krebszelllinien und zeigen deutlich längere Plasmahalbwertszeiten als der freie Wirkstoff.