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Recombinant Synthesis of Hybrid Lipid–Peptide Polymer Fusions that Self‐Assemble and Encapsulate Hydrophobic Drugs
Author(s) -
Luginbuhl Kelli M.,
Mozhdehi Davoud,
Dzuricky Michael,
Yousefpour Parisa,
Huang Fred C.,
Mayne Nicholas R.,
Buehne Kristen L.,
Chilkoti Ashutosh
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201704625
Subject(s) - myristoylation , chemistry , recombinant dna , peptide , liposome , conjugated system , drug delivery , micelle , biochemistry , biophysics , combinatorial chemistry , polymer , organic chemistry , biology , membrane , aqueous solution , gene
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.