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

Kelli M. Luginbuhl, Davoud Mozhdehi, Michael Dzuricky, Parisa Yousefpour, Fred C. Huang, Nicholas R. Mayne, Kristen L. Buehne, Ashutosh Chilkoti

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13979-13984
Number of pages6
JournalAngewandte Chemie - International Edition
Volume56
Issue number45
DOIs
StatePublished - Nov 6 2017

Keywords

  • drug delivery
  • lipidation
  • myristic acid
  • post-translational modification
  • self-assembly

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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