Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control

Miriam Amiram, Kelli M. Luginbuhl, Xinghai Li, Mark N. Feinglos, Ashutosh Chilkoti

Research output: Contribution to journalArticlepeer-review

Abstract

Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable "peak-and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system-Protease Operated Depots (PODs)-to provide sustained and tunable release of a peptide drug from an injectable s.c. depot.We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagonlike peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic schemewehad previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.

Original languageAmerican English
Pages (from-to)2792-2797
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number8
DOIs
StatePublished - 19 Feb 2013
Externally publishedYes

Keywords

  • Drug delivery
  • Peptide polymers
  • Sustained release

All Science Journal Classification (ASJC) codes

  • General

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