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Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action.

Publication ,  Journal Article
Gilroy, CA; Roberts, S; Chilkoti, A
Published in: Journal of controlled release : official journal of the Controlled Release Society
May 2018

Fibroblast growth factor 21 (FGF21) is under investigation as a type 2 diabetes protein drug, but its efficacy is impeded by rapid in vivo clearance and by costly production methods. To improve the protein's therapeutic utility, we recombinantly expressed FGF21 as a fusion with an elastin-like polypeptide (ELP), a peptide polymer that exhibits reversible thermal phase behavior. Below a critical temperature, ELPs exist as miscible unimers, while above, they associate into a coacervate. The thermal responsiveness of ELPs is retained upon fusion to proteins, which has notable consequences for the production and in vivo delivery of FGF21. First, the ELP acts as a solubility enhancer during E. coli expression, yielding active fusion protein from the soluble cell lysate fraction and eliminating the protein refolding steps that are required for purification of FGF21 from inclusion bodies. Second, the ELP's phase transition behavior is exploited for facile chromatography-free purification of the ELP-FGF21 fusion. Third, the composition and molecular weight of the ELP are designed such that the ELP-FGF21 fusion undergoes a phase transition triggered solely by body heat, resulting in an immiscible viscous phase upon subcutaneous (s.c.) injection and thereby creating an injectable depot. Indeed, a single s.c. injection of ELP-FGF21 affords up to five days of sustained glycemic control in ob/ob mice. The ELP fusion partner massively streamlines production and purification of FGF21, while providing a controlled release method for delivery that reduces the frequency of injection, thereby enhancing the pharmacological properties of FGF21 as a protein drug to treat metabolic disease.

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Published In

Journal of controlled release : official journal of the Controlled Release Society

DOI

EISSN

1873-4995

ISSN

0168-3659

Publication Date

May 2018

Volume

277

Start / End Page

154 / 164

Related Subject Headings

  • Random Allocation
  • Pharmacology & Pharmacy
  • Mice, Obese
  • Mice
  • Male
  • Hypoglycemic Agents
  • Humans
  • Hot Temperature
  • HEK293 Cells
  • Fibroblast Growth Factors
 

Citation

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Gilroy, C. A., Roberts, S., & Chilkoti, A. (2018). Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action. Journal of Controlled Release : Official Journal of the Controlled Release Society, 277, 154–164. https://doi.org/10.1016/j.jconrel.2018.03.015
Gilroy, Caslin A., Stefan Roberts, and Ashutosh Chilkoti. “Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action.Journal of Controlled Release : Official Journal of the Controlled Release Society 277 (May 2018): 154–64. https://doi.org/10.1016/j.jconrel.2018.03.015.
Gilroy CA, Roberts S, Chilkoti A. Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action. Journal of controlled release : official journal of the Controlled Release Society. 2018 May;277:154–64.
Gilroy, Caslin A., et al. “Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action.Journal of Controlled Release : Official Journal of the Controlled Release Society, vol. 277, May 2018, pp. 154–64. Epmc, doi:10.1016/j.jconrel.2018.03.015.
Gilroy CA, Roberts S, Chilkoti A. Fusion of fibroblast growth factor 21 to a thermally responsive biopolymer forms an injectable depot with sustained anti-diabetic action. Journal of controlled release : official journal of the Controlled Release Society. 2018 May;277:154–164.
Journal cover image

Published In

Journal of controlled release : official journal of the Controlled Release Society

DOI

EISSN

1873-4995

ISSN

0168-3659

Publication Date

May 2018

Volume

277

Start / End Page

154 / 164

Related Subject Headings

  • Random Allocation
  • Pharmacology & Pharmacy
  • Mice, Obese
  • Mice
  • Male
  • Hypoglycemic Agents
  • Humans
  • Hot Temperature
  • HEK293 Cells
  • Fibroblast Growth Factors