Effects of hydrophobic tail length variation on surfactant-mediated protein stabilization

Mckenna G Hanson, Joshua S. Katz, Hua Ma, Miriam Putterman, Benjamin A. Yezer, Oliver Petermann, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Recently, protein therapeutics have gained significant attention as a result of their enhanced selectivity and diminished side effects compared to traditional small-molecule drugs. Despite their advantages, protein formulations typically suffer from stability issues because of aggregation and denaturation during production and storage, often resulting in detrimental immune responses. Surfactants can be used to stabilize and protect proteins in solution by preventing protein adsorption onto interfaces or by forming protective structures in solution. Herein, a detailed structure-activity relationship study is described, demonstrating the role that hydrophobic tail length plays in surfactant-mediated stabilization of the model therapeutic protein IgG. The FM1000 series, originating from a surfactant scaffold that allows for easy structure modulation, was synthesized by a simple 2-step procedure. First, phenylalanine was acylated with a variety of acyl chlorides of differing lengths to yield n-acyl phenylalanine, which was then coupled to Jeffamine M1000, a polyethylene glycol-based amine, to yield the final surfactant. With this FM1000 series, it was observed that the 14 carbon-long tail surfactant (14FM1000) was optimal at preventing IgG aggregation compared to surfactants with tails that were longer or shorter. Using a combination of dynamic surface tensiometry and quartz crystal microbalance with dissipation, it was hypothesized that 14FM1000 was able to prevent IgG adsorption, and therefore aggregation, by adsorbing appreciably onto surfaces quickly. 14FM1000 had the fastest rate of initial adsorption compared to the other surfactants studied. Short-tail surfactants were slow to and did not adsorb appreciably onto surfaces, allowing IgG adsorption. Although long-tail surfactants were also slow to adsorb, allowing IgG to adsorb and aggregate, their equilibrium adsorption was strong. Additionally, 14FM1000 was the most reversibly adsorbed surfactant, likely improving its ability to desorb and adsorb quickly to transient surfaces, therefore protecting the IgG at each new hydrophobic surface and preventing aggregation. By understanding the structure-activity relationship between surfactants and protein stabilization, we move toward more efficient design of future surfactants increasing the stability and utility of important protein therapeutics.

Original languageEnglish (US)
Pages (from-to)4302-4311
Number of pages10
JournalMolecular pharmaceutics
Volume17
Issue number11
DOIs
StatePublished - Nov 2 2020

Bibliographical note

Funding Information:
We are grateful for the financial support of DuPont Nutrition and Biosciences. We thank Susan Jordan and Abigail Nolin at DuPont de Nemours and Monica Ohnsorg at the University of Minnesota for useful discussions. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant no. CON-75851, project 00074041. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.

Funding Information:
We are grateful for the financial support of DuPont Nutrition and Biosciences. We thank Susan Jordan and Abigail Nolin at DuPont de Nemours and Monica Ohnsorg at the University of Minnesota for useful discussions. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant no. CON-75851, project 00074041. Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation.

Publisher Copyright:
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Keywords

  • IgG
  • aggregation
  • antibody
  • surfactant
  • tail length

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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