Reducible disulfide poly(beta-amino ester) hydrogels for antioxidant delivery

Andrew L. Lakes, Carolyn T. Jordan, Prachi Gupta, David A. Puleo, J. Zach Hilt, Thomas D. Dziubla

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Recently, biomaterials have been designed to contain redox-sensitive moieties, such as thiols and disulfides, to impart responsive degradation and/or controlled release. However, due to the high sensitivity of cellular redox-based systems which maintain free-radical homeostasis (e.g. glutathione/glutathione disulfide), if these biomaterials modify the cellular redox environment, they may inadvertently affect cellular compatibility and/or oxidative stress defenses. In this work, we hypothesize that the degradation products of a poly(β-amino ester) (PBAE) hydrogel formed with redox sensitive disulfide (cystamine) crosslinking could serve as a supplement to the environmental cellular antioxidant defenses. Upon introduction into a reducing environment, these disulfide-containing hydrogels cleave to present bound-thiol groups, yet remain in the bulk form at up to 66 mol% cystamine of the total amines. By controlling the molar fraction of cystamine, it was apparent that the thiol content varied human umbilical vein endothelial cell (HUVEC) viability IC50 values across an order of magnitude. Further, upon introduction of an enzymatic oxidative stress generator to the cell culture (HX/XO), pre-incubated thiolated hydrogel degradation products conferred cellular and mitochondrial protection from acute oxidative stress, whereas non-reduced disulfide-containing degradation products offered no protection. This polymer may be an advantageous implantable drug delivery system for use in acute oxidative stress prophylaxis and/or chronic oxidative stress cell therapies due to its solid/liquid reversibility in a redox environment, controlled thiolation, high loading capacity through covalent drug-addition, and simple post-synthesis modification which bound-thiols introduce. Statement of Significance: In this work, we demonstrate a unique property of disulfide containing degradable biomaterials. By changing the redox state of the degradation products (from oxidized to reduced), it is possible to increase the IC50 of the material by an order of magnitude. This dramatic shift is linked directly to the oxidative stress response of the cells and suggests a possible mechanism by which one can tune the cellular response to degradable biomaterials.

Original languageEnglish
Pages (from-to)178-189
Number of pages12
JournalActa Biomaterialia
Volume68
DOIs
StatePublished - Mar 1 2018

Bibliographical note

Funding Information:
The project described was graciously supported by Grant Number R25CA153954 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Special thanks to John May of the University of Kentucky Environmental Research Training Laboratories (ERTL) for assistance in running mass spectrometry.

Funding Information:
The project described was graciously supported by Grant Number R25CA153954 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Special thanks to John May of the University of Kentucky Environmental Research Training Laboratories (ERTL) for assistance in running mass spectrometry.

Publisher Copyright:
© 2018 Acta Materialia Inc.

Keywords

  • Antioxidant
  • Biocompatibility
  • Disulfide
  • Hydrogel
  • Oxidative stress

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

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