Tuning small molecule release from polymer micelles: Varying H2S release through crosslinking in the micelle core

Ryan J. Carrazzone, Jeffrey C. Foster, Zhao Li, John B. Matson

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Polymer micelles, used extensively as vehicles in the delivery of active pharmaceutical ingredients, represent a versatile polymer architecture in drug delivery systems. We hypothesized that degree of crosslinking in the hydrophobic core of amphiphilic block copolymer micelles could be used to tune the rate of release of the biological signaling gas (gasotransmitter) hydrogen sulfide (H2S), a potential therapeutic. To test this hypothesis, we first synthesized amphiphilic block copolymers of the structure PEG-b-P(FBEA) (PEG = poly(ethylene glycol), FBEA = 2-(4-formylbenzoyloxy)ethyl acrylate). Using a modified arm-first approach, we then varied the crosslinking percentage in the core-forming block via addition of an O,O'-alkanediyl bis(hydroxylamine) crosslinking agent. We followed incorporation of the crosslinker by 1H NMR spectroscopy, monitoring the appearance of the oxime signal resulting from reaction of pendant aryl aldehydes on the block copolymer with hydroxylamines on the crosslinker, which revealed crosslinking percentages of 5, 10, and 15%. We then installed H2S-releasing S-aroylthiooxime (SATO) groups on the crosslinked polymers, yielding micelles with SATO units in their hydrophobic cores after self-assembly in water. H2S release studies in water, using cysteine (Cys) as a trigger to induce H2S release from the SATO groups in the micelle core, revealed increasing half-lives of H2S release, from 117 ± 6 min to 210 ± 30 min, with increasing crosslinking density in the micelle core. This result was consistent with our hypothesis, and we speculate that core crosslinking limits the rate of Cys diffusion into the micelle core, decreasing the release rate. This method for tuning the release of covalently linked small molecules through modulation of micelle core crosslinking density may extend beyond H2S to other drug delivery systems where precise control of release rate is needed.

Original languageEnglish
Article number110077
JournalEuropean Polymer Journal
Volume141
DOIs
StatePublished - Dec 5 2020
Externally publishedYes

Funding

This work was supported by the US National Science Foundation (DMR-1454754), the US National Institutes of Health (R01GM123508), and the Dreyfus Foundation. We thank Prof. Richey Davis for use of the DLS instrument, Prof. Tim Long for use of the DSC instrument, Prof. Abby Whittington for use of the plate reader, and Kearsley Dillon, Sarah Swilley, and Yumeng (Jackie) Zhu for critical readings of the manuscript. The authors also thank Dr. Mehdi Ashraf-Khorassani for help with HRMS and confirmation of molecular structure. Finally, we thank the reviewers for several good suggestions that improved the quality of this manuscript. 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 funding agencies. This work was supported by the US National Science Foundation (DMR-1454754), the US National Institutes of Health (R01GM123508), and the Dreyfus Foundation. We thank Prof. Richey Davis for use of the DLS instrument, Prof. Tim Long for use of the DSC instrument, Prof. Abby Whittington for use of the plate reader, and Kearsley Dillon, Sarah Swilley, and Yumeng (Jackie) Zhu for critical readings of the manuscript. The authors also thank Dr. Mehdi Ashraf-Khorassani for help with HRMS and confirmation of molecular structure. Finally, we thank the reviewers for several good suggestions that improved the quality of this manuscript. 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 funding agencies.

Keywords

  • Chain mobility
  • Controlled drug delivery
  • Hydrogen sulfide
  • Oxime crosslinking
  • RAFT polymerization

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