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PreprintCC BYChemRxiv

Unmasking the Non-Covalent Nature of HA–Dopamine Assemblies: Insights from 1H NMR Degradation Tracking and Multidimensional NMR

  • Xingang Liu1
  • Derk J. Wiersma1
  • Alessia Lasorsa1
  • Pieter van der Meulen2
  • Adrivit Mukherjee1
  • Patrick C.A. van der Wel1
  1. 1Zernike Institute for Advanced Materials, Faculty of Science and Engineering, University of Groningen, Nijenborgh 3, Groningen, Netherlands, 9747 AG
  2. 2Stratingh Institute of Chemistry, Faculty of Science and Engineering, University of Groningen, Nijenborgh 3, Groningen, Netherlands, 9747 AG
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Abstract

Hyaluronic acid (HA) is a polysaccharide with diverse clinical and industrial applications. One of the key challenges is its sensitivity to enzymatic degradation. Chemical modifications offer a potential for modulating enzymatic susceptibility, as well as other functional properties. We report an NMR-based examination of the effect of HA modifications on hyaluronidase degradation. Chemical modification of HA with dopamine (HADN) has been widely reported, based on 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (EDC) chemistry. We describe a 1H NMR strategy for a convenient and sensitive analysis of hyaluronidase degradation rates. Surprisingly, HADN exhibited a degradation profile nearly identical to that of native HA, while methacrylated HA resisted degradation. The finding that HADN showed no protective effect prompted a rigorous re-investigation of HADN using 2D NMR. Our findings revealed that HADN is not a covalent conjugate, but a non-covalent and reversible system involving an unexpected EDC-dopamine adduct. Thermal and alkaline stress facilitate the release of dopamine from the non-covalent HADN complex. Our data highlight risks in the use of EDC-based conjugation experiments applied to many types of polysaccharides. Our NMR methods provide a robust platform for the dynamic comparison of degradation rates of HA, and identify a fingerprint test for characteristic residual EDC adducts.

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Cite

BibTeXRIS
BibTeX
@misc{liu2026unmasking,
  title = {{Unmasking the Non-Covalent Nature of HA–Dopamine Assemblies: Insights from 1H NMR Degradation Tracking and Multidimensional NMR}},
  author = {Xingang Liu and Derk J. Wiersma and Alessia Lasorsa and Pieter van der Meulen and Adrivit Mukherjee and Patrick C.A. van der Wel},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15009034/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009034/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Unmasking the Non-Covalent Nature of HA–Dopamine Assemblies: Insights from 1H NMR Degradation Tracking and Multidimensional NMR
AU  - Xingang Liu
AU  - Derk J. Wiersma
AU  - Alessia Lasorsa
AU  - Pieter van der Meulen
AU  - Adrivit Mukherjee
AU  - Patrick C.A. van der Wel
PY  - 2026
DA  - 2026/09/18
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009034/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009034/v1
AB  - Hyaluronic acid (HA) is a polysaccharide with diverse clinical and industrial applications. One of the key challenges is its sensitivity to enzymatic degradation. Chemical modifications offer a potential for modulating enzymatic susceptibility, as well as other functional properties. We report an NMR-based examination of the effect of HA modifications on hyaluronidase degradation. Chemical modification of HA with dopamine (HADN) has been widely reported, based on 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (EDC) chemistry. We describe a 1H NMR strategy for a convenient and sensitive analysis of hyaluronidase degradation rates. Surprisingly, HADN exhibited a degradation profile nearly identical to that of native HA, while methacrylated HA resisted degradation. The finding that HADN showed no protective effect prompted a rigorous re-investigation of HADN using 2D NMR. Our findings revealed that HADN is not a covalent conjugate, but a non-covalent and reversible system involving an unexpected EDC-dopamine adduct. Thermal and alkaline stress facilitate the release of dopamine from the non-covalent HADN complex. Our data highlight risks in the use of EDC-based conjugation experiments applied to many types of polysaccharides. Our NMR methods provide a robust platform for the dynamic comparison of degradation rates of HA, and identify a fingerprint test for characteristic residual EDC adducts.
ER  -