Bioresponsive Hyaluronic Acid-Based Hydrogel Inhibits Matrix Metalloproteinase-2 in Glioblastoma Microenvironment

ChemMedChem. 2025 Aug 2;20(15):e202401040. doi: 10.1002/cmdc.202401040. Epub 2025 Jun 24.

Abstract

Glioblastoma multiforme (GBM) is an extremely malignant cancer, resistant to standard therapies. Tumor resection is associated with better outcomes but a complete resection of GBMs is challenging for anatomical limitation and for the high degree of invasiveness. A bioresponsive hydrogel based on hyaluronic acid (HA) cross-linked with a branched metalloproteinase (MMP) inhibitor (MMPI) is proposed. The fully characterized hydrogel, HA-MMPI, presents physical properties suitable for filling the surgical resection cavity and for in situ delivery of the inhibitor. The bioresponsive material selectively inhibits MMP-2 versus MMP-9 in glioblastoma microenvironment.

Keywords: MMP‐2; MMP‐9; bioinstructive hydrogel; glioblastoma multiforme; hyaluronic acid; microenvironment.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Glioblastoma* / drug therapy
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Hyaluronic Acid* / chemistry
  • Hyaluronic Acid* / pharmacology
  • Hydrogels* / chemical synthesis
  • Hydrogels* / chemistry
  • Hydrogels* / pharmacology
  • Matrix Metalloproteinase 2* / metabolism
  • Matrix Metalloproteinase Inhibitors* / chemical synthesis
  • Matrix Metalloproteinase Inhibitors* / chemistry
  • Matrix Metalloproteinase Inhibitors* / pharmacology
  • Molecular Structure
  • Structure-Activity Relationship
  • Tumor Microenvironment / drug effects

Substances

  • Hyaluronic Acid
  • Hydrogels
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase Inhibitors
  • MMP2 protein, human
  • Antineoplastic Agents