N-Acetylation of Biodegradable Supramolecular Peptide Nanofilaments Selectively Enhances Their Proteolytic Stability for Targeted Delivery of Gold-Based Anticancer Agents

ACS Biomater Sci Eng. 2023 Jun 12;9(6):3379-3389. doi: 10.1021/acsbiomaterials.3c00312. Epub 2023 May 16.

Abstract

Peptide materials are promising for various biomedical applications; however, a significant concern is their lack of stability and rapid degradation in vivo due to non-specific proteolysis. For materials specifically designed to respond to disease-specific proteases, it would be desirable to retain high susceptibility to target proteases while minimizing the impact of non-specific proteolysis. We describe N-terminal acetylation as a simple synthetic modification of amphiphilic self-assembling peptides that contain an MMP-9-cleavable segment and form soluble, nanoscale filaments. We found that the N-terminus capping of these peptides did not significantly impact their self-assembly behavior, critical aggregation concentration, or ability to encapsulate hydrophobic payloads. By contrast, their proteolytic stability in human plasma (especially for anionic peptide sequences) was considerably increased while susceptibility to hydrolysis by MMP-9 was retained when compared to non-acetylated peptides, especially during the first 12 h. We note, however, that due to the longer time scale required for in vitro studies (72 h), non-specific proteolysis of both anionic acetylated peptides leads to similar activity in vitro despite differing MMP-9 kinetics during the early stages. Overall, the enhanced stability against non-specific proteases, combined with the ability of these nanofilaments to enhance the effectiveness of gold-based drugs toward cancerous cells compared to healthy cells, brings these acetylated peptide filaments a step closer toward clinical translation.

Keywords: MMP-9; acylation; drug delivery; metallodrugs; peptides; proteolytic stability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Antineoplastic Agents* / pharmacology
  • Gold
  • Humans
  • Matrix Metalloproteinase 9* / metabolism
  • Peptide Hydrolases / metabolism
  • Peptides / chemistry
  • Peptides / pharmacology
  • Proteolysis

Substances

  • Matrix Metalloproteinase 9
  • Gold
  • Peptides
  • Peptide Hydrolases
  • Antineoplastic Agents