Improved anti-cancer effect of epidermal growth factor-gold nanoparticle conjugates by protein orientation through site-specific mutagenesis

Aiwen Zhang, Jun Nakanishi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Epidermal growth factor (EGF)-nanoparticle conjugates have the potential for cancer therapeutics due to the unique cytotoxic activity in cancer cells with EGF receptor (EGFR) overexpression. To gain its maximum activity, the EGF molecule should be immobilized on the nanoparticle surface in a defined orientation so as the bulky nanoparticle will not interfere EGF-EGFR interaction. Herein, we demonstrate successful enhancement of the anti-cancer activity of EGF-gold nanoparticle conjugates (EGF-GNPs) by controlling the EGF orientation on the surface of the nanoparticle through site-specific mutagenesis. Three lysine-free EGF variants (RR, RS, and SR) were designed, where two endogenous lysine residues were replaced with either arginine (R) or serine (S). The EGF mutants can be conjugated to the GNPs in a controlled orientation through the single amino group at the N-terminus. The ability of the mutants to induce extracellular signal-regulated kinase (ERK) phosphorylation was no different from wild type EGF (WT) in soluble form, rather lowered for one mutant (RR). However, after conjugated to GNPs, the SR mutants exhibited an enhanced biological activity than WT, in terms of ERK phosphorylation and growth inhibition of cancer cells. Further analysis of the binding constant of each mutant indicated the emergent enhanced activity of the GNP conjugates of the SR mutant was not solely contributed to the orientation, but to its higher binding activity to EGFR. These results validate the present genetic recombination strategy to improve the anticancer efficiency of EGF-GNPs.

Original languageEnglish
Pages (from-to)616-626
Number of pages11
JournalScience and Technology of Advanced Materials
Volume22
Issue number1
DOIs
Publication statusPublished - 2021

Keywords

  • 211 Scaffold / Tissue engineering/Drug delivery
  • 212 Surface and interfaces, Nanoparticles
  • 30 Bio-inspired and biomedical materials
  • binding activity
  • EGF-nanoparticle conjugates
  • growth inhibition
  • Nanomedicine
  • phosphorylation signaling
  • protein orientation

ASJC Scopus subject areas

  • Materials Science(all)

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