Conjugating Carboxyl Functionalized Gold Nanoparticles

Attaching Ligands to COOH Functionalized Gold Nanoparticles:

Carboxylic Acid Functionalized Gold Nanoparticles, unlike other gold nanoparticles, are pre-ready for covalent conjugation. The carboxlic acid groups on the surface of the gold nanoparticles are easily reacted with primary amines via a condensation reaction which yields strong amide bonds. Usually, this is achieved by using a water-soluble  carbodiimide linker such as EDC.1,2


EDC - linker for "Click Chemistry" conjugation of amines to carboxyl gold nanoparticles

The process to attach a ligand using EDC chemistry is most efficient in acidic conditions and should be conducted in buffers lacking extraneous carboxyls and amines. The process is explained briefly as:

      1. EDC chemistry relies on the formation of an unstable intermediate with the carboxylic moiety which is reactive with primary amines present on the surface of a chosen ligand.
      2. Nucleophilic attack from the amino group displaces the O-acylisourea intermediate resulting in a stable amide bond with the carboxyl group of the gold nanoparticle.

(Note the O-acylisourea intermediate is unstable in aqueous solutions. If unreacted it will hydrolyze and regenerate the carboxyl group.)

"Click Chemistry" for conjugation of biomolecules to carboxyl functionalized gold nanoparticles


Another popular, and more efficient, route for conjugation of carboxylic acid functionalized nanoparticles uses N-hydroxysuccinimide (NHS) or the water-soluable analogue (Sulfo-NHS). Including NHS in EDC coupling creates a stable amine-reactive intermediate and improves the overall conjugation efficiency.

NHS - linker for stable conjugation of carboxylic acid gold nanoparticles

Briefly the stages of this protocol are:

  1. Like above, -COOH gold nanoparticles and EDC form an unstable intermediate
  2. With NHS however, EDC couples NHS to carboxyls on the o-Acylisourea intermediate, forming a dry-stable and amine reactive NHS ester. The NHS ester is considerably more stable than the preceding o-Acylisourea.
  3. Finally, the NHS ester allows for efficient conjugation to primary amines at physiologic pH forming a stable ligand-gold nanoparticle conjugate.

NHS-EDC reaction for conjucation of carboxylic acid functionalized gold nanoparticles


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[1] Jazayeri, Mir Hadi, et al. "Various methods of gold nanoparticles (GNPs) conjugation to antibodies." Sensing and Bio-Sensing Research 9 (2016): 17-22.
[2] R.-A. Sperling, W. Parak “Surface modification, functionalization and bioconjugation of colloidal inorganic nanoparticles” Philos. Trans. R. Soc. Lond. A Math. Phys. Eng. Sci., 368 (1915) (2010), pp. 1333–1383.