# Ligand-dependent pharmacokinetic modulation via copper doping in ultrasmall gold nanoparticles

## TL;DR

Copper doping in ultrasmall gold nanoparticles improves their performance in drug delivery only when paired with glutathione, not PEG, showing a key synergy for nanomedicine design.

## Contribution

The study reveals a core–ligand coupling principle where copper doping's pharmacokinetic effect depends on the nanoparticle's surface ligand chemistry.

## Key findings

- Copper doping significantly enhances pharmacokinetics in glutathione-coated nanoparticles but not in PEGylated ones.
- GS-AuCuNPs show 1.6-fold higher tumor accumulation and reduced renal excretion compared to undoped GS-AuNPs.
- Interfacial reconfiguration due to copper doping increases surface charge and modulates nanoparticle–biological interactions.

## Abstract

Ultrasmall gold nanoparticles (AuNPs, <3 nm) exhibit great potential for precision nanomedicine. While ligand engineering and core doping have each been explored to enhance their performance, whether surface chemistry dictates the in vivo efficacy of alloyed nanoparticles remains unknown. To address this question, we used glutathione (GSH) and polyethylene glycol (PEG) as model stabilizing ligands, systematically comparing four corresponding nanoparticle groups: GSH-coated or PEGylated AuNPs, each with or without copper doping at comparable levels. Strikingly, copper doping induced negligible pharmacokinetic changes in PEGylated nanoparticles but significantly enhanced GSH-coated nanoparticles. GS-AuCuNPs exhibited significantly enhanced pharmacokinetics compared to undoped GS-AuNPs, with a 1.6-fold increase in the area under the plasma concentration-time curve. Tumor accumulation efficiency improved by 1.6-fold at 1 h and 1.5-fold at 12 h post-injection, accompanied by reduced renal excretion. This ligand-specific enhancement arises from a copper-induced interfacial reconfiguration, characterized by enhanced COO−–metal anchoring and increased exposure of –NH2 groups of GSH, which together increase the surface positive charge. These interfacial changes modulate nanoparticle–biological interactions, resulting in prolonged circulation and reduced renal excretion while preserving the intrinsic clearance pathway. Our findings reveal a core-ligand coupling principle whereby metal doping becomes pharmacokinetically effective only when paired with a chemically synergistic ligand shell.

Copper doping exerts a ligand-dependent pharmacokinetic effect in ultrasmall nanoparticles. While negligible in PEGylated nanoparticles, it significantly prolongs blood circulation, enhances tumor targeting, and modulates renal clearance in glutathione-coated nanoparticles, elucidating a core–ligand synergy principle for rational nanomedicine design.Image 1

•Copper doping shows a ligand-dependent pharmacokinetic effect, pronounced for glutathione-coated ultrasmall gold nanoparticles and minimal for PEGylated nanoparticles.•In glutathione-coated ultrasmall gold nanoparticles, copper doping reduces renal excretion, prolongs blood exposure, and leads to enhanced tumor accumulation in vivo.•These results reveal a core and ligand coupling principle for designing ultrasmall nanoparticles with tunable circulation and targeting.

Copper doping shows a ligand-dependent pharmacokinetic effect, pronounced for glutathione-coated ultrasmall gold nanoparticles and minimal for PEGylated nanoparticles.

In glutathione-coated ultrasmall gold nanoparticles, copper doping reduces renal excretion, prolongs blood exposure, and leads to enhanced tumor accumulation in vivo.

These results reveal a core and ligand coupling principle for designing ultrasmall nanoparticles with tunable circulation and targeting.