Surface charge modulates the internalization vs. penetration of gold nanoparticles: comprehensive scrutiny on monolayer cancer cells, multicellular spheroids and solid tumors by SERS modality

Precise control over the dynamics of nanoparticles (NPs) in a tumor microenvironment is highly warranted for the development of an efficient nanotheranostic agent. Even though inductively coupled plasma mass spectrometry can provide a quantitative assessment regarding the uptake efficiency of metal NPs, enumeration of deep tissue penetration capacity remains as a challenge. Herein, we have demonstrated an accurate tracking of the uptake efficiency and penetration phenomenon of gold nanoparticles (AuNPs: 40–50 nm) with respect to three different surface charges in monolayer (2D) cells, multicellular spheroids (3D) and in vivo tumors by surface-enhanced Raman spectroscopy (SERS). While positively charged AuNPs showed around two-fold increased internalization in monolayer cells, SERS-tag-based line scanning on multi-layered tumor spheroids illustrated almost nine-fold superior penetration capability with negatively charged AuNPs. Further, the enhanced solid tumor distribution contributed by the negatively charged AuNPs could appreciably escalate its clinical utility in cancer management.