Gold nanoparticles have been widely investigated as platforms for drug delivery and imaging applications. They can be typically synthesized in a wide range of sizes and shapes, and can be functionalized with a variety of molecules including antibodies, peptides, and drugs. Whereas the cellular internalization and distribution of larger nanoparticles such as colloidal gold and quantum dots continues to be intensively investigated by several labs around the world, the uptake of ultrasmall (diameter less than 2 nm) nanoparticles has not been as well studied, due in part to difficulties in visualizing these particles both in vitro and inside cells by conventional electron microscopy. A combination of light and electron microscopy has been used to characterize ultrasmall gold clusters as a first step to studying the mechanism by which they are internalized into cells. The clusters that we have synthesized are of a well defined composition and show an extremely homogeneous size distribution by scanning transmission electron microscopy (STEM). The surface of the clusters has been modified to enable future experiments aimed at attaching cell penetrating peptides (CPPs), which are short polycationic peptides capable of shuttling a variety of attached cargo molecules (including nanoparticles) across the cell's plasma membrane. The homogeneity of the synthetic nanoparticles makes them suitable for functionalization and incubation with live cells, which will provide insight into the mechanisms of internalization of CPPs attached to model gold nanoparticles, as well as shed light on the intracellular fate of the conjugates.
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