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Dendrimer Gold Nanoparticles

Dendrimer-entrapped metal nanoparticles have been primarily used in catalysis, optics, and other applications unrelated to biomedical sciences. The absence of biological applications is largely due to the toxicity of these particles and technical difficulties with their surface manipulation. We demonstrated that Au DENPs prepared using amine-terminated generation 5 poly(amidoamine) (PAMAM) dendrimers (G5.NH2) as templates can be surface modified with acetyl and hydroxyl groups, thereby significantly reducing the toxicity of Au DENPs (Shi X, Wang S, Sun H, Baker JR Jr. Improved biocompatibility of surface functionalized dendrimer-entrapped gold nanoparticles.  Soft Matter, 3:71-74, 2007.

The ability to chemically functionalize preformed Au DENPs led us to develop Au DENPs as a multifunctional platform for cancer cell targeting, imaging, and treatment. One major advantage of using functionalized Au DENPs to image cancers is its ability to differentiate cancer cells from surrounding cells or tissues by using contrast agents with high electron density. The use of Au DENPs also aids in understanding the mechanism for targeted drug delivery and therapeutics, using dendrimer-based nanodevices. In addition, it is possible to use Au DENPs for laser hyperthermia cancer therapeutics through inductive heating of cancer cells that specifically internalize the particles.

Dendrimer Gold Nanoparticles

Figure 1. Selected equilibrated configurations of {(Au0)51.2-G5-FI5-FA5-Ac} DENPs.
Atoms in the PAMAM dendrimer platform are shown as sticks, gold atoms as gold spheres, atoms comprising FA as pink spheres, and atoms for FI as green spheres.

We demonstrate that dendrimer-entrapped gold nanoparticles (Au DENPs) can be covalently linked with targeting ligands and imaging molecules for cancer cell targeting and imaging. Au DENPs (Au NP diameter at 3.2 nm) linked with defined numbers of folic acid (FA) and fluorescein isothiocyanate (FI) molecules are water-soluble, stable, and biocompatible. Our molecular dynamics simulation studies show that the attached FI moieties on Au DENP surfaces are distant from the Au nanoparticles, which minimize the fluorescence quenching effect with metal Au, while the attached FA moieties extend substantially outward, thus becoming available for interaction with FAR on the surface of target cells (Figure 1). These properties allow the Au DENPs to perform perfectly in the binding and detection of cancer cells through receptor-ligand interactions. We show that the FA- and FI-modified Au DENPs can specifically bind to KB cells (a human epithelial carcinoma cell line) that overexpress high affinity folate receptors and be internalized predominantly into lysosomes of target cells within 2 h.

These findings document a facile approach to use Au DENPs as a platform for the targeting and imaging of cancer cells. This work has been published in Small (Shi X, Wang S, Meshinchi S, Van Antwerp ME, Bi X, Lee I, Baker JR Jr. Dendrimer-Entrapped Gold Nanoparticles as a Platform for Cancer-Cell Targeting and Imaging. Small. 2007 May 24;3(7):1245-1252).

We are currently conducting in vivo experiments to evaluate the suitability of this system for clinical applications.

 

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