Understanding and controlling the interactions between nanoscale objects and living cells is of great importance for arising diagnostic and therapeutic applications of nanoparticles and for nanotoxicology studies. Here we report a detailed transmission electron microscopy (TEM) study of the uptake of ca. 16 nm surface-modified gold nanoparticles by human fibroblast cells (HeLa cells). It is demonstrated that the well-established endosomal route of cellular uptake can be bypassed to a significant extent by controlling the uptake mechanism either via the delivery of the nanoparticles by liposomes or by surface modification of the nanoparticles with so-called cell penetrating peptides (CPPs). Successful nuclear targeting is demonstrated using surface modification with a cocktail of CPPs and a peptide acting as a nuclear localization signal (NLS).

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H2O)2]2NO3 was added to the PEG surface to yield a supramolecular complex with 280 (±20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

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We show that low-intensity laser irradiation of cancer cells containing endosomal gold nanoparticles leads to endosome rupture and escape of the nanoparticles into the cytosol without affecting the cells' viability. The low light intensity of our experiments allows us to rule out photothermal effects as the underlying mechanism, and we present results that suggest photoinduced radicals as the photogenerated active species. This nonthermal mechanism may also be important in the context of cell death at higher laser intensities, which had been reported previously.