title: Ultrasmall gold-doxorubicin conjugates rapidly kill apoptosis-resistant cancer cells.
abstract: Ultrasmall (mean diameter, 2.7 nm) gold nanoparticles conjugated to doxorubicin (Au-Dox) are up to 20-fold more cytotoxic to B16 melanoma cells than the equivalent concentration of doxorubicin alone, and act up to six times more quickly. Ultrasmall Au-Dox enters the cell endocytic vesicles and is also seen free in the cytoplasm and nuclei. This is in distinct contrast to larger particles reported in previous studies, which are excluded from the nucleus and which show no increased toxicity over Dox alone. Cell death with Au-Dox is confirmed to be apoptotic by TUNEL staining and ultrastructural examination using transmission electron microscopy. To further explore the mechanism of action, two other cell lines were examined: HeLa cells which are highly sensitive to Dox, and HeLa cells overexpressing Bcl-2 which show impaired apoptosis and Dox resistance. Interestingly, the Dox-sensitive cells show a slightly decreased sensitivity to Au-Dox relative to Dox alone, whereas the Dox-resistant cells are not resistant to Au-Dox. These results have implications for the design of chemotherapeutic nanoparticles, suggesting that it is possible to selectively target apoptosis-resistant cancer cells while at the same time reducing cytotoxicity to normal cells.
authors.affiliation: Department of Biomedical Engineering, McGill University, 3775 University Street, Montreal, Quebec, Canada H3A 2B4.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Hicham
authors.initials: H
authors.lastname: Chibli
authors.forename: Randall
authors.initials: R
authors.lastname: Mielke
authors.forename: Jay
authors.initials: J
authors.lastname: Nadeau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D010316:Particle Size; D017382:Reactive Oxygen Species / Q000032:analysis; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D006046:Gold; D004317:Doxorubicin