lunes, 23 de abril de 2012

Direct Observation of Nanoparticle Cancer Cell Nucleus Interactions

The nucleus is the most important organelle in the growth, proliferation, and apoptosis of a cell. Controlling the processes governed by the nucleus has been a primary goal for nuclear-targeted cancer therapy. Conventionally, viral vectors are used to deliver drugs to cell nuclei, but a drawback is the resulting immunogenic response.

Recently, nuclear targeting by peptide-modified gold NPs has seen some success and shown improved anticancer efficacy; however, the mechanism responsible for the increased cell death is unknown because no nanoscale direct visualization of how the NPs affected the nucleus was shown.

Nucleolin is the most abundant nucleolar phosphoprotein in the nucleus of normal cells but in metastatic and rapidly dividing cells is overexpressed in the cytoplasm and translocated to the cell membrane. The trafficking ability of nucleolin has been implicated in transporting anticancer ligands from the cell surface to the nucleus.

This report includes the direct visualization of interactions between drug-loaded nanoparticles and the cancer cell nucleus. Nanoconstructs composed of nucleolin-specific aptamers and gold nanostars were actively transported to the nucleus and induced major changes to the nuclear phenotype via nuclear envelope invaginations near the site of the construct. The number of local deformations could be increased by ultrafast, light-triggered release of the aptamers from the surface of the gold nanostars. Cancer cells with more nuclear envelope folding showed increased caspase 3 and 7 activity (apoptosis) as well as decreased cell viability. This
newly revealed correlation between drug-induced changes in nuclear phenotype and increased therapeutic efficacy could provide new insight for nuclear-targeted cancer therapy.

Duncan Hieu M. Dam, Jung Heon Lee, Patrick N. Sisco, Dick T. Co, Ming Zhang, Michael R. Wasielewski, and Teri W. Odom 

Department of Chemistry and Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208, United States, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois 60611, United States, and School of Advanced Materials Science and Engineering, Sungkyunkwan University (SKKU), Suwon, South Korea 

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