Short-Interfering RNA-Gold Nanoparticle Bioconjugates: A New Cancer Therapy

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DESCRIPTION (provided by applicant): In 2006, cancer surpassed heart disease as the leading cause of death in the United States. While intensive research efforts have led to an overall improvement in the 5-year survival rate of cancer patients, those diagnosed with lung and breast cancer have experienced only nominal improvements in quality of life and survival rate. RNAi is an enzyme-mediated pathway that uses short-interfering RNA oligonucleotides (siRNAs) to specifically degrade a target sequence and knockdown expression of the target gene. siRNAs are promising new treatments for cancer because down-regulation of certain genes, such as survivin, that are over-expressed in cancer cells can induce apoptosis (cell death), while leaving normal cells unaffected. As a result, these genes are attractive therapeutic targets for siRNA therapy. Development of siRNA therapeutics, however, has been hampered by inefficient extracellular delivery and uptake of the oligonucleotides. Gold nanoparticle oligodeoxynucleotide bioconjugates are non-toxic antisense agents that deliver oligonucleotides across the cell membrane, increase resistance to nucleases, and knockdown gene expression specifically. The objective of this research proposal is to develop siRNA gold-nanoparticle agents to silence the survivin gene in lung and breast cancer models, ultimately inducing cell-death. The siRNA nanoparticle agents will be prepared by solid phase synthesis, solution methods and gold-thiol chemistry. The cellular uptake and specific gene silencing ability of these antisense agents will be quantitatively determined for different model cell lines using gene-expression analysis (PCR and Western Blot). Additionally, targeting agents that increase the uptake of the siRNA nanoparticles by cancer cells will be added to the nanoparticle scaffold in addition to the siRNAs. This innovative strategy for the treatment of cancer has the potential to create substantive improvements in survival rates and quality of life for cancer patients, while using fundamental advances in nanotechnology to provide insight into the function and treatment of disease. This research program will allow me to build upon my scientific background by working in an interdisciplinary environment exploring the treatment and functioning of disease using nanotechnology. I expect that developing and studying this antisense platform will be a valuable experience as I start an independent career as a university faculty member whose research is devoted to applying the tools of nanotechnology to health-related issues. Cancer is the leading cause of death in the United States and treatment of this disease is a public health priority. The proposed research uses nanotechnology to knock out cancer-causing genes, which will lead to powerful therapies for treating breast and lung cancer.