Abstract
Cell-specific delivery of therapeutic agents and targeted therapy are highly pursued topics in medical researches for treating cancers and other diseases. We aim to develop technologies enabling delivery of siRNA to cancer cells to retard or inhibit metastasis of the cancer cells with minimal adverse effects to normal cells. As long as the cancer cells do not invade and are confined, they can be eradicated by means such as surgical resection or radiation therapy.
Oligonucleotides of different sequences can fold into different conformations to bind to their targets with high specificity and affinity. These structured oligonucleotides are known as aptamers. We have identified new surface markers which prevalently expressed on lung cancer cells. By identifying functional aptamers against the surface marker proteins, we show that once the marker protein is activated by the aptamer, the surface marker protein/aptamer complex internalizes into the lung cancer cells. Therefore, it is feasible to employ the functional aptamer as a carrier to deliver siRNA into cancer cells to silence the expression of genes associated with metastasis. The aptamer-siRNA chimera is formed by chemical synthesis and bioconjguation methods. The chimera consists of an aptamer, which delivers therapeutic siRNA specifically to cancer cells but not normal cells to knock down the target genes that are pivotal in signaling pathways associated with the events of metastasis cascade. The effective knockdown of the metastasis associated genes by the nucleic acid chimera is verified by employing a series of invasion assays such as wound healing, Matrigel, filopodia formation, and others. The in vitro experimental results show that the aptamer-siRNA chimera is able to deliver therapeutics to specific target cells and silence the expression of the target genes in the cells. The in vitro experimental results are further verified by in vivo xenograft mouse model with immunohistochemistry examination, tumor size measurement, and circulating tumor cell detection by use of Alu sequence as the marker. By using lung cancer as a model, the data indicate that it is durable to employ the aptamer-siRNA chimera for cell- and target-specific therapy of cancer metastasis.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):B34.
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