Targeting eIF2alpha siRNA to alpha(v)beta(3) Integrin-bearing Tumor Cells

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DESCRIPTION (provided by applicant): As a mode of cell death, apoptosis has an advantage in that it does not invoke an inflammatory response, thus there is decrease possibility of deleterious local and systemic events associated with tissue inflammation. Eukaryotic translation initiation factor eIF2? is chosen as a target because it is important in protein synthesis and is a central target of several types of translational regulation involving specific phosphorylation of this protein subunit of factor eIF2. Inhibition of protein synthesis contributes to cellular apoptosis and this process is often targeted by different viruses for the induction of apoptosis. In this proposed project, targeted delivery of apoptotic eIF2? siRNA to ?v?3 integrin-bearing tumor cells using polycationic chitosan as the vector will be studied. According to published accounts, shortened circulatory half-lives of oligonucleotide carriers in the bloodstream prevent sufficient oligonucleotides from reaching the target cells. To mitigate phagocytosis of eIF2? siRNA carriers, we propose to conjugate the "marker of self" integrin-associated protein (CD47) to chitosan-based siRNA carriers. In addition to its antiphagocytic feature, CD47 protein conjugated on siRNA nanovectors will act as a ligand targeted for tumor cells highly expressed with ?v?3 integrins. The proposed CD47-conjugated chitosan/siRNA nanovectors are expected to have much extended half-lives in blood circulation, hence allowing for more efficient site binding via ?v?3 integrin and eliciting apoptosis of tumor neovasculature by eIF2? siRNA. With regard to educational aspect of this project, the multidisciplinary nature of this project will produce students with training in biomedical engineering, molecular biology, gene/drug delivery, and nanomedicine. In addition to training graduate students, the educational plan of this project will recruit several undergraduates that are Chemical Engineering major with biochemical/biomedical emphasis and provide them with the opportunity of hands-on meritorious research. The undergraduate student researchers will actively participate in the development of new technology and explore their possible career path in biomedical fields. PUBLIC HEALTH RELEVANCE: Eukaryotic translation initiation factor eIF2? is chosen as a target because it is important in protein synthesis. Since inhibition of protein synthesis contributes to cellular apoptosis, integrin-associated protein (CD47) conjugated eIF2? siRNA vectors are proposed to target tumor cells highly expressed with ?v?3 integrins and deliver apoptotic eIF2? siRNA.