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RISS 인기검색어
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- 저자 : J. Boado, Ruben (검색결과 2 건)
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Lee, Hwa Jeong,Boado, Ruben J.,Brassch, Dwaine A.,Corey, David R.,Pardridge, William M. 梨花女子大學校 藥學硏究所 2002 藥學硏究論文集 Vol.- No.11
Disease-specific genes of unknown function can be imaged invivo with antisense radiopharmaceuticals, providing the trans-cellular transport of these molecules is enabled with drug-tar-geting technology. The current studies describe the productionof 16-mer peptide nucleic acid (PNA) that is antisense aroundthe methionine initiation codon of the huntingtin gene of Hun-tington's disease (HD). Methods: The PNA is biotinylated,which allows for rapid capture by a conjugate of streptavidinand the rat 8D3 monoclonal antibody (mAb) to the mouse trans-ferrin receptor (TfR), and contains a tyrosine residue, whichenables radiolabeling with ^125I. The reformulated PNA antisenseradiopharmaceutical that is conjugated to the 8D3 mAb is des-ignated ^125I-PNA/8D3, This form of the PNA is able to accessendogenous transferrin transport pathways at both the blood-brain barrier and the brain cell membrane and undergoes bothimport from the blood to the brain and export from the brain tothe blood through the TfR. Results: The ability of the PNA tohybridize to the target huntingtin RNA, despite conjugation tothe mAb, was shown both with cell-free translation assays andwith ribonuclease protection assays. The ^123I-PNA/8D3 conju-gate was administered intravenously to either littermate controlmice or to R6/2 transgenic mice, which express the exon 1 ofthe human HD gene. The mice were sacrificed 6 h later forfrozen sectioning of the brain and quantitative autoradiography.The studies showed a 3-fold increase in sequestration of the^125I-PNA/8D3 antisense radiopharmaceutical in the brains of theHD transgenic mice in vivo, consistent with the selective ex-pression of the HD exon-1 messenger RNA in these animals.Conclusion: These results support the hypothesis that geneexpression in vivo can be quantitated with antisense radiophar-maceuticals, providing these molecules are reformulated withdrug-targeting technology. Drug targeting enables access of theantisense agent to endogenous transport pathways, which per-mits passage across the cellular barriers that separate bloodand intracellular compartments of target tissues.
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Receptor-mediated delivery of an antisense gene to human brain cancer cells
Zhang, Yun,Lee, Hwa Jeong,J. Boado, Ruben,M. Pardridge, William 梨花女子大學校 藥學硏究所 2002 藥學硏究論文集 Vol.- No.11
Background The goal of this work was the development of a gene targetingtechnology that will enable the delivery of therapeutic genes to brain cancercells in vivo following intravenous administration. High-grade brain gliomasoverexpress the epidermal growth factor receptor (EGFR) and EGFR anti-sense gene therapy could reduce the growth of EGFR-dependent gliomas. Methods A human EGFR antisense gene driven by the SV4O promoter ina non-virat plasmid carrying elements that facilitate extra-chromosomalreplication was packaged in the interior of 85 nm pegylated immuno-liposomes (PILs) . The PILs were targeted to U87 human glioma cells withthe 83-14 murine monoclonal antibody (MAb) to the human insulin receptor(HIR). Results Confocal fluorescent microscopy demonstrated that the unconju-gated HIR MAb is rapidly internalized by the glioma cells. Endoytosisfellowed by entry into the nucleus was also demonstrated for the HIR MAbconjugated PILs carrying fluorescein-labeled plasmid DNA. The PILs deliveredenogenous genes to virtually all cells in culture, based on β-galactosidasehistochemistry. The targeting of a luciferasr gene to the U87 cells with thePILs resulted in luciferase levels in excess of 150 pg/mg protein after 72 h ofincubation. The level of luciferase gene expression in the U87 cells acHievedwith the PIL gene targeting system was comparable to that with lipo-fectamine. Targeting the EGFR antisense gene to U87 glioma cells with thePILs resulted in more than 70% reduction in [^3H]thymidine incorporationinto the cells; this was paralleled by a 79% reduction in the level ofimmunoreactive EGFR. Conclusion The present work describes the targeting of an EGFR antisensegene to human brain cancer cells, which results in a 70-80% inhibition incancer cell growth. PILs provide a new approach to gene targeting that iseffective in vivo following intravenous administration without viral vectors.
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