The efficacy of conventional chemotherapeutic agents is limited by poor selectivity and widespread toxicity which compromises the road towards recovery. Thus, the ability to specifically seek and destroy cancer would be an extraordinary feat in the treatment of the cancer epidemic. Towards this goal, we have designed, synthesized and evaluated the biological activity of potent oncogene therapeutics, namely short-interfering RNA, siRNA that may selectively silence GRP78 overexpression in HepG2 liver cancer cells leading to significant anti-cancer effects. Specifically, branch and hyperbranch siRNAs have been prepared by automated solid-phase RNA synthesis. Following isolation of the branch and hyperbranch siRNAs by RP-IP HPLC and denaturing PAGE, siRNAs were characterized by thermal denaturation and CD spectroscopy to assess their bio-physical and structural properties, respectively. Interestingly, branch and hyperbranch siRNAs retained the pre-requisite hybrid A-type helical structure for triggering potent RNAi effects. With this mission at heart, siRNAs were tested and proved potent silencing of GRP78 expression (~40-60%) in HepG2 cell lines, and the ability to solicit cancer cell death (~20%) to a greater extent relative to the linear siRNA controls (~5%). Thus, branch and hyperbranch siRNAs effectively extend the repertoire of potent oncogene therapeutics and may serve as interesting leads in the development of RNAi screening methods. This presentation will highlight our latest research efforts towards the development of an effective cancer gene therapy approach.1References.Maina, A.; Blackman, B.A.; Parronchi, C.J.; Morozko, E.; Bender, M.E.; Blake, A.D.; Sabatino D. Solid-phase synthesis, characterization and RNAi activity of branch and hyperbranch siRNAs. Bioorg. Med. Chem. Lett.  2013, 23, 5270-5274.

Synthesis, characterization, and cancer gene therapy applications of branch and hyperbranch siRNAs

248th National Meeting (2014)

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