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Short interfering RNA (siRNA) drugs have entered clinical trials in various disease areas. However, systemic use of siRNA drugs faces a challenge of tissue in-specificity and membrane impenetrability. In this study, we hypothesized that the combined of lipidic molecules with a pegylated cationic polymer through random polymerization of Micheal reaction could enhance the hepatocyte's preferential uptake and improve membrane penetrability. We reported the efficacy of in vitro knockdown of apoB mRNA in HepG2 cell line and in vivo knockdown of the liver apoB mRNA using a pegylated lipopolymer–siapoB complex. Results show that apoB mRNA in the nu/nu and C57BL/6 black mice was knockdown to ∼60–80%, up to 2 weeks, at low doses of 1.0–2.5 mg/kg of siRNA. The finding sets a new stage for further developments for apoB siRNA therapeutics.