Biomedical Group, Nitto Denko Technical Corporation, 501 Via Del Monte, Oceanside, CA 92058, USA.
Int J Pharm. 2012 May 1;427(1):58-63. doi: 10.1016/j.ijpharm.2011.11.006. Epub 2011 Nov 11.
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.
短干扰 RNA（siRNA）药物已在各个疾病领域的临床试验中进入临床研究。然而，siRNA 药物的全身使用面临着组织非特异性和膜不可穿透性的挑战。在这项研究中，我们假设通过 Michael 反应的随机聚合将脂质分子与聚乙二醇化阳离子聚合物结合，可以增强肝细胞的优先摄取并提高膜通透性。我们报道了使用聚乙二醇化 lipopolymer-siapoB 复合物在 HepG2 细胞系中体外敲低 apoB mRNA 和在 nu/nu 和 C57BL/6 黑鼠体内敲低肝 apoB mRNA 的功效。结果表明，在低剂量 1.0-2.5mg/kg 的 siRNA 下，apoB mRNA 在 nu/nu 和 C57BL/6 黑鼠中被敲低至约 60-80%，持续 2 周。这一发现为 apoB siRNA 治疗的进一步发展开辟了新的阶段。
